lithium-chloride and Morphine-Dependence

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

The chronic use of opioids is often accompanied by the development of tolerance and/or dependence upon these agents due to the adaptive changes in the response of the subject to the agent. On cellular level, these phases of altered responsiveness have been shown to be the sequelae of a combination of multiple independent components acting in concert. Changes in the number, affinity, or membrane trafficking of opioids receptors, the coupling of receptors to G-proteins or in associated second messenger systems have been implicated in underlying the aforementioned phenomena. Several observations have been shown that lithium is able to contradict the expected response in animals pre-treated with morphine. These facts clearly manifest the involvement of lithium in at least one of the diverse pathways that lead to morphine dependence and/or tolerance. The aim of the present study was to investigate the effect of lithium on acute morphine-induced tolerance and dependence in an in vitro model of isolated guinea pig ileum which has been extensively used for the assessment of these effects of opioids. Morphine inhibited electrically stimulated twitch of ileum in a concentration-dependent manner (pD(2)=7.27+/-0.16). Tolerance to this effect was induced by the incubation of ileum with 2xIC(50) of morphine for 2 h that induced a degree of tolerance of 14.7. The co-incubation of ileum with morphine along lithium chloride (1 mM) reduced the degree of tolerance significantly (P<0.001) and restored the sensitivity of ileum to the morphine inhibitory effect. Lithium chloride can also reduce the expression of tolerance to morphine significantly (P<0.01). Dependence was induced by incubation with 4xIC(50) of morphine for 2 h and was assessed based on naloxone-induced contractions (10(-5 )M). Lithium chloride (1 mM) can attenuate the development but not the expression of dependence to morphine as shown by the significant decrease in naloxone-induced contractions (P<0.05). These results suggest that lithium chloride can reduce the development and expression of acute tolerance to and development of dependence on morphine in the myenteric plexus of guinea pig ileum.

Topics: Animals; Dose-Response Relationship, Drug; Drug Tolerance; Guinea Pigs; Ileum; In Vitro Techniques; Lithium Chloride; Male; Morphine; Morphine Dependence; Muscle Contraction; Nitric Oxide

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

Three experiments examined the effect of chronic morphine treatment on cocaine-, sucrose-, and lithium chloride (LiCl)-induced suppression of saccharin intake in Sprague-Dawley rats. All rats were either water- or food-deprived and then implanted subcutaneously with 1 morphine (75 mg) or vehicle pellet for 5 days. They were then given brief access to 0.15% saccharin and soon thereafter injected with either cocaine (10 mg/kg s.c.), LiCl (0.009 M, 1.33 ml/100 g body weight i.p.), or saline, or, in Experiment 2, given a 2nd access period to either a preferred 1.0 M sucrose solution or the same 0.15% saccharin solution. There was 1 taste-drug or taste-taste pairing per day for a number of days. The results showed that a history of chronic morphine treatment exaggerated the suppressive effects of a rewarding sucrose solution and cocaine but not those of the aversive agent, LiCl. These data provide further support for the reward comparison hypothesis.

Topics: Animals; Association Learning; Cocaine; Conditioning, Classical; Dose-Response Relationship, Drug; Drinking; Lithium Chloride; Male; Morphine Dependence; Motivation; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Reaction Time; Saccharin; Sucrose; Taste; Tegmentum Mesencephali

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

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