neuropeptide-y and Substance-Withdrawal-Syndrome

Benzodiazepines are known to modulate the activity of the hypothalamo-pituitary-adrenocortical (HPA) axis by antagonizing the effects of corticotropin-releasing factor (CRH). Besides regulating the HPA axis CRH evolves properties of a neurotransmitter in the limbic system that is closely involved in the delivery of the emotional consequences of the stress response. At a superordinated level Neuropeptide Y (NPY) and Cholecystokinin (CCK) affect the release of CRH and modulate thereby the intensity of the physiological stress response. Benzodiazepine treatment interferes not only with the release of CRH but also with the release of NPY and CCK. Alterations in the intracortical ratio of NPY, CCK and CRH are correlated with behavioural changes like increased respectively decreased anxiety and subsequent alterations in the activity of the HPA axis. Recent research offers the possibility that the alterations of plasma levels of these neuropeptides are not only a secondary phenomenon due to drug intake, but that low levels of those neuropeptides that modulate anxiety and fear can possibly explain addiction to substances that counterbalance these deficits. Depending on the available results possible implications of NPY and CCK on benzodiazepine addiction and withdrawal symptoms are reviewed, thereby providing topics for further research.

Topics: Animals; Benzodiazepines; Cholecystokinin; Corticotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Limbic System; Neuropeptide Y; Neurosecretory Systems; Pituitary-Adrenal System; Receptors, GABA-A; Substance Withdrawal Syndrome; Substance-Related Disorders

Alcoholism is a chronic relapsing disorder, accompanied by alterations in psychological and physiological functioning, which reaches an addictive state where an individual demonstrates uncontrollable compulsive alcohol drinking and impairment in social and occupational functioning. Withdrawal is one of the defining characteristics of dependence, characterized by impaired physiological function and enhanced negative affect, and is thought to be a major contributing factor to relapse. The negative emotional aspects of withdrawal appear to be more involved in continued alcohol craving because physical withdrawal symptoms are not highly correlated with relapse in alcoholics. Allostasis describes maintaining stability outside the homeostatic range by varying the internal milieu to match environmental demands. This concept has been applied to neurobiological models of drug addiction and is thought to contribute to the vulnerability of drug addicts to relapse, as addicts continue to use drugs in order to maintain their psychological state within a homeostatic range. With regard to alcohol, two neuropeptides appear to be involved in the regulation of alcohol-related stress, corticotropin-releasing factor (CRF), which is associated with an increased stress response and negative affect, and neuropeptide Y (NPY), a neuropeptide with anxiolytic properties. The hypothesis to be developed in the present review is that a dysregulation of the CRF and NPY systems significantly contributes to the motivational basis of continued alcohol-seeking behavior during alcohol dependence. It appears that increases in CRF contribute to the negative affective state that is strongly associated with alcohol withdrawal, and NPY provides a motivational basis to consume alcohol because the anxiolytic effects of alcohol, which are strongly associated with relapse, appear to be regulated in part by this neuropeptide.

Topics: Alcoholism; Animals; Anxiety; Behavior, Addictive; Corticotropin-Releasing Hormone; Homeostasis; Humans; Neuropeptide Y; Substance Withdrawal Syndrome

Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.

Topics: Alcoholism; Amygdala; Animals; Arousal; Brain Mapping; Corticotropin-Releasing Hormone; Disease Models, Animal; Ethanol; Humans; Motivation; Nerve Net; Neuropeptide Y; Prosencephalon; Reward; Substance Withdrawal Syndrome

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Ethanol; Humans; Leptin; Motivation; Neuropeptide Y; Neuropeptides; Rats; Substance Withdrawal Syndrome

It has been hypothesized that anxiety disorders play an important role in the initiation and maintenance of alcohol drinking behaviors. However, the molecular mechanisms for the association between anxiety and alcohol abuse are not well understood. Structures of the extended amygdala, particularly the central nucleus of amygdala, are involved in anxiety and in motivational aspects of alcohol drinking behaviors. Here, I propose that cAMP response element-binding protein (CREB) has a role in anxiety and alcohol drinking behaviors. The CREB gene transcription factor regulates the expression of the gene encoding neuropeptide Y (NPY), and decreased concentrations of NPY are implicated in anxiety and alcohol drinking behaviors. Therefore, decreased function of CREB in the central nucleus of the amygdala might regulate anxiety and alcohol intake via decreased expression of NPY, and might provide a common link between anxiety and alcohol abuse disorders. I also suggest that, via CREB, NPY might interact with other CREB target genes, such as the gene encoding brain-derived neurotrophic factor, and that this CREB-mediated interaction might be important in the regulation of anxiety and alcohol drinking behaviors.

Topics: Alcoholism; Animals; Anxiety; Cyclic AMP Response Element-Binding Protein; Humans; Neuropeptide Y; Substance Withdrawal Syndrome

Neuropeptide Y (NPY) and its receptors are involved in the regulation of mood, stress, and anxiety. In parallel, NPY signaling may play a vital role in the negative affective state induced by drug withdrawal. This study examined the changes in the transcript levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system during chronic nicotine exposure and withdrawal. Rats were administered with nicotine (initial dose: 25 μg/ml, maintenance dose: 50 μg/ml, free base) in drinking water for 12 weeks. Control group received only tap water. In the final week of the study, some of the nicotine-treated animals continued to receive nicotine (0-W), whereas some were withdrawn for either 24 (24-W) or 48 (48-W) h. All animals were decapitated after the evaluation of somatic signs (frequency of gasps, eye blinks, ptosis, shakes, teeth chatter) and the duration of locomotor activity and immobility. mRNA levels of NPY, Y1, Y2, and Y5 receptors in the mesocorticolimbic system were measured by quantitative real-time PCR (qRT-PCR). Results showed that nicotine withdrawal increased overall somatic signs. Moreover, chronic nicotine treatment increased the duration of locomotor activity, whereas withdrawal increased the duration of immobility. qRT-PCR analysis revealed that chronic nicotine treatment increased NPY mRNA levels in the hippocampus. On the other hand, 24- and 48-h withdrawals increased NPY mRNA levels in the amygdala and medial prefrontal cortex (mPFC), Y1 and Y2 mRNA levels in the nucleus accumbens and mPFC, and Y5 mRNA levels in the mPFC. These findings suggest that nicotine withdrawal enhances NPY signaling in the mesocorticolimbic system, which could be an important mechanism involved in regulating the negative affective state triggered during nicotine withdrawal.

Topics: Administration, Oral; Animals; Behavior, Animal; Limbic System; Male; Mesencephalon; Motor Activity; Neuropeptide Y; Nicotine; Nicotinic Agonists; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, Neuropeptide Y; RNA, Messenger; Substance Withdrawal Syndrome

Introduction The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has a key role in drug addiction susceptibility. In addition to the well-known relationship between cortisol and the HPA axis, other molecules are involved with stress response and could modify the HPA activation, such as the neuropeptide Y (NPY), which has anxiolytic proprieties. There are few studies evaluating the effect of NPY levels on addiction, especially in crack cocaine dependence. Objective To evaluate NPY in crack users during early withdrawal to determine its relationship with drug use and cortisol levels. Methods We analyzed 25 male inpatient crack users. Serum NPY levels were measured at admission and discharge (mean of 24 days). Morning salivary cortisol was measured at admission. Results Serum NPY levels at admission and discharge were very similar. Lower NPY levels at discharge were associated with higher lifetime crack use. Also, a negative correlation was found between morning cortisol and delta NPY (NPY discharge - NPY admission). Conclusion These preliminary findings indicate that crack use influences the modulation of NPY levels and modifies stress response. The NPY pathway may play an important role in the pathophysiology of crack addiction, and the anxiolytic effect of NPY may be impaired in crack users. Future studies should consider NPY as a measurable indicator of the biological state in addiction.

Topics: Adult; Cocaine-Related Disorders; Crack Cocaine; Humans; Hydrocortisone; Inpatients; Male; Middle Aged; Neuropeptide Y; Stress, Psychological; Substance Withdrawal Syndrome

Several studies have demonstrated the vulnerability of the hippocampal formation (HF) to chronic alcohol consumption and withdrawal. Among the brain systems that appear to be particularly vulnerable to the effects of these conditions are the neuropeptide Y (NPY)-ergic and the cholinergic systems. Because these two systems seem to closely interact in the HF, we sought to study the effects of chronic alcohol consumption (6months) and subsequent withdrawal (2months) on the expression of NPY and on the cholinergic innervation of the rat dentate hilus. As such, we have estimated the areal density and the somatic volume of NPY-immunoreactive neurons, and the density of the cholinergic varicosities. In addition, because alcohol consumption and withdrawal are associated with impaired nerve growth factor (NGF) trophic support and the administration of exogenous NGF alters the effects of those conditions on various cholinergic markers, we have also estimated the same morphological parameters in withdrawn rats infused intracerebroventricularly with NGF. NPY expression increased after withdrawal and returned to control values after NGF treatment. Conversely, the somatic volume of these neurons did not differ among all groups. On other hand, the expression of vesicular acetylcholine transporter (VAChT) was reduced by 24% in ethanol-treated rats and by 46% in withdrawn rats. The administration of NGF to withdrawn rats increased the VAChT expression to values above control levels. These results show that the effects of prolonged alcohol intake and protracted withdrawal on the hilar NPY expression differ from those induced by shorter exposures to ethanol and by abrupt withdrawal. They also suggest that the normalizing effect of NGF on NPY expression might rely on the NGF-induced improvement of cholinergic neurotransmission in the dentate hilus.

Topics: Alcohol Drinking; Analysis of Variance; Animals; Central Nervous System Depressants; Dentate Gyrus; Ethanol; Male; Nerve Growth Factor; Neurons; Neuropeptide Y; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Vesicular Acetylcholine Transport Proteins

The role of neuropeptide Y (NPY) in the central nucleus of amygdala (CeA) in the preventive effects of acupuncture against ethanol withdrawal-induced anxiety was investigated. Rats were treated with 3g/kg/day of ethanol for 28 days, followed by 3 days of withdrawal. Bilateral acupuncture treatment at HT7 (Shen-Men), PC6 (Nei-Guan) or a non-acupoint was respectively added to the rats during the withdrawal once a day for three days. Enzyme-linked immunosorbent assays and real-time polymerase chain reaction analyses showed there was a significant decrease in NPY protein and mRNA expression in the CeA during ethanol withdrawal, which was reversed by acupuncture at HT7 but neither at PC6 nor at a non-acupoint. Acupuncture at HT7 also greatly inhibited the decrease in cAMP response element-binding protein (CREB) phosphorylation in the CeA. In elevated plus maze tests, a selective NPY Y1 receptor antagonist BIBP 3226 into the CeA before the acupuncture abolished almost completely the anxiolytic effect of acupuncture at HT7. These results suggest that acupuncture at HT7 rescues the depletion of amygdaloid NPY and reverses the decrease in CREB phosphorylation to produce anxiolytic effects during ethanol withdrawal.

Topics: Acupuncture Therapy; Amygdala; Animals; Anxiety; Arginine; Benzazepines; Cyclic AMP Response Element-Binding Protein; Ethanol; Male; Maze Learning; Neuropeptide Y; Phosphorylation; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Substance Withdrawal Syndrome

A rat model of the novelty-seeking phenotype predicts vulnerability to the expression of behavioral sensitization to nicotine, where locomotor reactivity to novelty is used to screen experimentally-naïve rats for high (HR) versus low (LR) responders. The present study examines the long-term neuropeptidergic and neuroplastic adaptations associated with the expression of locomotor sensitization to a low dose nicotine challenge and social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Our data show that the expression of behavioral sensitization to nicotine and abstinence-related anxiety are detected in nicotine pre-exposed HRs even across a long (3 wks) abstinence. Moreover, these behavioral effects of nicotine are accompanied by a persistent imbalance between neuropeptide Y and corticotrophin releasing factor systems, and a persistent increase in brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in the amygdala. Furthermore, treatment with the cannabinoid receptor 1 antagonist, AM251 (5 mg/kg) during a short (1 wk) abstinence is ineffective in reversing nicotine-induced anxiety, fluctuations in BDNF and spinophilin mRNAs, and the neuropeptidergic dysregulations in the amygdala; although this treatment is effective in reversing the expression of locomotor sensitization to challenge nicotine even after a long abstinence. Interestingly, the identical AM251 treatment administered during the late phase of a long abstinence further augments anxiety and associated changes in BDNF and spinophilin mRNA in the basolateral nucleus of the amygdala in nicotine pre-exposed HRs. These findings implicate long-lasting neuropeptidergic and neuroplastic changes in the amygdala in vulnerability to the behavioral effects of nicotine in the novelty-seeking phenotype.

Topics: Aging; Amygdala; Animals; Anxiety; Brain-Derived Neurotrophic Factor; Corticotropin-Releasing Hormone; Exploratory Behavior; In Situ Hybridization; Interpersonal Relations; Male; Microfilament Proteins; Motor Activity; Nerve Tissue Proteins; Neuronal Plasticity; Neuropeptide Y; Neuropeptides; Nicotine; Nicotinic Agonists; Phenotype; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Substance Withdrawal Syndrome

Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.

Topics: Alcohol Drinking; Alcoholism; Animals; Anxiety Disorders; Benzamides; Conditioning, Operant; Ethanol; Injections, Intraventricular; Models, Animal; Neuropeptide Y; Piperazines; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Recurrence; Reinforcement, Psychology; Self Administration; Substance Withdrawal Syndrome

An outbred rat model of novelty-seeking phenotype has predictive value for the expression of locomotor sensitization to nicotine. When experimentally naïve rats are exposed to a novel environment, some display high rates of locomotor reactivity (HRs, scores ranking at top 1/3rd of the population), whereas some display low rates (LRs, scores ranking at bottom 1/3rd of the population). Basally, HRs display lower anxiety-like behavior compared to LRs along with higher neuropeptide Y (NPY) mRNA in the amygdala and the hippocampus. Following an intermittent behavioral sensitization to nicotine regimen and 1 wk of abstinence, HRs show increased social anxiety-like behavior in the social interaction test and robust expression of locomotor sensitization to a low dose nicotine challenge. These effects are accompanied by a deficit in NPY mRNA levels in the medial nucleus of the amygdala and the CA3 field of the hippocampus, and increases in Y2R mRNA levels in the CA3 field and corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. Systemic and daily injections of a Y2R antagonist, JNJ-31020028, during abstinence fully reverse nicotine-induced social anxiety-like behavior, the expression of locomotor sensitization to nicotine challenge, the deficit in the NPY mRNA levels in the amygdala and the hippocampus, as well as result an increase in Y2R mRNA levels in the hippocampus and the CRF mRNA levels in the amygdala in HRs. These findings implicate central Y2R in neuropeptidergic regulation of social anxiety in a behavioral sensitization to nicotine regimen in the LRHR rats.

Topics: Amygdala; Animals; Anxiety; Benzamides; CA3 Region, Hippocampal; Corticosterone; Corticotropin-Releasing Hormone; Disease Models, Animal; Exploratory Behavior; Interpersonal Relations; Male; Motor Activity; Neuropeptide Y; Nicotine; Phenotype; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Substance Withdrawal Syndrome

The purpose of this study was to evaluate whether wild ginseng (WG) administration could attenuate anxiety- and depression-like behaviors and expression of corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY) following withdrawal from repeated morphine administration in rats. Male rats were administered daily doses of WG (50, 100, or 200 mg/kg, i.p.) for 5 days, 30 min before morphine injection (40 mg/kg, s.c). The anxiety- and depression-like behavioral responses were measured 72 h after the last morphine injection using an elevated plus maze (EPM) and forced swimming test (FST), respectively. Changes in hypothalamic CRF and NPY expressions were also examined by analyzing their immunoreactivities in the hypothalamus. Daily administration of WG significantly reduced anxiety-and depression-like behavior, and elicited the suppression of CRF expression and the stimulation of NPY expression in the hypothalamus. Our results demonstrated that WG extract might be effective at inhibiting the anxiety and depression responses due to morphine withdrawal by possibly modulating the hypothalamus CRF and NPY systems. Furthermore, these findings imply that WG extract can be used for developing new medication to cure or alleviate morphine withdrawal symptoms and to prevent relapses of morphine use.

Topics: Animals; Anxiety; Corticotropin-Releasing Hormone; Depression; Disease Models, Animal; Humans; Male; Maze Learning; Morphine; Neuropeptide Y; Panax; Plant Extracts; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Swimming

Depressive symptoms in alcohol-dependent individuals are well-recognized and clinically relevant phenomena. The etiology has not been elucidated although it is clear that the depressive symptoms may be alcohol independent or alcohol induced. To contribute to the understanding of the neurobiology of chronic ethanol use, we investigated the effects of chronic intermittent ethanol vapor exposure on behaviors in the forced swim test (FST) and neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) levels in specific brain regions. Adult male Wistar rats were subjected to intermittent ethanol vapor (14 h on/10 h off) or air exposure for 2 weeks and were then tested at three time points corresponding to acute withdrawal (8-12 h into withdrawal) and protracted withdrawal (30 and 60 days of withdrawal) in the FST. The behaviors that were measured in the five-min FST consisted of latency to immobility, swim time, immobility time, and climbing time. The FST results showed that the vapor-exposed animals displayed depressive-like behaviors; for instance, decreased latency to immobility in acute withdrawal and decreased latency to immobility, decreased swim time and increased immobility time in protracted withdrawal, with differences between air- and vapor-exposed animals becoming more pronounced over the 60-day withdrawal period. NPY levels in the frontal cortex of the vapor-exposed animals were decreased compared with the control animals, and CRF levels in the amygdala were correlated with increased immobility time. Thus, extended ethanol vapor exposure produced long-lasting changes in FST behavior and NPY levels in the brain.

Topics: Animals; Behavior, Animal; Brain Chemistry; Corticotropin-Releasing Hormone; Depression; Ethanol; Immobility Response, Tonic; Latency Period, Psychological; Male; Neuropeptide Y; Rats; Rats, Wistar; Self Administration; Substance Withdrawal Syndrome; Swimming; Volatilization

Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility.. Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects.. Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels.. These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.

Topics: Adrenocorticotropic Hormone; Adult; Animals; beta-Endorphin; Case-Control Studies; Chronobiology Disorders; CLOCK Proteins; Drug Users; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Heroin Dependence; Humans; Hydrocortisone; Hypothalamus; Interleukin-2; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Nuclear Proteins; Period Circadian Proteins; Rats; RNA; Substance Withdrawal Syndrome; Time Factors; Trans-Activators; Transcription Factors; Tumor Necrosis Factor-alpha

Previous studies show that chronic ethanol treatment induces prominent changes in brain neuropeptide Y (NPY). The purpose of the present study was to explore ethanol effects at a deeper NPY-system level, measuring expression of NPY and its receptors (Y1, Y2, Y5) as well as NPY receptor binding and NPY-stimulated [(35)S]GTPgammaS functional binding. Rats received intragastric ethanol repeatedly for 4 days, and the NPY system was studied in the hippocampal dentate gyrus (DG), CA3, CA1, and piriform cortex (PirCx) and neocortex (NeoCx) during intoxication, peak withdrawal (16 hr), late withdrawal (3 days), and 1 week after last ethanol administration. NPY mRNA levels decreased during intoxication and at 16 hr in hippocampal regions but increased in the PirCx and NeoCx at 16 hr. NPY mRNA levels were increased at 3 days and returned to control levels in most regions at 1 week. Substantial changes also occurred at the receptor level. Thus Y1, Y2, and Y5 mRNA labelling decreased at 16 hr in most regions, returning to control levels at 3 days, except for PirCx Y2 mRNA, which increased at 3 days and 1 week. Conversely, increases in NPY receptor binding occurred in hippocampal regions during intoxication and in functional binding in the DG and NeoCx during intoxication and at 16 hr and in PirCx during intoxication and at 1 week. Thus this study shows that ethanol intoxication and withdrawal induce complex plastic changes in the NPY system, with decreased/increased gene expression or binding occurring in a time- and region-specific manner. These changes may play an important role in mediating ethanol-induced changes in neuronal excitability.

Topics: Alcohol-Induced Disorders, Nervous System; Analysis of Variance; Animals; Brain; Disease Models, Animal; Guanosine 5'-O-(3-Thiotriphosphate); Male; Neuronal Plasticity; Neuropeptide Y; Protein Binding; Rats; Rats, Wistar; Receptors, Neuropeptide Y; RNA, Messenger; Substance Withdrawal Syndrome; Sulfur Isotopes; Time Factors; Up-Regulation

We investigated the role of neuropeptide Y Y(1) receptors in acute, chronic and withdrawal effects of nicotine with reference to feeding behavior. Rats were administered with nicotine, neuropeptide Y, neuropeptide Y Y(1) receptor agonist [Leu(31),Pro(34)]neuropeptide Y or antagonist BIBP3226 (N(2)-diphenylacetyl)-N-[(4-hydroxy-phenyl)-methyl]-D-arginine amide) via i.c.v. route, and food intake was measured at 2 and 6 h post-injection time-points. While acute nicotine or BIBP3226 reduced food intake, increase was observed following neuropeptide Y or [Leu(31),Pro(34)]neuropeptide Y. Nicotine-induced anorexia was antagonized by pre-treatment with neuropeptide Y or [Leu(31),Pro(34)]neuropeptide Y, and potentiated by BIBP3226. Furthermore, effects of chronic nicotine (i.p.) and its withdrawal, alone and in combination with BIBP3226 were evaluated with reference to feeding and body weight. Concurrent administration of BIBP3226 with nicotine prevented the development of tolerance to nicotine-induced anorexia, and withdrawal hyperphagia and weight gain. Moreover, acute BIBP3226 attenuated the hyperphagia following nicotine termination. Additionally, immunocytochemical profile of neuropeptide Y in the hypothalamus was studied following differential nicotine treatments. Acute nicotine treatment dramatically reduced neuropeptide Y immunoreactivity in the arcuate and paraventricular nuclei. Chronic nicotine administration decreased neuropeptide Y immunoreactivity in arcuate, but not in paraventricular nucleus. Nicotine withdrawal resulted in significant increase in the neuropeptide Y immunoreactivity in both the nuclei. Neuropeptide Y immunoreactivity in the lateral hypothalamus did not change following any of the treatments. The results suggest that neuropeptide Y in the arcuate and paraventricular nuclei of hypothalamus may be involved in acute, chronic and withdrawal effects of nicotine on the feeding behavior, possibly via neuropeptide Y Y(1) receptors.

Topics: Animals; Arginine; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Eating; Fluorescent Antibody Technique, Indirect; Immunohistochemistry; Injections, Intraventricular; Male; Microinjections; Neuropeptide Y; Nicotine; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Substance Withdrawal Syndrome; Time Factors

Although morphine is a potent antinociceptive agent, its chronic use developed tolerance in neuropathic pain (NP). Furthermore, opioid antagonist naloxone attenuated the antinociceptive effect of neuropeptide Y (NPY). The present study investigated the role of NPY and NPY Y1/Y5 receptors in acute and chronic actions of morphine in neuropathic rats using thermal paw withdrawal test and immunocytochemistry. In acute study, intracerebroventricular (icv) administration of morphine, NPY or NPY Y1/Y5 receptors agonist [Leu(31),Pro(34)]-NPY produced antinociception, whereas selective NPY Y1 receptors antagonist BIBP3226 caused hyperalgesia. While NPY or [Leu(31),Pro(34)]-NPY potentiated, BIBP3226 attenuated morphine induced antinociception. Chronic icv infusion of morphine via osmotic minipumps developed tolerance to its antinociceptive effect, and produced hyperalgesia following withdrawal. However, co-administration of NPY or [Leu(31),Pro(34)]-NPY prevented the development of tolerance and withdrawal hyperalgesia. Sciatic nerve ligation resulted in significant increase in the NPY-immunoreactive (NPY-ir) fibers in ventrolateral periaqueductal gray (VLPAG) and locus coeruleus (LC); fibers in the dorsal part of dorsal raphe nucleus (DRD) did not respond. While chronic morphine treatment significantly reduced NPY-ir fibers in VLPAG and DRD, morphine withdrawal triggered significant augmentation in NPY-immunoreactivity in the VLPAG. NPY-immunoreactivity profile of LC remained unchanged in all the morphine treatment conditions. Furthermore, removal of sciatic nerve ligation reversed the effects of NP, increased pain threshold and restored NPY-ir fiber population in VLPAG. NPY, perhaps acting via Y1/Y5 receptors, might profoundly influence the processing of NP information and interact with the endogenous opioid system primarily within the framework of the VLPAG.

Topics: Analgesics, Opioid; Animals; Arginine; Behavior, Animal; Drug Tolerance; Hyperalgesia; Male; Morphine; Neuropeptide Y; Pain Measurement; Peripheral Nervous System Diseases; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Sciatic Nerve; Substance Withdrawal Syndrome

Heroin use and withdrawal cause abnormality in the endocrine system. However, the time course of neuroendocrine alterations in heroin addicts during pharmacologically unassisted withdrawal is still unclear.. To investigate alterations in cortisol, adrenocorticotrophic hormone (ACTH), beta-endorphin (beta-EP), leptin, and neuropeptide Y (NPY) during the first month of abstinence in heroin addicts.. Twelve heroin addicts and eight matched healthy control subjects were recruited for this study. The neuroendocrine alterations and self-reported heroin craving, anxiety, and depression in heroin addicts were assessed at different time points (days 3, 10, and 30) of first month of abstinence from heroin use.. Self-reported heroin craving, anxiety, and depression in heroin addicts decreased gradually during the first month of abstinence. The cortisol levels increased from abstinence day 3 to 30, while ACTH and beta-EP levels decreased over this period in heroin addicts. The leptin and NPY levels were significantly decreased on days 3 and 10 but had normalized on day 30 of abstinence. A positive correlation between cortisol level and heroin craving, anxiety, and depression was observed, while a negative correlation was observed between beta-EP level and craving and anxiety and between leptin and depression and NPY and anxiety.. Abnormal alterations in the neuroendocrine system, including levels of cortisol, ACTH and beta-EP persist throughout the first month of abstinence. These results suggest that neuroendocrine system dysfunctions in heroin abusers is independent of the acute and protracted withdrawal syndromes, and may thus contribute to relapse to heroin use.

Topics: Adrenocorticotropic Hormone; Adult; Analysis of Variance; Anxiety; beta-Endorphin; Case-Control Studies; Depression; Heroin; Heroin Dependence; Humans; Hydrocortisone; Leptin; Male; Neuropeptide Y; Neurosecretory Systems; Patient Selection; Psychiatric Status Rating Scales; Radioimmunoassay; Substance Withdrawal Syndrome; Time Factors

Previous studies have shown that GABAergic neuroactive steroids increase Y1 receptor (Y1R) gene expression in the amygdala of Y1R/LacZ transgenic mice, harbouring the murine Y1R gene promoter linked to a LacZ reporter gene. As ethanol is known to increase GABAergic neuroactive steroids, we investigated the relationship between fluctuations in the brain content of neuroactive steroids induced by chronic voluntary ethanol consumption or ethanol discontinuation and both the level of neuropeptide Y (NPY) immunoreactivity and Y1R gene expression in the amygdala of Y1R/LacZ transgenic mice. Ethanol discontinuation (48 h) after voluntary consumption of consecutive solutions of 3%, 6%, 10% and 20% (v/v) ethanol over 4 weeks produced an anxiety-like behaviour as measured by elevated plus maze. Voluntary ethanol intake increased the cerebrocortical concentration of the progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) that returned to control level 48 h after discontinuation of ethanol intake. Ethanol discontinuation significantly decreased NPY immunoreactivity and concomitantly increased Y1R/LacZ transgene expression in the amygdala, whereas chronic ethanol intake failed to affect these parameters. The 5alpha-reductase inhibitor finasteride prevented both the increase in the cerebrocortical concentration of 3alpha,5alpha-TH PROG apparent after 4 weeks of ethanol intake and the changes in NPY immunoreactivity and transgene expression induced by ethanol discontinuation. Data suggest that 3alpha,5alpha-TH PROG plays an important role in the changes in NPY-Y1R signalling in the amygdala during ethanol discontinuation.

Topics: Alcohol Drinking; Amygdala; Animals; Ethanol; Gene Expression Regulation; Lac Operon; Male; Mice; Mice, Transgenic; Neuropeptide Y; Receptors, Neuropeptide Y; Steroids; Substance Withdrawal Syndrome

Acupuncture, likely the most well-known 'alternative' medical treatment, has been shown to have effects in several types of animal model of drug dependence, including nicotine addiction. We investigated the effect of acupuncture on anxiety-like behavior and corticotrophin-releasing factor (CRF) and neuropeptide Y (NPY) mRNA expression in the amygdala during nicotine withdrawal. Rats were given repeated nicotine injections (0.1mg/kg s.c., once daily for 7 days) or saline. Acupuncture groups were treated with acupuncture at acupoint HT7 or ST36 during withdrawal. The anxiogenic response was measured at 72h after the termination of nicotine injection using an elevated plus maze. CRF and NPY mRNA levels were also evaluated using reverse transcription polymerase chain reaction (RT-PCR) analysis at this time. Rats undergoing nicotine withdrawal (NW) were less likely to explore the open arms of the plus maze compared with the saline-treated controls. The percentage of open arm entries in the HT7 acupuncture group, but not in the ST36 acupuncture group, was significantly increased compared with the NW group. Consistent with this behavior, CRF mRNA levels in the NW group were increased compared with the control group. CRF mRNA levels in the HT7 acupuncture group were significantly decreased compared with the NW group. However, NPY mRNA levels were not different among the groups. These findings indicate that increases in CRF may be involved in the negative affect state associated with nicotine withdrawal and that acupuncture may attenuate anxiety-like behavior following nicotine withdrawal by modulating CRF in the amygdala.

Topics: Acupuncture; Amygdala; Analysis of Variance; Animals; Anxiety; Behavior, Animal; Corticotropin-Releasing Hormone; Disease Models, Animal; Male; Maze Learning; Motor Activity; Neuropeptide Y; Nicotine; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

There is strong evidence that blocking CB1 receptors may reduce alcohol intake in alcohol-dependent individuals. However, there is still limited evidence that CB1 receptor antagonists may also be beneficial in the attenuation of alcohol withdrawal syndrome, even though alcohol withdrawal appears to be milder in CB1 receptor knockout mice. Here we have examined whether the CB1 receptor antagonist rimonabant (SR141716) can alleviate the behavioral symptoms and revert the neurochemical imbalance elicited by a 3-h interruption of chronic alcohol exposure (7.2% in the drinking water for 10 days) in male Wistar rats. Administration of rimonabant attenuated the strong anxiogenic traits of the animals that developed when regular alcohol intake was interrupted. This may reflect the correction of the GABA/glutamate imbalances developed by the animals that received rimonabant in various brain regions involved in emotional (e.g. prefrontal cortex) and motor (e.g. caudate-putamen and globus pallidus) responses. In addition, rimonabant also affected the dopamine deficits generated by alcohol abstinence in the amygdala and ventral-tegmental area, albeit to a lesser extent. However, this antagonist was unable to correct the impairment caused by alcohol abstinence in serotonin and neuropeptide Y. The endocannabinoid activity in the brain of alcohol-abstinent rats indicated that the behavioral and neurochemical improvements caused by rimonabant were not related to the attenuation of a possible increase in this activity generated by alcohol withdrawal. Conversely, the density of CB1 receptors was reduced in alcohol-abstinent animals (e.g. globus pallidus, substantia nigra), as were the levels of endocannabinoids and related N-acylethanolamines (e.g. amygdala, caudate-putamen). Thus, rimonabant possibly enhances an endogenous response generated by interrupting the regular use of alcohol. In summary, rimonabant might attenuate withdrawal symptoms associated with alcohol abstinence, an effect that was presumably due to the normalization of GABA and glutamate, and to a lesser extent, dopamine transmission in emotion- and motor-related areas.

Topics: Animals; Anxiety; Appetite; Arachidonic Acids; Autoradiography; Benzoxazines; Brain Chemistry; Cannabinoid Receptor Modulators; Central Nervous System Depressants; Chromatography, High Pressure Liquid; Emotions; Endocannabinoids; Enkephalins; Ethanol; Ethanolamines; Glycerides; In Situ Hybridization; Male; Morpholines; Motor Activity; Naphthalenes; Neuropeptide Y; Neurotransmitter Agents; Piperidines; Polyunsaturated Alkamides; Protein Precursors; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Stress, Psychological; Substance Withdrawal Syndrome

The treatment of alcoholism requires the proper management of ethanol withdrawal symptoms, such as anxiety, to prevent further alcohol use and abuse. In this study, we investigated the potential role of brain chromatin remodeling, caused by histone modifications, in alcoholism. We found that the anxiolytic effects produced by acute alcohol were associated with a decrease in histone deacetylase (HDAC) activity and increases in acetylation of histones (H3 and H4), levels of CREB (cAMP-responsive element binding) binding protein (CBP), and neuropeptide Y (NPY) expression in the amygdaloid brain regions of rats. However, the anxiety-like behaviors during withdrawal after chronic alcohol exposure were associated with an increase in HDAC activity and decreases in acetylation of H3 and H4, and levels of both CBP and NPY in the amygdala. Blocking the observed increase in HDAC activity during alcohol withdrawal with the HDAC inhibitor, trichostatin A, rescued the deficits in H3 and H4 acetylation and NPY expression (mRNA and protein levels) in the amygdala (central and medial nucleus of amygdala) and prevented the development of alcohol withdrawal-related anxiety in rats as measured by the elevated plus maze and light/dark box exploration tests. These results reveal a novel role for amygdaloid chromatin remodeling in the process of alcohol addiction and further suggest that HDAC inhibitors may be potential therapeutic agents in treating alcohol withdrawal symptoms.

Topics: Alcoholism; Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Chromatin Assembly and Disassembly; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Enzyme Inhibitors; Ethanol; Exploratory Behavior; Gene Expression; Histone Acetyltransferases; Histone Deacetylases; Hydroxamic Acids; Male; Maze Learning; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Tobacco addiction is a chronic disorder that is characterized by dysphoria upon smoking cessation and relapse after periods of abstinence. Previous research suggests that Neuropeptide Y (NPY) and Y1 receptor agonists attenuate negative affective states and somatic withdrawal signs. The aim of the present experiments was to investigate the effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats. The intracranial self-stimulation procedure was used to assess the effects of nicotine withdrawal on brain reward function as this procedure can provide a quantitative measure of emotional states in rodents. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In the first experiment, NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Similar to NPY, [D-His(26)]-NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Neither NPY nor [D-His(26)]-NPY affected the response latencies. In a separate experiment, it was demonstrated that the specific Y1 receptor antagonist BIBP-3226 prevented the NPY-induced elevations in brain reward thresholds. NPY attenuated the overall somatic signs associated with precipitated nicotine withdrawal. [D-His(26)]-NPY did not affect the overall somatic signs associated with precipitated nicotine withdrawal, but decreased the number of abdominal constrictions. Both NPY and [D-His(26)]-NPY attenuated the overall somatic signs associated with spontaneous nicotine withdrawal. These findings indicate that NPY and [D-His(26)]-NPY attenuate somatic nicotine withdrawal signs, but do not prevent the deficit in brain reward function associated with precipitated nicotine withdrawal. In addition, NPY decreases the sensitivity to rewarding electrical stimuli via an Y1 dependent mechanism.

Topics: Animals; Arginine; Brain; Drug Implants; Electric Stimulation; Electrodes, Implanted; Male; Neuropeptide Y; Nicotine; Nicotinic Agonists; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Reward; Self Stimulation; Substance Withdrawal Syndrome

The present experiment examines the effects of NPY administered into the amygdala on ethanol drinking by alcohol-preferring P rats following long-term continuous ethanol access, with and without multiple periods of imposed ethanol abstinence. P rats had access to 15% (v/v) ethanol and water for 11 weeks followed by 2 weeks of ethanol abstinence, re-exposure to ethanol for 2 weeks, 2 more weeks of ethanol abstinence, and a final ethanol re-exposure. Immediately prior to the second ethanol re-exposure, 4 groups of rats received bilateral infusions NPY (0.25, 0.5, 1.0 microg) or artificial cerebrospinal fluid (aCSF) into the amygdala. Two additional groups were given uninterrupted ethanol access and were infused with a single NPY dose (1.0 microg) or aCSF. The highest NPY dose (1.0 microg) suppressed ethanol intake for 24 h in rats with a history of ethanol abstinence (i.e. deprivation) periods, but had no effect in rats with a history of continuous ethanol access. Water and food intakes were not altered. These results suggest that the amygdala mediates the suppressive effects of centrally administered NPY on ethanol drinking, and that NPY may block relapse-like drinking by opposing the anxiogenic effects of ethanol abstinence.

Topics: Alcohol Drinking; Amygdala; Animals; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Eating; Female; Microinjections; Neuropeptide Y; Rats; Stereotaxic Techniques; Substance Withdrawal Syndrome

Nicotine is known to decrease body weight in normal rodents and human smokers, whereas nicotine withdrawal or smoking cessation can increase body weight. We have found that mice fed a high fat diet do not show the anorectic effect of chronic nicotine treatment, but do increase their body weight following nicotine withdrawal. Nicotine withdrawal is accompanied by increased expression of the orexigenic peptides neuropeptide Y and Agouti-related protein in the hypothalamus, and decreased expression of the metabolic protein uncoupling protein-3 in brown adipose tissue. These data suggest that diet can influence the ability of nicotine to modulate body weight regulation and demonstrate that chronic nicotine exposure results in adaptive changes in central and peripheral molecules which regulate feeding behavior and energy metabolism.

Topics: Adipose Tissue, Brown; Agouti Signaling Protein; Agouti-Related Protein; Analysis of Variance; Animals; Body Weight; Dietary Fats; Hypothalamus; Intercellular Signaling Peptides and Proteins; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Neuropeptide Y; Nicotine; Nicotinic Agonists; Receptors, Adrenergic, beta; Substance Withdrawal Syndrome; Uncoupling Protein 3

Ethanol withdrawal is associated with neuronal hyperexcitability and increased hippocampal glutamate release. Neuropeptide Y (NPY) appears to play an important role in regulation of hippocampal neuronal excitability by inhibiting glutamate release. Expression of NPY and its receptors Y1, Y2, and Y5 was studied in hippocampal areas of rats during ethanol withdrawal after repeated intragastric ethanol administration for 2 or 4 days using in situ hybridization. Withdrawal was associated with decreased hippocampal expression of NPY and each of its receptors, particularly Y2, after 2 and/or 4 days of ethanol compared to control rats. These data suggest that the hippocampal NPY system is downregulated during ethanol withdrawal and these neuroadaptational changes could play a role in mediating withdrawal hyperexcitability.

Topics: Animals; Down-Regulation; Ethanol; Male; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; RNA, Messenger; Substance Withdrawal Syndrome; Time Factors

Recent evidence suggests that neuropeptide Y (NPY) may be involved in the neurobiological responses to drugs of abuse. This study was designed to assess the possible contribution of NPY to opiate withdrawal behaviors. Here we report that mice lacking the NPY gene show normal conditioned place aversion to opiate withdrawal, but show attenuated opiate withdrawal somatic signs.

Topics: Animals; Avoidance Learning; Behavior, Animal; Brain; Brain Chemistry; Conditioning, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Fear; Limbic System; Male; Mice; Mice, Knockout; Morphine; Motor Activity; Narcotic Antagonists; Narcotics; Neural Pathways; Neuropeptide Y; Opioid-Related Disorders; Substance Withdrawal Syndrome

Chronic treatment with cannabinoid agonists leads to tolerance. One possible mechanism for this is receptor internalization, but tolerance has also been reported with compounds that only cause internalization to a low degree. Furthermore, cannabinoid antagonist administration precipitates a characteristic withdrawal syndrome in tolerant subjects, accompanied by neuronal activation and enhanced release of corticotropin-releasing hormone (CRH) in the central amygdala. The underlying molecular mechanisms are unknown. We examined the role of cannabinoid tolerance and withdrawal for the expression of the cannabinoid 1 (CB1) receptor and of CRH in rats. Tolerance was first established functionally. An acute dose (100 microg/kg) of the CB1 agonist HU-210 suppressed locomotor activity, and had an anxiogenic-like effect on the elevated plus-maze. Both effects were absent following daily treatment with the same agonist or a lower (40 microg/kg) dose for 14 days. Next, withdrawal was reliably precipitated by a single dose (3 mg/kg) of the CB1 antagonist SR141716A in rats treated subchronically with 14-day HU-210. Using in situ hybridization, a robust suppression of CB1 mRNA expression was found in the caudate-putamen, indicating a downregulation of CB1 expression levels as one mechanism for tolerance to the locomotor suppressant effects of HU-210. The CRH transcript was upregulated in the central amygdala in precipitated withdrawal compared to nonwithdrawn tolerant subjects, suggesting that increased gene expression contributes to the previously reported CRH release in withdrawal. Most importantly, this increase occurred from a suppressed level in tolerant subjects, and behavioral signs of withdrawal, presumably mediated by CRH, were seen at the CRH expression that had only returned to normal nontolerant levels. This suggests the possibility of an allostatic shift, as previously proposed on theoretical grounds. The expression of CRH-R1, CRH-R2alpha, NPY, and its Y1 receptor mRNA was analyzed in search of neural substrates for the allostatic shift observed, but did not seem to contribute to the dysregulated state.

Topics: Amygdala; Analysis of Variance; Animals; Behavior, Animal; Cannabinoids; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Dronabinol; Drug Administration Schedule; Drug Tolerance; Excitatory Amino Acid Antagonists; Gene Expression Regulation; In Situ Hybridization; Locomotion; Male; Maze Learning; Neostriatum; Neuropeptide Y; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Rimonabant; RNA, Messenger; Substance Withdrawal Syndrome; Time Factors

Chronic stressors alter brain function and may leave traces after their relief. We used intermittent morphine treatment to examine the relationships between stress-induced changes in energy balance and hypothalamo-pituitary-adrenal (HPA) activity and the recovery thereafter. We studied the effects of morphine injections on energy balance, hormones and fat stores, brain neuropeptide expression, and the ACTH and corticosterone responses to restraint 12 hr after the final injection and 8 d later during recovery. Weight gain, food intake, and caloric efficiency decreased at morphine onset, and these were maintained throughout the morphine injections. At 12 hr, fat stores, leptin, insulin, and testosterone concentrations were reduced. Subsequently, body weight gain and food intake increased and caloric efficiency was above control during the final days. By the eighth recovery day, fat stores and peripheral hormones were no longer depressed. At 12 hr, an over-response of CRF mRNA to restraint occurred in the hypothalamus, similar to the facilitated ACTH and corticosterone responses. On day 8, the hypothalamic CRF mRNA response to restraint was still facilitated, opposite to inhibited ACTH responses. Hypothalamic CRF mRNA correlated highly with mesenteric fat weight in morphine-treated rats. We conclude that there is a prolonged recovery from chronic stressors involving interrelated changes in energy balance and HPA activity. Nonetheless, 8 d after withdrawal from morphine, rats still display facilitated central stress responses, similar to the HPA symptoms described in posttraumatic stress disorder patients. Repeated partial withdrawal associated with intermittent morphine treatment, compounded by complete withdrawal associated with termination of the treatment, is likely required for these metabolic and HPA derangements.

Topics: Animals; Arginine Vasopressin; Body Weight; Brain; Corticotropin-Releasing Hormone; Drug Administration Schedule; Energy Metabolism; Hypothalamo-Hypophyseal System; Male; Morphine; Neuropeptide Y; Neuropeptides; Organ Size; Pituitary-Adrenal System; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stress, Physiological; Substance Withdrawal Syndrome; Time Factors

Neuropeptide Y (NPY) is widely expressed in the brain and is known to affect consummatory behaviors including drinking alcohol as well as to play a role in seizures. We investigated the effects of a 4 day binge ethanol treatment model that is known to induce physical dependence and withdrawal seizures to determine the effects of ethanol dependence and withdrawal on NPY expression.. Male Sprague Dawley rats were treated with ethanol or control nutritionally complete diets by intragastric treatment three times per day for 2 or 4 days with an average daily dose of approximately 8 g/kg ethanol per day. Ethanol-fed rats treated for 4 days and then withdrawn for 24, 72, and 168 hr also were studied. Brains were perfused and sectioned for immunohistochemistry for NPY, phospho-cyclic adenosine monophosphate responsive element binding (pCREB), and other proteins.. NPY immunoreactivity (NPY-IR) was found in several brain regions, with the hippocampus and cerebral cortex showing the most pronounced changes. NPY-IR was reduced by ethanol treatment in hippocampus and cortex, although at 72 hr of withdrawal there was a dramatic increase in NPY-IR in the hilus of the dentate gyrus and in CA3 and CA2 fields of hippocampus. Ethanol withdrawal seizures occurred around 12 to 24 hr of withdrawal, preceding the changes in NPY-IR at 72 hr. pCREB immunoreactivity (pCREB-IR) tended to decrease during ethanol treatment but showed a dramatic increase in dentate gyrus at 72 hr of withdrawal. Parvalbumin immunoreactivity indicated that some of the pCREB-IR and NPY-IR were within inhibitory interneuron basket cells of the hippocampal hilus. NPY-IR returned to control levels by 168 hr of withdrawal.. These studies suggest that hippocampal NPY is reduced during the development of ethanol dependence. Ethanol withdrawal seizures precede a dramatic increase in hippocampal NPY-IR. Previous studies have suggested that NPY in the hippocampus reduces seizure activity and that NPY is induced by seizure activity. Thus, the increase in NPY-IR at 72 hr of withdrawal after binge ethanol treatment may be protective against prolonged withdrawal seizure activity.

Topics: Animals; Brain; Brain Chemistry; Ethanol; Immunochemistry; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

We recently reported that neuropeptide Y (NPY) protein levels and cAMP responsive element binding (CREB) protein phosphorylation are lower in amygdaloid structures during ethanol withdrawal after chronic exposure. Furthermore, we reported that normalization of CREB phosphorylation by infusing protein kinase A (PKA) activator into the central amygdala prevents anxiety-like effects in rats during ethanol withdrawal. Here we investigated whether normalization of CREB phosphorylation by infusing PKA activator (Sp-cAMP) into the central amygdala also normalizes the expression of NPY during ethanol withdrawal. Sprague-Dawley male rats were cannulated targeting the central amygdala and then treated either with Lieber-DeCarli ethanol diet or control diet for 15 days. Subsequently ethanol-fed rats were withdrawn for 0 and 24h. The control-diet fed and ethanol-withdrawn rats were infused twice with PKA activator or inhibitor (Rp-cAMP). The protein and mRNA levels of NPY were determined in amygdaloid structures using gold-immunolabeling and the in situ RT-PCR procedure. It was found that chronic ethanol treatment has no effect on mRNA and protein levels of NPY in the central, medial, or basolateral amygdala. On the other hand, ethanol withdrawal produced significant reductions in mRNA and protein levels of NPY in the central and medial but not in the basolateral amygdala. The reductions in mRNA and protein levels of NPY were normalized in the central amygdala by infusion with PKA activator in ethanol-withdrawn rats. On the other hand, PKA-inhibitor infusion does not have any effect on mRNA and protein levels of NPY in the central amygdala of ethanol-withdrawn rats, but significantly decreased the expression of NPY in the central amygdala of control-diet fed rats. These results suggest that the decreased cellular expression of NPY in the central amygdala may play an important role in the CREB-mediated regulation of anxiety-like behaviors during ethanol withdrawal.

Topics: Alcohol Drinking; Amygdala; Animals; Cyclic AMP-Dependent Protein Kinases; Ethanol; Gene Expression Regulation; Gold; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; RNA, Messenger; Staining and Labeling; Substance Withdrawal Syndrome

Cigarette smoking produces feeding and weight suppression in humans that often rebound following cessation. Nicotine (NIC) administration produces similar effects in rats, but the neural mechanisms responsible are not fully known. Recent evidence shows that hypothalamic levels of neuropeptide Y (NPY) change with NIC administration. Infusions of NPY into the paraventricular nucleus of the hypothalamus (PVN), which normally produce robust feeding, were used to investigate changes in the PVN-NPY system that may contribute to NIC's effects on energy balance.. To characterize potential differences in PVN-NPY-induced feeding during NIC treatment versus withdrawal.. Three groups of female rats ( n=66) bearing unilateral PVN cannulae were implanted for 14 days with subcutaneous Alzet mini-pumps containing NIC (0, 6, or 12 mg/kg per day). Dark-onset (1800-2000 hours) NPY feeding tests occurred five times: pre-implant, 2 days and 12 days post-implant and 2 days and 8 days after implant removal. Feeding tests consisted of 1 h of pre-feeding prior to lights off, then two 1-h measures of feeding after PVN injections of 0.4 microl saline or NPY (78 pmol, 235 pmol).. NIC initially suppressed body weight gain, followed by steady recovery that was briefly exaggerated after withdrawing NIC. Daily feeding was acutely suppressed by NIC but acutely potentiated after NIC cessation. PVN-NPY-induced feeding was suppressed by both doses of NIC 2 days after pump implant, elevated 2 days after pump removal, but returned to pre-NIC levels 8 days after pump removal.. These findings provide behavioral support that changes in PVN-NPY neurotransmission may play a functional role in the food intake and weight-modulating effects of NIC.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Female; Injections, Intraventricular; Neuropeptide Y; Nicotine; Nicotinic Agonists; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Neuropeptide Y (NPY) modulates ethanol drinking in rodents. The C-allele of the T1128C polymorphism of the human NPY gene has been previously associated with elevated alcohol consumption in a Finn population study. The present study tested the hypothesis that the T1128C polymorphism is associated with the diagnosis of alcoholism or with severe forms of alcohol withdrawal and with the daily consumption of alcohol in alcoholic patients. After PCR-RFLP genotyping, two groups of alcoholics with severe withdrawal symptoms (delirium tremens, n = 83; withdrawal seizures, n = 65) were compared to alcoholics with mild withdrawal symptoms (n = 97). An elevated frequency of the C-allele in the individuals with severe withdrawal symptoms was found, however not reaching statistical significance. Further a group of healthy controls (n = 102) was compared to all included alcoholics (n = 216) revealing no significant result. Alcoholics carrying the C-allele reported a non significantly elevated daily consumption of alcohol compared to alcoholics with the TT genotype. All alcohol dependent subjects with severe withdrawal symptoms revealed a significantly elevated daily consumption of alcohol compared to alcoholics with only mild withdrawal symptoms. More studies on different ethnic groups are needed to further elucidate the influence of the NPY gene on alcoholism.

Topics: Adult; Alcohol Withdrawal Delirium; Alcoholism; Alleles; Case-Control Studies; Cysteine; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Severity of Illness Index; Substance Withdrawal Syndrome; Threonine

Neuropeptide Y (NPY) has been implicated in the alcohol-drinking behaviors of rodents. This study investigated the possible involvement of NPY in the neuroadaptational mechanisms to chronic ethanol exposure and its withdrawal.. Male Sprague-Dawley rats were treated either with Lieber-DeCarli ethanol diet or control diet for 15 days, and ethanol-fed rats were withdrawn for 0 and 24 hr. The protein expression of NPY was determined in cortical, hippocampal, amygdaloid, striatal, and hypothalamic structures by using the gold-immunolabeling histochemical procedure.. It was found that ethanol withdrawal, but not ethanol treatment, produced significant reductions in NPY protein levels in (1) layers IV and V of the frontal and parietal cortex, (2) layer II of the piriform cortex, (3) the central and medial nuclei of the amygdala, and (4) the paraventricular nucleus of the hypothalamus in rat brain. Chronic ethanol exposure and its withdrawal had no effect on the NPY protein levels in layers II, III, and VI of the frontal and parietal cortex or cingulate gyrus, in hippocampal (CA1, CA2, CA3, and dentate gyrus) and striatal (caudate putamen and globus pallidus) structures, or in the ventro-medial hypothalamus and basolateral amygdala. However, chronic ethanol exposure and its withdrawal produced significant reductions in NPY protein levels in the arcuate nucleus of the hypothalamus and in layers IV and V of the cingulate gyrus.. These results suggest that the decreased protein levels of NPY in the central and medial nuclei of the amygdala, as well as in the cortical and hypothalamic structures, during ethanol withdrawal may play an important role in the neuromechanisms of some ethanol withdrawal symptoms.

Topics: Alcohol Drinking; Amygdala; Animals; Brain; Brain Chemistry; Corpus Striatum; Ethanol; Hippocampus; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Neuropeptide Y (NPY) was previously shown in our laboratory to attenuate behavioral signs of morphine withdrawal. To further characterize the anti-withdrawal effect of NPY, the present study attempted to identify specific brain regions where NPY inhibits neuronal activity during withdrawal. Morphine dependence was induced in male Wistar rats by two daily subcutaneous injections of morphine at increasing doses, and the withdrawal syndrome was precipitated acutely by intraperitoneal administration of naloxone. Rats were pre-treated with an intracerebroventricular (icv) injection of NPY (12 nmol) or vehicle 30 min before the naloxone challenge. Withdrawal behavior was quantified using a point scoring technique based on motor- and non-motor-related signs. Brain areas involved in the attenuation of morphine withdrawal were delineated by radioactive in situ hybridization for the immediate early gene c-fos, which is a marker for neuronal activity. The present study confirmed the inhibitory effect of NPY on withdrawal behavior. Inhibition of behavioral signs of naloxone-precipitated morphine withdrawal was accompanied by significantly reduced c-fos expression in the locus coeruleus, lateral septal nucleus, ventral part of the periaqueductal grey, cingulate and frontal cortices, and septohippocampal nucleus. Our data suggest that neo- and allo-cortical areas as well as specific brainstem nuclei are involved in the anti-withdrawal effects of NPY.

Topics: Animals; Brain; Genes, fos; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Neuropeptide Y; Rats; Rats, Wistar; RNA, Messenger; Substance Withdrawal Syndrome

The effects of acute, subchronic ( 14 days) or chronic (28 days) intraperitoneal (i.p.) administration of chlorpromazine (2 or 10 mg/kg), haloperidol (0.5 or 2 mg/kg) or sulpiride (50 or 100 mg/kg) on the neuropeptide Y (NPY) system in the rat nucleus accumbens were studied. NPY-like immunoreactivity (NPY-LI) decreased in a dose- and time-dependent manner, and was the lowest after haloperidol. NPY-LI levels increased 8 days after withdrawal of chronic drugs treatment. Acute administration of haloperidol reduced NPY mRNA, while Subchronic treatment did not change it. Subchronic i.p. administration of the dopamine D1-like antagonist SCH 23390 (1 mg/kg) reduced NPY-LI levels but the alpha1-adrenergic antagonist prazosin (0.2 mg/kg) had no effect. The effect of sulpiride coadministered with SCH 23390 was greater than that of SCH 23390 alone, while prazosin coadministered with sulpiride insignificantly reduced the effect of sulpiride. The dopamine D2/D3 agonist quinpirole given as a single injection (3 mg/kg) did not alter NPY-LI content by itself but antagonized the chlorpromazine-induced decrease and attenuated the haloperidol-induced decrease. Our findings indicate that the accumbens NPY system is markedly affected by the antipsychotics studied, and suggest that their effects may be in part mediated by blockade of D2-like (D2, D3) and D1 dopaminergic receptors.

Topics: Animals; Antipsychotic Agents; Chlorpromazine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Immunohistochemistry; In Situ Hybridization; Male; Neuropeptide Y; Nucleus Accumbens; Rats; Rats, Wistar; Receptors, Dopamine D1; RNA, Messenger; Substance Withdrawal Syndrome; Sulpiride; Time Factors

The effects of intracerebroventricular injection of neuropeptide Y (NPY) and various NPY-related peptides were studied on naloxone-precipitated withdrawal from morphine in rats. The withdrawal reaction was assessed using an overall motor score, including jumping, wet dog shakes and other motor-related signs as well as a nonmotor score. At doses of 3, 6 or 12 nmol, NPY strongly and dose-dependently reduced the motor score. A less prominent inhibitory effect was revealed on the nonmotor score. At 6 nmol, [Leu31,Pro34]-NPY, NPY 3-36, peptide YY and human pancreatic polypeptide all significantly attenuated the motor score, whereas NPY 13-36 was without effect. This pharmacological profile suggests that the antiwithdrawal effect of NPY is mediated via the recently cloned Y5 receptor. Our data are consistent with a potential role for NPY and Y5-like receptors in basic mechanisms and as a therapeutic target in opioid dependence and withdrawal.

Topics: Animals; Dose-Response Relationship, Drug; Male; Morphine; Motor Activity; Naloxone; Neuropeptide Y; Peptide YY; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Structure-Activity Relationship; Substance Withdrawal Syndrome

Morphine dependence was experimentally induced in rats by daily injection of increasing doses of morphine for seven days. Withdrawal was precipitated in half of the morphine-dependent rats by a single injection of naloxone on day 8. Behavioral signs of withdrawal were evident in the morphine/naloxone group. Gene expression in locus coeruleus (LC) neurons was investigated using quantitative in situ hybridization analysis. Messenger RNA (mRNA) levels for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and for precursors to galanin (GAL) and neuropeptide Y (NPY), peptides that coexist with norepinephrine in LC neurons, were not altered by chronic morphine treatment or naloxone-precipitated withdrawal. In contrast, mRNA levels for c-fos were dramatically elevated in the LC following naloxone-precipitated withdrawal. Chronic morphine treatment caused a small decrease in levels of mRNA encoding the precursor to corticotropin-releasing factor (CRF) in Barrington's nucleus. Although long-term adaptations of LC neurons have previously been implicated in the development of morphine tolerance, dependence, and withdrawal, alterations in the levels of TH, GAL, or NPY mRNA in the LC apparently do not underlie this process.

Topics: Animals; Autoradiography; Galanin; Gene Expression; In Situ Hybridization; Locus Coeruleus; Male; Morphine; Naloxone; Neuropeptide Y; Neuropeptides; Peptides; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substance Withdrawal Syndrome; Time Factors; Tyrosine 3-Monooxygenase