neuropeptide-y and Substance-Related-Disorders

The hypothalamus is an integrated energy sensing system interfacing with higher motivational structures of the mesocorticolimbic dopamine (DA) system. This interconnectivity is strictly regulated by a number of orexigenic hypothalamic neuropeptides, including especially ghrelin, orexins and neuropeptide Y (NPY), enabling the latter to modulate salient events of natural and chemical reinforcers. In this review we aim to analyse the current knowledge on these three orexigenic neuropeptide systems that are involved in the DAergic regulation of psychostimulant behaviours. We will first review the co-existing interactions between ghrelin, orexins and NPY in hypothalamic nuclei. We will next outline whether these neuropeptides can affect DAergic neurotransmission by either regulating the firing rate of DA neurons in the ventral tegmental area (VTA) or by presynaptically interacting on the DAergic nerve terminals. Finally, we will underscore the main studies that outlined the involvement of ghrelin, orexins and NPY with rewarding, reinforcing and incentive properties of natural reinforcers and drugs of abuse. The reciprocal hypothalamic interaction of ghrelin, orexins and NPY might represent a new central view on neuronal mechanisms regulating the behavioural phenomenology of addiction maintained by the DA system.

Topics: Animals; Behavior, Addictive; Dopamine; Dopaminergic Neurons; Drug Users; Ghrelin; Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Limbic System; Motivation; Neural Pathways; Neuropeptide Y; Neuropeptides; Orexins; Reinforcement, Psychology; Reward; Substance-Related Disorders; Synaptic Transmission

Benzodiazepines are very often prescribed because of their anxiolytic, sedative and hypnotic properties. However, long term treatment is associated with development of benzodiazepine dependence. Besides development of physical dependence, which is linked to a typical benzodiazepine withdrawal syndrome when drug intake is discontinued, also behavioural addiction to benzodiazepines has been described. Benzodiazepines are known to enhance GABAergic neurotransmission. Counter regulation of enhanced GABAergic neurotransmission by enhancement of glutamatergic neurotransmission is thought to be one reason underlying the typical symptoms of benzodiazepine withdrawal. Also alterations in the expression of neuropeptides like Corticotropin Releasing Hormone and Neuropeptide Y are thought to be involved in the development of benzodiazepine dependence. However, until today the knowledge of neural mechanisms underlying the development of benzodiazepine dependence remains incomplete. Because even long term treatment with small doses of benzodiazepines is associated with adverse reactions like cognitive dysfunctions withdrawal from benzodiazepines should be aimed. Anticonvulsants and antidepressants seem to reduce the intensity of benzodiazepine withdrawal and to enhance long term prognosis of dependence.

Topics: Animals; Benzodiazepines; Corticotropin-Releasing Hormone; gamma-Aminobutyric Acid; Humans; Hypnotics and Sedatives; Long-Term Care; Neuropeptide Y; Receptors, GABA; Substance-Related Disorders

Evidence that psychoactive substance use disorders, bulimia nervosa, pathological gambling, and sexual addiction share an underlying biopsychological process is summarized. Definitions are offered for addiction and addictive process, the latter being the proposed designation for the underlying biopsychological process that addictive disorders are hypothesized to share. The addictive process is introduced as an interaction of impairments in three functional systems: motivation-reward, affect regulation, and behavioral inhibition. An integrative review of the literature that addresses the neurobiology of addiction is then presented, organized according to the three functional systems that constitute the addictive process. The review is directed toward identifying candidate neurochemical substrates for the impairments in motivation-reward, affect regulation, and behavioral inhibition that could contribute to an addictive process.

Topics: Affect; Dopamine and cAMP-Regulated Phosphoprotein 32; Humans; Motivation; Neurobiology; Neuropeptide Y; Norepinephrine; Psychometrics; Receptors, Dopamine; Receptors, GABA-A; Reward; Serotonin; Substance P; Substance-Related Disorders

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

It is known that 9-13% of individuals with a diagnosis of schizophrenia commits suicide. In addition, patients with schizophrenia have approximately a 50% lifetime risk for attempting suicide. The authors review the identified risk factors for suicide in schizophrenia. The most significant risk factors include the age of the patient, male gender, depression, presence of positive symptoms and substance abuse. There is evidence that implicates the serotonin system in the suicide of individuals with schizophrenia. Overactivity of the hypothalamo-pituitary-adrenal axis has also been reported in individuals who went on to attempt suicide. The authors review the molecular biology of suicide in schizophrenia. With regard to prevention of suicide, pharmacological intervention with typical antipsychotics and antidepressants may be helpful. It is suggested that atypical anti-psychotics, in particular clozapine may provide additional benefit in reducing the rate of suicide attempts. The authors emphasise the importance of early treatment of individuals with a diagnosis of schizophrenia, the role of maintenance therapy and the importance of a collaborative approach between in- and outpatient services.

Topics: Age Factors; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Female; Humans; Male; Neuropeptide Y; Polymorphism, Genetic; Risk Factors; Schizophrenia; Schizophrenic Psychology; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Substance-Related Disorders; Suicide; Suicide Prevention

Epidemiological and clinical data indicate high comorbidity between depression and drug dependence that may reflect an attempt to self-medicate with drugs of abuse. The present review examines whether these two psychiatric disorders are related by attempting to identify similarities in the neurobiology of depression and drug dependence. Emphasis is put on the neuromechanisms that may mediate specific core symptoms of both disorders that reflect alterations in reward and motivational processes. First, the epidemiological and clinical data on the comorbidity of the two disorders are reviewed briefly. Then, the neuroadaptations associated with psychomotor stimulant, opiate, ethanol, nicotine, and benzodiazepine dependence in animals are reviewed. Finally, the neurotransmitter systems whose function appears to be altered in depression (i.e., serotonin, norepinephrine, acetylcholine, dopamine, gamma-aminobutyric acid, corticotropin releasing factor, neuropeptide Y, and somatostatin), as revealed primarily by animal studies, are discussed. It is concluded that drug dependence and depression may be associated with alterations in some of the same neurotransmitter systems and, in particular, with alterations of neurotransmitter function in limbic-related brain structures. Thus, these two psychiatric disorders may be linked by some shared neurobiology. Nevertheless, it remains unclear whether drug abuse and depression are different symptomatic expressions of the same preexisting neurobiological abnormalities, or whether repeated drug abuse leads to the abnormalities mediating depression (i.e., drug-induced depressions). The hypothesis of self-medication of non-drug- and drug-induced depressions with drugs of abuse is also discussed as a potentially important explanatory concept in understanding the observed clinical comorbidity of these two psychiatric disorders.

Topics: Animals; Brain; Comorbidity; Corticotropin-Releasing Hormone; Depressive Disorder; Neuropeptide Y; Norepinephrine; Serotonin; Substance-Related Disorders

Many risk factors lead to opioid use and drug-related problems. One of the challenges to understand behavioural factors, drug problems and psychopathology is to identify biological markers that are suitable for research on broad substance abuse and dependence involving human participants.. The study has examined the relationships between the self-reported childhood history of trauma, parental bonding, psychopathology, impulsivity, current resiliency, two neuropeptides, possible markers of behaviour and emotion regulation, and severity of drug-related problems.. One hundred and sixty-seven individuals with a history of opioid use completed questionnaires. Serum neuropeptide Y (NPY) and substance P (SP) levels were analysed. Moderating and mediating relationships between variables were examined using structural equation modelling (SEM).. Antisocial features, depression, impulsivity, SP, NPY, emotional neglect and resilience are associated with severity of drug-related problems. SP is associated with antisocial personality traits.. The novelty of this study is the proposed possible link between biochemical markers, antisocial features and behavioural and emotional regulation. Serum NPY and SP levels have a potential to be used as a biomarker in opioid users before and in the treatment process to account for interactions between biological vulnerabilities and childhood risk factors in predicting behavioural adjustment and more severe drug-related problems.

Topics: Adult; Child; Child Abuse; Female; Humans; Male; Mental Health; Neuropeptide Y; Object Attachment; Parents; Self Report; Substance P; Substance-Related Disorders

Acute and chronic stress-related mechanisms play an important role in the development of addiction and its chronic, relapsing nature. Multisystem adaptations in brain, body, behavioral, and social function may contribute to a dysregulated physiological state that is maintained beyond the homeostatic range. In addition, chronic abuse of substances leads to an altered set point across multiple systems. Resilience can be defined as the absence of psychopathology despite exposure to high stress and reflects a person's ability to cope successfully in the face of adversity, demonstrating adaptive psychological and physiological stress responses. The study of resilience can be approached by examining interindividual stress responsibility at multiple phenotypic levels, ranging from psychological differences in the way people cope with stress to differences in neurochemical or neural circuitry function. The ultimate goal of such research is the development of strategies and interventions to enhance resilience and coping in the face of stress and prevent the onset of addiction problems or relapse.

Topics: Adaptation, Psychological; Dopamine; Endocannabinoids; Humans; Hypothalamo-Hypophyseal System; Neuropeptide Y; Norepinephrine; Pituitary-Adrenal System; Resilience, Psychological; Serotonin; Stress, Psychological; Substance-Related Disorders

Neuropeptide Y (NPY) is involved in stress regulation. Genetic variations predict plasma NPY and neural correlates of emotion and stress. We examined whether the functional NPY haplotype modulates stress-induced NPY and anxiety responses, and if plasma NPY stress responses are associated with substance dependence outcomes.. Thirty-seven treatment-engaged, abstinent substance dependent (SD) patients and 28 healthy controls (HCs) characterized on NPY diplotypes (HH: high expression; HLLL: intermediate/low expression) were exposed to stress, alcohol/drug cues and neutral relaxing cues, using individualized guided imagery, in a 3-session laboratory experiment. Plasma NPY, heart rate and anxiety were assessed. Patients were prospectively followed for 90-days post-treatment to assess relapse outcomes.. HH individuals showed significantly lower stress-induced NPY with greater heart rate and anxiety ratings, while the HLLL group showed the reverse pattern of NPY, anxiety and heart rate responses. This differential genetic modulation of NPY stress response was suppressed in the SD group, who showed no stress-related increases in NPY and higher heart rate and greater anxiety, regardless of diplotype. Lower NPY predicted subsequent higher number of days and greater amounts of post-treatment drug use.. These preliminary findings are the first to document chronic drug abuse influences on NPY diplotype expression where NPY diplotype modulation of stress-related plasma NPY, heart rate and anxiety responses was absent in the substance abuse sample. The finding that lower stress-related NPY is predictive of greater relapse severity provides support for therapeutic development of neuropeptide Y targets in the treatment of substance use disorders.

Topics: Adult; Anxiety; Case-Control Studies; Cues; Female; Haplotypes; Heart Rate; Humans; Imagery, Psychotherapy; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Recurrence; Stress, Psychological; Substance-Related Disorders

Anticonvulsant tolerance and dependence are two obstacles that restrict the clinical use of benzodiazepines (BDZ). In order to explore the mechanism of these two adverse reactions, changes of neuropeptide Y (NPY) and its receptors in the hippocampus of rat models, in relation to flurazepam (FZP, a member of BDZ) tolerance and dependence, were investigated.. The mRNA of preproNPY and its receptors (Y1, Y2, and Y5) in the hippocampus were determined by competitive RT-PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry.. A decrease of preproNPY mRNA in the hippocampus was found in tolerant and dependent rats. The level of preproNPY mRNA in the hippocampus was reversely correlated with the degree of tolerance and dependence, measured by the threshold of pentylenetetrazol-induced seizures. Immunohistochemistry indicated a decrease of NPY-immunoreactive material in neurons of the CA1, CA3, and dentate gyrus regions of both tolerant and dependent rats. The mRNA of NPY receptors Y1 and Y5 decreased in tolerant rats but did not change in dependent rats. The mRNA of NPY receptor Y2 increased in tolerant rats but decreased in dependent rats.. A decrease of NPY in the hippocampus might be involved in anticonvulsant tolerance and dependence following long-term treatment with FZP. Y1, Y2, and Y5 mRNA were also altered in FZP tolerance and dependence.

Topics: Animals; Dentate Gyrus; Drug Tolerance; Flurazepam; Hippocampus; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Substance-Related Disorders