Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking

Rationale GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. Objective We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure. Methods α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). Results No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Conclusions Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking

mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism

Abstract Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca++ channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlies MPEP-induced glutamate release. This interpretation was further supported by our findings that genetic deletion of CB1 receptors in CB1-knockout mice blocked both MPEP-enhanced extracellular glutamate and MPEP-induced reductions in cocaine self-administration. Together, these results indicate that the therapeutic anti-cocaine effects of mGluR5 antagonists are mediated by elevation of extracellular glutamate in the NAc via an endocannabinoid-CB1 receptor disinhibition mechanism

On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats

RATIONALE: Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic “crash”. OBJECTIVE: To determine whether individual differences in the relative value of cocaine’s positive and negative effects would account for variations in subsequent drug self-administration. METHODS: The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0 mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15 min post-injection) and a runway test (where animals developed approach-avoidance “retreat” behaviors about entering a goal-box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration. RESULTS: a) larger place preferences were associated with faster runway start latencies (r(s)=−0.64), but not with retreat frequency or run times; b) larger place aversions predicted slower runway start times (r(s)=0.62) and increased run times (r(s)=0.65) and retreats (r(s)=0.62); c) response escalation was observed in both the 1-h and 6-h self-administration groups and was associated with increased CPPs (r(s)=0.58) but not CPAs, as well as with faster run times (r(s)=−0.60). CONCLUSIONS: Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction