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Abstract: Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) has a role in synaptic plasticity, and evidence suggests its role in a range of effects produced by alcohol in the central nervous system. The aim of the current study was to investigate the role of the nNOS gene in the development of ethanol-induced conditioned place preference (CPP) in mice. The CPP paradigm is designed to investigate the reinforcing properties of drugs of abuse and the development of maladaptive behaviors, such as conditioned response to drug-associated stimuli, after repeated drug exposure. Adult male and female wild type (WT) and nNOS knockout (KO) mice on a mixed B6;129S genetic background were trained by a morning saline session and afternoon ethanol (1, 2, and 3g/kg; intraperitoneally) session for 4 days. Place preference in a drug-free state was recorded on the following day. Results show that WT males and females developed robust CPP, whereas nNOS KO mice did not (with the exception of female nNOS KO mice conditioned by 2g/kg ethanol). The differential response of WT and nNOS KO mice was not due to genotypic differences in motor behavior. To investigate if the absence of the nNOS gene causes specific impairment in processing the motivational effect of ethanol or an overall impairment in associative learning, WT and nNOS KO mice were trained by LiCl (150mg/kg) which causes conditioned place aversion (CPA). Results show that both WT and nNOS KO mice developed significant CPA. The findings that the absence of the nNOS gene impaired ethanol-induced CPP but not LiCl-induced CPA suggest that NO signaling has a specific role in processing the motivational effect of ethanol. Hence, inhibition of nNOS may attenuate the development of maladaptive behaviors associated with alcohol exposure. [Copyright &y& Elsevier]

Background: The rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood. Methodology/Principal Findings: In this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increased the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, and a priming dose of 5 mg/kg reinstated the extinguished preference. The higher doses of Haloperidol, Raclopride and CGS 10746B and both doses of SCH 23390 blocked acquisition of the MDMA-induced CPP. However, only Haloperidol blocked expression of the CPP. Reinstatement of the extinguished preference was not affected by any of the drugs studied. Analysis of brain monoamines revealed that the blockade of CPP acquisition was accompanied by an increase in DA concentration in the striatum, with a concomitant decrease in DOPAC and HVA levels. Administration of haloperidol during the Post-C test produced increases in striatal serotonin, DOPAC and HVA concentrations. In mice treated with the higher doses of haloperidol and CGS an increase in SERT concentration in the striatum was detected during acquisition of the CPP, but no changes in DAT were observed. Conclusions/Significance: These results demonstrate that, in adolescent mice, the dopaminergic system is involved in the acquisition and expression of MDMA-induced CPP, but not in its reinstatement. [ABSTRACT FROM AUTHOR]

The conditioned place preference (CPP) paradigm entails appetitive learning and is utilized to investigate the motivational effects of drug and natural reward in rodents. However, a typical CPP design does not allow dissociation between cue- and context-dependent appetitive learning. In humans, context and cues that had been associated with drug reward can elicit conditioned response and drug craving. Therefore, we investigated (a) methods by which to discriminate between cue- and context-dependent appetitive learning, and (b) the role of the neuronal nitric oxide synthase (nNOS) gene in appetitive learning. Wild-type (WT) and nNOS knockout (KO) mice were trained by cocaine (20 mg/kg) in a discrete context paired with a light cue (a compound context-cue stimulus). In test 1, approach behaviour to either the training context or to the cue in a novel context was determined. WT mice showed robust preference for both cocaine-associated context and cue. nNOS KO mice acquired approach behaviour for the cocaineassociated context but not cue. This finding suggests that the nNOS gene is required for cue-dependent appetitive learning. On the following day (test 2), mice were tested for approach behaviour to the compound context-cue stimulus. Context but not cue exposure in test 1 reduced approach behaviour to the compound context-cue stimulus in test 2, suggesting that repeated context but not cue exposures diminished the conditioned response. Hence, this modified CPP paradigm is useful for the investigation of approach behaviour for both drug-associated context and cue, and allows further investigation of mechanisms underlying cue- and context-dependent appetitive learning. [ABSTRACT FROM AUTHOR]