lithium-chloride and Substance-Withdrawal-Syndrome

The GABAergic tail of the ventral tegmental area (tVTA), also named rostromedial tegmental nucleus (RMTg), exerts an inhibitory control on dopamine neurons of the VTA and substantia nigra. The tVTA has been implicated in avoidance behaviors, response to drugs of abuse, reward prediction error, and motor functions. Stimulation of the lateral habenula (LHb) inputs to the tVTA, or of the tVTA itself, induces avoidance behaviors, which suggests a role of the tVTA in processing aversive information. Our aim was to test the impact of aversive stimuli on the molecular recruitment of the tVTA, and the behavioral consequences of tVTA lesions. In rats, we assessed Fos response to lithium chloride (LiCl), β-carboline, naloxone, lipopolysaccharide (LPS), inflammatory pain, neuropathic pain, foot-shock, restraint stress, forced swimming, predator odor, and opiate withdrawal. We also determined the effect of tVTA bilateral ablation on physical signs of opiate withdrawal, and on LPS- and LiCl-induced conditioned taste aversion (CTA). Naloxone-precipitated opiate withdrawal induced Fos in μ-opioid receptor-positive (15%) and -negative (85%) tVTA cells, suggesting the presence of both direct and indirect mechanisms in tVTA recruitment during withdrawal. However, tVTA lesion did not impact physical signs of opiate withdrawal. Fos induction was also present with repeated, but not single, foot-shock delivery. However, such induction was mostly absent with other aversive stimuli. Moreover, tVTA ablation had no impact on CTA. Although stimulation of the tVTA favors avoidance behaviors, present findings suggest that this structure may be important to the response to some, but not all, aversive stimuli.

Topics: Animals; Antimanic Agents; Behavior, Animal; Carbolines; Conditioning, Classical; Disease Models, Animal; Lipopolysaccharides; Lithium Chloride; Male; Morphine Dependence; Naloxone; Narcotic Antagonists; Neuralgia; Neurotoxins; Olfactory Perception; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Ventral Tegmental Area

DREAM (downstream regulatory element antagonistic modulator) is a novel transcriptional repressor for the prodynorphin gene, and genetic deletion of DREAM in mice results in a phenotype of ongoing analgesia by virtue of its effect on opioid gene expression. In the present study, we evaluated the motivational effects of opioids (morphine), cannabinoids [Delta(9)-tetrahydrocannabinol (THC)] and cocaine in mice lacking the dream gene (dream(-/-)). The aversive effects of THC were potentiated in dream(-/-) mice in a kappa-opioid receptor-dependent fashion, whereas morphine reward and the aversive effects of morphine withdrawal remained intact. The rewarding and aversive effects of cocaine were likewise unperturbed in dream(-/-) mice. Moreover, the aversive properties of lithium chloride and naloxone were unaffected by the absence of DREAM, indicating that the effect of DREAM on THC-induced dysphoria is not due to a general involvement in the behavioral response to aversive stimuli. Additionally, physical dependence to morphine and the locomotor-sensitizing effects of cocaine were unaltered in these animals. Finally, whereas the absence of DREAM reduced the analgesic efficacy of THC, morphine analgesia was unaffected in dream(-/-) mice.

Topics: Analgesia; Analgesics; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Cocaine; Conditioning, Operant; Dose-Response Relationship, Drug; Dronabinol; Lithium Chloride; Male; Mice; Mice, Knockout; Morphine; Motivation; Motor Activity; Naloxone; Narcotic Antagonists; Reaction Time; Repressor Proteins; Substance Withdrawal Syndrome; Transcription Factors

Lithium is an established mood stabilizer and neuroprotective agent frequently used in the treatment of bipolar disorder and as an adjuvant in drug-resistant unipolar depression. The mechanisms underlying both the therapeutic efficacy of lithium and the exacerbation of symptoms following rapid withdrawal are not understood. From previous studies showing antidepressant and neuroprotective activities of thyrotropin releasing hormone (TRH) and TRH-related neuropeptides we hypothesized that lithium may have substantial effects on the expression and secretion of these peptides and/or their receptors in various rat brain regions involved in the regulation of mood. Chronic lithium effect on TRH receptor binding studies: The effect of 1 and 2 weeks of dietary lithium on [(3)H]3-Me-His-TRH binding to plasma membranes of nucleus accumbens, amygdala and pituitary of young adult male Wistar and the endogenously 'depressed' Wistar Kyoto (WKY) rats was measured by the method of Burt and Taylor [Burt, D.R., Taylor, R.L., Endocrinology 106 (1980) 1416-1423]. Acute, chronic and withdrawal effect of lithium on TRH and TRH-like peptide levels in young, adult male Sprague-Dawley rats: Rats were divided into four lithium treatment groups. Control animals received a standard laboratory rodent chow. The acute group received a single i.p. injection of 1.5 milli-equivalents of LiCl 2 h prior to killing. The chronic and withdrawal groups received standard rodent chow containing 1.7 g/kg LiCl for 2 weeks. Withdrawal rats were returned to standard chow 48 h prior to killing while the chronic animals continued on the LiCl diet. TRH, TRH-Gly (pGlu-His-Pro-Gly, a TRH precursor), EEP (pGlu-Glu-Pro-NH(2), a TRH-like peptide with antidepressant activity) and Ps4 (a prepro-TRH-derived TRH-enhancing decapeptide) immunoreactivity (IR) were measured in 13 brain regions. The remaining samples were pooled and fractionated by high-pressure liquid chromatography followed by EEP radioimmunoassay. Chronic lithium treatment increased [(3)H]3Me-TRH binding in the nucleus accumbens and amygdala about two-fold in both Wistar and WKY rats but no change was observed in pituitary binding. The most widespread changes in TRH and TRH-related peptide levels were observed in the withdrawal group compared to the controls. The direction of change for the total IR was consistent for all TRH-IR and TRH-related peptide-IR within a given tissue. For example, withdrawal increased all peptide levels in the pyriform co

Topics: Acute Disease; Animals; Brain; Chromatography, High Pressure Liquid; Drug Administration Schedule; Lithium Chloride; Male; Neuropeptides; Protein Binding; Protein Precursors; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Thyrotropin-Releasing Hormone; Substance Withdrawal Syndrome; Thyrotropin-Releasing Hormone

We have previously reported that mesolimbic dopamine (DA) substrates are critically involved in the rewarding effects of opiates only during states of opiate-dependence and withdrawal. However, in previously drug-naive animals, opiate reward is mediated through a DA-independent neural system. In the present study, we report that bilateral microinjections of a DA receptor antagonist, alpha-flupenthixol (0.3-3 microg/0.5 microl) into the nucleus accumbens (NAc), blocks morphine reward (10 mg/kg, i.p.) in opiate-withdrawn animals, but not in opiate-naive animals, suggesting that accumbal dopamine receptors are required for opiate reward signaling in drug-deprived motivational states. Next, the role of dopamine was examined in the development of opiate dependence and somatic withdrawal, and expression of withdrawal aversions. Pretreatment with alpha-flupenthixol (0.8 mg/kg, i.p.) before morphine injections during the development of opiate dependence did not effect expression of withdrawal aversions or the expression of somatic withdrawal. We have previously reported that pretreatment with a dopamine receptor antagonist, alpha-flupenthixol, blocks the aversive effects of opiate withdrawal. We now report that pretreatment with a direct dopamine receptor agonist, apomorphine (1.0-5.0 mg/kg, i.p.) before conditioning in a state of withdrawal, also blocks the aversive effects of opiate withdrawal. We propose that the aversive motivational effects of opiate withdrawal may be mediated by a specific dopaminergic neuronal signal.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Conditioning, Operant; Dopamine; Flupenthixol; Limbic System; Lithium Chloride; Male; Microinjections; Morphine; Morphine Dependence; Motivation; Narcotics; Nucleus Accumbens; Rats; Rats, Wistar; Reward; Substance Withdrawal Syndrome

The role of central oxytocin in inhibitory action of lithium on the development of morphine dependence was behavioral investigated in rats. Acute lithium could enhance the morphine-induced analgesia in rats with or without chronic morphine treatment; this effect could be inhibited by intraventricular injection of oxytocin antagonist d (CH(2))(5)-Tyr (Me)-[Orn(8)]-Vasotocin (OVT). Lithium could attenuate naloxone-precipitated withdrawal signs in morphine dependent rats. The reduction of the expression of naloxone-precipitated withdrawal signs by lithium was reversed by ICV of OVT. The lithium significantly inhibited the conditioned place preference (CPP) induced by morphine, which inhibitory action of lithium could also reverse by ICV injection of OVT. These results suggested that lithium might inhibit the physical dependence on morphine as well as psychological dependence in rats, and that this inhibitory effect of lithium on the development of morphine dependence might be associated with oxytocin systems in the central nervous system.

Topics: Analgesics, Opioid; Animals; Antimanic Agents; Behavior, Animal; Conditioning, Psychological; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Hypothalamo-Hypophyseal System; Hypothalamus, Anterior; Lithium Chloride; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Neurosecretion; Oxytocin; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Previous studies from this laboratory indicated that D2 dopamine (DA) receptors within the nucleus accumbens (NAc) are important for regulating somatic signs of opiate withdrawal. The present study measured the expression of Fos-related antigens (FRAs) within the NAc during opiate withdrawal to determine whether decreases in somatic withdrawal signs produced by a D2 receptor agonist are accompanied by related changes in accumbens neuronal activity. In an initial experiment, quantitative analyses of FRA immunoreactivity revealed increases in the number of FRA-positive cells throughout the NAc of opiate dependent animals undergoing naltrexone-precipitated withdrawal relative to dependent or non-dependent animals that did not experience withdrawal. A second experiment showed that somatic signs and FRA expression within the NAc could each be attenuated when the D2 agonist propylnorapomorphine (NPA; 0.1 or 0.3 mg/kg, i.p.) was administered prior to naltrexone-precipitated withdrawal. These findings suggest that D2 regulation of neuronal activity within the NAc may be important for the expression of opiate withdrawal symptoms.

Topics: Animals; Apomorphine; Behavior, Animal; Dopamine Agonists; Dopamine Antagonists; Immunohistochemistry; Lithium Chloride; Male; Morphine; Naltrexone; Narcotic Antagonists; Narcotics; Nucleus Accumbens; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Substance Withdrawal Syndrome

The researchers asked whether clonidine, an alpha 2-noradrenergic agonist, would block selectively the motivational effects of opiate withdrawal and whether clonidine's effects would respect the boundary between nondeprived and deprived motivational states. In a place conditioning paradigm, clonidine (0.05 mg/kg ip) blocked the rewarding effects of morphine in opiate-withdrawn rats (as well as the aversive properties of withdrawal itself), but did not affect morphine place preferences (2 and 20 mg/kg) in drug-naive rats. Furthermore, clonidine blocked the acquisition of morphine (15 mg/kg), but not LiCl (15 mg/kg), conditioned taste aversions in water-deprived rats. The results suggest that the motivational system activated in deprived animals includes dopaminergic and noradrenergic components that are in series with each other.

Topics: Adrenergic alpha-Agonists; Animals; Arousal; Association Learning; Avoidance Learning; Clonidine; Conditioning, Classical; Dose-Response Relationship, Drug; Lithium Chloride; Male; Mental Recall; Morphine; Morphine Dependence; Motivation; Norepinephrine; Rats; Rats, Wistar; Social Environment; Substance Withdrawal Syndrome; Taste

1. This study examines the effects of chronic lithium administration on changes induced by amphetamine administration and withdrawal on open field locomotor activity of rats, and considered as an animal model of behaviors displayed in bipolar disorders. 2. For 21 days, rats were administered either single daily intraperitoneal injections (IP) of 0.9% saline, 0.15 mEq/kg, or 1.5 mEq/kg lithium chloride (LiCl). From day 7 to day 16, half of the animals in each group consisting of 12 rats were administered twice daily IP injections of either 1.5 mg/kg d-amphetamine or 0.9% saline. From day 17 to 21, d-amphetamine was withdrawn. 3. Neither dose of LiCl significantly altered the increases in activity levels produced by amphetamine. The withdrawal of amphetamine lead to an immediate return to baseline activity levels which neither dose of LiCl significantly affected. 4. The absence of interactive effects suggests that the influence of lithium and amphetamine on activity are mediated by different neurotransmitter systems.

Topics: Animals; Bipolar Disorder; Chlorides; Dextroamphetamine; Disease Models, Animal; Lithium; Lithium Chloride; Male; Motor Activity; Rats; Rats, Inbred Strains; Reference Values; Substance Withdrawal Syndrome

The effect of chronic lithium administration and withdrawal on locomotor activity and apomorphine-induced locomotor stimulation in rats was studied. Chronic lithium administration caused a decrease in locomotor activity, which might be due to a lithium-induced decrease of exploratory behaviour. Chronic lithium administration had no effect on apomorphine-induced locomotor stimulation. However, apomorphine-induced locomotor stimulation was increased two days after the withdrawal of lithium while no difference was found after four days, suggesting a transient increase in postsynaptic dopamine (DA) receptor sensitivity following lithium withdrawal.

Topics: Animals; Apomorphine; Chlorides; Exploratory Behavior; Lithium; Lithium Chloride; Male; Motor Activity; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Time Factors

The morphine withdrawal syndrome was studied in male Wistar rats. Spontaneous aggressiveness, enhanced apomorphine aggressiveness, lowered pain threshold and decreased dopamine turnover were observed after withdrawal of 10-day treatment with the increasing doses of morphine (30-300 mg/kg). These changes attested to the increased sensitivity of dopamine receptors. Administration of morphine in conjunction with lithium chloride in a dose of 2 mekv/kg prevented the development of dopamine receptor hypersensitivity. Also, this method did not produce the increased spontaneous and apomorphine aggressiveness or the decreased dopamine turnover. Meanwhile the pain threshold remained lowered.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Chlorides; Corpus Striatum; Dopamine; Homovanillic Acid; Humans; Lithium; Lithium Chloride; Male; Morphine; Rats; Receptors, Dopamine; Substance Withdrawal Syndrome; Time Factors