Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAA receptors.

Because GABA(A) receptors containing alpha2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with alpha2 gene deletion showed reduced synaptic GABA(A) receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of alpha2-GABA(A) receptors (alpha2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In alpha2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of alpha2-GABA(A) receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.

The duration of nicotine-induced attentional enhancement in the five-choice serial reaction time task: lack of long-lasting cognitive improvement.

There is evidence that nicotine-induced enhancements of cognition may persist for days or even weeks after the drug has been cleared, but the generality of this effect is not known. The objective was to determine the time course of nicotine's effects on performance of the five-choice serial reaction time task (5-CSRTT) when the drug is given acutely and chronically. In the 5-CSRTT, rats were trained to obtain food reinforcers by detecting light stimuli and then received daily postsession injections of nicotine (0.4 mg/kg) or saline. The dose-related effects of presession injections of various acutely administered doses of nicotine were then determined at three different times after injection, whereas controls received saline only (n=12). Finally, performance of all animals was tracked for 8 days after the end of all dosing with nicotine. Daily postsession administration of nicotine for 16 days had no effect on performance the next day. Acute presession administration of nicotine positively influenced several response indices, confirming previous results. Daily administration of nicotine over a total period of 50 days weakened the effect of nicotine on response accuracy, perhaps because of an elevation of the baseline, but had no effect on other measures of performance. The effects of presession nicotine were very clear in tests carried out at 10 or 25 min after injection, and were less consistent at 75 min. There were no persisting differences between the performance of rats as a function of previous histories of exposure to nicotine everyday for 50 days, either under baseline conditions or when task demands were increased. The data suggest that there are no effects of nicotine on attentional performance in the 5-CSRTT that persist after exposure to the drug has ended.

Different effects of ionotropic and metabotropic glutamate receptor antagonists on attention and the attentional properties of nicotine.

Distinct lines of evidence indicate that glutamate plays a primary role in modulating cognitive functions. Notably, competitive glutamate receptor antagonists acting at ionotropic N-methyl-d-aspartate (NMDA) or metabotropic glutamate 5 (mGlu5) receptors impair cognitive performance. Conversely, nicotine and other psychostimulants stimulate glutamatergic mechanisms and can act as cognitive enhancers. Hence we analysed the role of glutamate in performance of an attentional task and in nicotine-induced enhancement of attention by using the rodent five-choice serial reaction time task (5-CSRTT). Rats were trained to criterion performance and were then pre-dosed with either vehicle, the NMDA receptor antagonist (+)3-(2-carboxypiperazin-4-propyl)-1-propenyl-1-phosphonic acid (CPP, 0.3-2.0 mg/kg) or the mGlu5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 1.0-9.0 mg/kg) and challenged with nicotine (0.2 mg/kg). Nicotine improved attentional performance, an effect that was weakened by doses of CPP that themselves had little impact on performance; importantly, CPP dose-dependently blunted the ability of nicotine to improve response accuracy, the major measure of signal detection in the paradigm. MPEP dose-dependently impaired signal detection under conditions with a high attentional load, an effect that was reversed by nicotine; thus, MPEP did not block nicotine-induced attentional enhancement. Co-administration of either CPP or MPEP with nicotine also produced a general slowing of performance characterised by increases in omission errors and response latencies and reduced anticipatory responding. It is concluded that activation of NMDA receptors may be an important determinant of the effects of nicotine in the 5-CSRTT. Stimulation of nicotinic receptors may also reverse attentional deficits associated with the impaired function of the glutamate network.