Acquisition Of Conditioned Place Aversion Research Articles

Effects of CB1 receptor negative allosteric modulator Org27569 on oxycodone withdrawal symptoms in mice

Rationale/ObjectivesTargeting cannabinoid receptor type 1 (CB1R) has shown promise for treating opioid withdrawal symptoms. This study aimed to investigate the efficacy of a specific CB1R negative allosteric modulator (NAM), Org27569, in reducing both naloxone-precipitated and protracted withdrawal symptoms in oxycodone-dependent mice.MethodsMice received escalating doses of oxycodone (9–33 mg/kg IP) or saline twice daily for 9 days, followed by a final dose of oxycodone (33 mg/kg) or saline in the morning of day 9. In one cohort, the impact of Org27569 (3, 10, and 30 mg/kg) on naloxone (10 mg/kg IP) precipitated withdrawal symptoms was assessed. In another cohort, Org27569 (3 mg/kg) effects on the acquisition of conditioned place aversion to naloxone (0.6 mg/kg) precipitated opioid withdrawal, on behaviour following a 7–9-day abstinence period, and on naloxone (0.6 mg/kg) precipitated withdrawal-induced escape behaviour in a novel assay were assessed.ResultsAlthough Org27569 decreased opioid withdrawal-induced jumping at doses of 10 and 30 mg/kg, these effects were confounded by reduced locomotion. At all doses tested, Org27569 had a modest inhibitory effect on gastrointestinal motility. At the lower dose of 3 mg/kg, which was not confounded by locomotor effects, Org27569 did not impact naloxone-precipitated withdrawal-induced jumping, acquisition of oxycodone withdrawal-induced conditioned place aversion, or naloxone-precipitated withdrawal-induced escape behaviour in a novel assay. A clear protracted opioid withdrawal phenotype was not observed in assays of anxiety-like or social behaviour.ConclusionsOrg27569 effects on negative affective-like symptoms were confounded by locomotor effects and effects on gastrointestinal motility were not opioid withdrawal specific. Further studies are needed in a model that produces a more pronounced protracted withdrawal syndrome.

Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor-mediated activation of lateral habenula neurons.

There has been increasing interest in the lateral habenula (LHb) given its potent regulatory role in many aversion-related behaviors. Interestingly, ethanol can be rewarding as well as aversive; we therefore investigated whether ethanol exposure alters pacemaker firing or glutamate receptor signaling in LHb neurons in vitro and also whether LHb activity in vivo might contribute to the acquisition of conditioned place aversion to ethanol. Surprisingly, in epithalamic slices, low doses of ethanol (1.4 mM) strongly accelerated LHb neuron firing (by ~60%), and ethanol's effects were much reduced by blocking glutamate receptors. Ethanol increased presynaptic glutamate release, and about half of this effect was mediated by dopamine subtype 1 receptors (D1Rs) and cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. In agreement with these findings, c-Fos immunoreactivity in LHb regions was enhanced after a single administration of a low dose of ethanol (0.25 g/kg i.p.). Importantly, the same dose of ethanol in vivo also produced strong conditioned place aversion, and this was prevented by inhibiting D1Rs or neuronal activity within the LHb. By contrast, a higher dose (2 g/kg) led to ethanol conditioned place preference, which was enhanced by inhibiting neuronal activity or D1Rs within the LHb and suppressed by infusing aminomethylphosphonic acid or the D1R agonist SKF38393 within the LHb. Our in vitro and in vivo observations show, for the first time, that ethanol increases LHb excitation, mediated by D1R and glutamate receptors, and may underlie a LHb aversive signal that contributes to ethanol-related aversion.

Role of nucleus accumbens dopamine receptor subtypes in the learning and expression of alcohol-seeking behavior

These studies examined the roles of dopamine D1- and D2-like receptors within the nucleus accumbens (Acb) in the acquisition and expression of ethanol-induced (2g/kg) conditioned place preference (CPP) in adult male DBA/2J mice. Bilateral intra-Acb infusions of the D1-like dopamine receptor antagonist SCH23390 (0.05, 0.5μg/side) or the D2-like dopamine receptor antagonist raclopride (0.5–5.0μg/side) were administered 30min before each ethanol conditioning trial (acquisition studies) or before preference tests (expression studies). CPP was conditioned to tactile cues using an unbiased apparatus and procedure. Intra-Acb infusion of SCH23390 prevented CPP acquisition, whereas intra-Acb infusion of raclopride did not. Intra-Acb infusion of both antagonists, however, dose-dependently reduced ethanol-stimulated locomotor activity during conditioning. In contrast, intra-Acb antagonist infusion had no effect on ethanol CPP expression, suggesting that dopamine’s role in the Acb is limited to neurobiological processes engaged during the learning of the relationship between contextual cues and ethanol reward. Control experiments showed that intra-Acb injection of SCH23390 alone produced no place conditioning and did not interfere with the acquisition of conditioned place aversion induced by lithium chloride, suggesting that the antagonist’s effect on ethanol CPP was not due to a more general detrimental effect on associative learning. Overall, these data suggest that D1-like (but not D2-like) dopamine Acb receptors play an important role in the learning of context-ethanol associations, either by modulating the magnitude of ethanol reward or the rate of learning about ethanol reward.

Inhibition of the Acquisition of Conditioned Place Aversion by Dopaminergic Lesions of the Central Nucleus of the Amygdala in Morphine-Treated Rats

The negative affective state of opiate abstinence plays an important role in craving and relapse to compulsive drug use. The dopamine system participates in the reward effects of opiate use and the aversive effect of opiate abstinence. The amygdala is an essential neural substrate for associative learning of emotion. To establish a model of conditioned place aversion (CPA) in morphine-treated rats, we used different visual and tactual cues as conditioned stimuli (CS) within a conditioning apparatus. An injection of naloxone served as the unconditioned stimulus (US). The 6-hydroxydopamine (6-OHDA) lesion technique was used to investigate the effects of the dopaminergic system of the central nucleus of the amygdala (CeA) on naloxone-induced CPA. Rats were rendered physically dependent via administration of increasing doses of morphine delivered via intraperitoneal injection. Doses increased by 20 % each day for 14 days, starting from an initial dose of 6 mg/kg. All rats also received a low dose of naloxone (0.1 mg/kg) by injection 4 hours after morphine treatment on days 11 and 13 to induce CPA in a biased two-compartment conditioned place apparatus. Morphine-dependent rats with sham lesions were found to develop significant CPA after naloxone treatment. Bilateral 6-OHDA lesions of the CeA impaired the acquisition of CPA but had no effect on locomotor activity. These results suggest that the dopaminergic system of the CeA plays an important role in the negative affective state of opiate abstinence.

Involvement of the Amygdala on Place Aversion Induced by Naloxone in Single-Dose Morphine-Treated Rats

Signs characteristic of opiate withdrawal symptoms can be precipitated by an opiate antagonist after short-term infusion or even a single dose of an opiate both in humans and in animals. This phenomenon has been referred to as acute dependence. In contrast to extensive studies on chronic dependence, less is known about the neural mechanisms mediating acute dependence. It will benefit the development of appropriate therapies to facilitate opiate abstinence and reduced craving to better understand the mechanisms underlying acute opiate dependence and to determine whether there are dissociation and similarity between the early and fully developed stages of dependence. In the present study, we examined the influence of c-Fos expression in the amygdala in acquisition of conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h earlier. The effect of microinjection into the central amygdaloid nucleus (CeA) of various kinds of glutamatergic neurotransmission inhibitors was also investigated. Findings showed that CeA displayed significant increase in c-Fos expression in the acquisition of CPA. Furthermore, CPA was attenuated significantly and dose-dependently by microinjection into CeA of all glutamatergic neurotransmission inhibitors (NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801), AMPA receptor antagonist 1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI52466), metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), and glutamate release inhibitor riluzole). These findings suggest that CeA involves the acquisition of CPA induced by naloxone-precipitated withdrawal from a single morphine exposure, and the function of the glutamatergic system projected from the amygdala to nucleus accumbens plays a facilitative role in formation of morphine dependence.

The anti-craving drug acamprosate inhibits the conditioned place aversion induced by naloxone-precipitated morphine withdrawal in rats

The anti-craving drug acamprosate (Ca N-acetylhomotaurinate) is therapeutically used to prevent a relapse in weaned alcoholics. In the present place conditioning study, the effect of this compound on the motivational impact of morphine withdrawal was examined. Withdrawal was precipitated in rats by administration of the opioid antagonist naloxone (0.1 mg/kg, s.c.) 5–6 days after the subcutaneous implantation of a 75 mg morphine pellet. Aversion against the naloxone-paired cues was observed after conditioning in the drug-free state. The acquisition of conditioned place aversion was completely inhibited by the pretreatment with acamprosate (200 mg/kg, i.p.) 12 h and 30 min prior to conditioning. These results clarify that acamprosate inhibits the motivational component of morphine withdrawal and suggest that ethanol and opiates share similar properties in the neuronal mechanisms of conditioned withdrawal and craving.

P-4-2 - Mirtazapine vs tricyclic antidepressants in the treatment of severely depressed patients

The anti-craving drug acamprosate (Ca N-acetylhomotaurinate) is therapeutically used to prevent a relapse in weaned alcoholics. In the present place conditioning study, the effect of this compound on the motivational impact of morphine withdrawal was examined. Withdrawal was precipitated in rats by administration of the opioid antagonist naloxone (0.1 mg/kg, s.c.) 5–6 days after the subcutaneous implantation of a 75 mg morphine pellet. Aversion against the naloxone-paired cues was observed after conditioning in the drug-free state. The acquisition of conditioned place aversion was completely inhibited by the pretreatment with acamprosate (200 mg/kg, i.p.) 12 h and 30 min prior to conditioning. These results clarify that acamprosate inhibits the motivational component of morphine withdrawal and suggest that ethanol and opiates share similar properties in the neuronal mechanisms of conditioned withdrawal and craving.

P-3-7 - Acamprosate effect on changes of transferrin levels in ethanol preferring and non-preferring rats

The anti-craving drug acamprosate (Ca N-acetylhomotaurinate) is therapeutically used to prevent a relapse in weaned alcoholics. In the present place conditioning study, the effect of this compound on the motivational impact of morphine withdrawal was examined. Withdrawal was precipitated in rats by administration of the opioid antagonist naloxone (0.1 mg/kg, s.c.) 5–6 days after the subcutaneous implantation of a 75 mg morphine pellet. Aversion against the naloxone-paired cues was observed after conditioning in the drug-free state. The acquisition of conditioned place aversion was completely inhibited by the pretreatment with acamprosate (200 mg/kg, i.p.) 12 h and 30 min prior to conditioning. These results clarify that acamprosate inhibits the motivational component of morphine withdrawal and suggest that ethanol and opiates share similar properties in the neuronal mechanisms of conditioned withdrawal and craving.