Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction.

Positive social interaction could play an essential role in switching the preference of the substance dependent individual away from drug related activities. We have previously shown that conditioned place preference (CPP) for cocaine at the dose of 15 mg/kg and CPP for four 15-min episodes of social interaction were equally strong when rats were concurrently conditioned for place preference by pairing cocaine with one compartment and social interaction with the other. The aim of the present study was to investigate the differential activation of brain regions related to the reward circuitry after acquisition/expression of cocaine CPP or social interaction CPP. Our findings indicate that cocaine CPP and social interaction CPP activated almost the same brain regions. However, the granular insular cortex and the dorsal part of the agranular insular cortex were more activated after cocaine CPP, whereas the prelimbic cortex and the core subregion of the nucleus accumbens were more activated after social interaction CPP. These results suggest that the insular cortex appears to be potently activated after drug conditioning learning while activation of the prelimbic cortex-nucleus accumbens core projection seems to be preferentially involved in the conditioning to non-drug stimuli such as social interaction.

Preventive role of social interaction for cocaine conditioned place preference: correlation with FosB/DeltaFosB and pCREB expression in rat mesocorticolimbic areas.

The worsening of drug abuse by drug-associated social interaction is a well-studied phenomenon. In contrast, the molecular mechanisms of the beneficial effect of social interaction, if offered as a mutually exclusive choice to drugs of abuse, are under-investigated. In a rat place preference conditioning (CPP) paradigm, four 15 min episodes of social interaction with a gender- and weight-matched male early-adult conspecific inhibited cocaine-induced reinstatement of cocaine CPP, a model of relapse. These protective effects of social interaction were paralleled by a reduced activation, as assessed by Zif268 expression, in brain areas known to play pivotal roles in drug-seeking behavior. Here we show that social interaction during extinction of cocaine CPP also reduced cocaine-CPP-stimulated FosB expression in the nucleus accumbens shell and core. In addition, social interaction during cocaine CPP extinction increased pCREB (cAMP response element binding protein) expression in the nucleus accumbens shell and the cingulate cortex area 1 (Cg1). Our results show that FosB and pCREB may be implicated in the protective effect of social interaction against cocaine-induced reinstatement of CPP. Thus, social interaction, if offered in a context that is clearly distinct from the previously drug-associated one, may profoundly inhibit relapse to cocaine addiction.

Differential effects of accumbens core vs. shell lesions in a rat concurrent conditioned place preference paradigm for cocaine vs. social interaction.

BACKGROUND: A main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. Among these activities, social interaction is doubly important because treatment adherence itself depends on it. We previously developed a rat experimental model based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male conspecific (i) reversed CPP from cocaine to social interaction despite continuing cocaine training and (ii) prevented the reinstatement of cocaine CPP. In the present study, we investigated if the two subregions of the nucleus accumbens (Acb), i.e., the core (AcbC) and the shell (AcbSh), would differentially affect CPP for cocaine vs social interaction. METHODOLOGY/PRINCIPAL FINDINGS: Animals were concurrently trained for CPP pairing cocaine with one compartment and social interaction with the other (i.e., mutually exclusive stimulus presentation during training). Excitotoxic lesioning of the AcbC or the BLA shifted CPP toward social interaction, whereas AcbSh inactivation shifted CPP toward cocaine. CONCLUSIONS: Overall, our findings suggest that inactivation of the AcbC or the BLA is sufficient to shift CPP away from a drug of abuse toward social interaction. Lesioning the AcbSh produced the opposite effect.

Reversal of cocaine-conditioned place preference and mesocorticolimbic Zif268 expression by social interaction in rats.

Little is known how social interaction, if offered as an alternative to drug consumption, affects neural circuits involved in drug reinforcement and substance dependence. Conditioned place preference (CPP) for cocaine (15 mg/kg i.p.) or social interaction (15 minutes) as an alternative stimulus was investigated in male Sprague-Dawley rats. Four social interaction episodes with a male adult conspecific completely reversed cocaine CPP and were even able to prevent reacquisition of cocaine CPP. Social interaction also reversed cocaine CPP-induced expression of the immediate-early gene zif268 in the nucleus accumbens shell, the central and basolateral amygdala and the ventral tegmental area. These findings suggest that social interaction, if offered in a context that is clearly distinct from the previously drug-associated ones, may profoundly decrease the incentive salience of drug-associated contextual stimuli. The novel experimental design facilitates the neurobiological investigation of this phenomenon which may be beneficial for human drug users in treatment.

Sigma1 receptor antagonist BD1047 enhances reversal of conditioned place preference from cocaine to social interaction.

We have previously shown that only four 15-min social interaction episodes with a male adult conspecific reversed cocaine conditioned place preference (CPP) even despite continuing CPP training with cocaine. In the present study, we investigated if BD1047, a sigma1 receptor antagonist that has been shown to inhibit the expression of cocaine CPP, is able to enhance this effect. BD1047, given as a 10-min pretreatment, dose-dependently (ED50 of 0.0036 mg/kg i.p.) decreased the time spent in the previously cocaine-associated compartment in favour of the time spent in the compartment in which a single social interaction had taken place. Our findings indicate that sigma1 blockade may be used therapeutically to enhance treatment adherence in social interaction-based rehabilitation programs.

Conditioned place preference for social interaction in rats: contribution of sensory components.

A main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. We previously developed a rat experimental model based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male Sprague Dawley rat (1) reversed CPP from cocaine to social interaction despite continuing cocaine training and (2) prevented the reinstatement of cocaine CPP. In the present study, we investigated which of the sensory modalities of the composite stimulus "social interaction" contributes most to the rats' preference for it. If touch was limited by steel bars spaced at a distance of 2 cm and running across the whole length of a partitioning, CPP was still acquired, albeit to a lesser degree. If both rats were placed on the same side of a partitioning, rats did not develop CPP for social interaction. Thus, decreasing the available area for social interaction from 750 to 375 cm(2) prevented the acquisition of CPP to social interaction despite the fact that animals could touch each other more intensely than through the bars of the partitioning. When touch was fully restricted by a glass screen dividing the conditioning chambers, and the only sensory modalities left were visual and olfactory cues, place preference shifted to place aversion. Overall, our findings indicate that the major rewarding sensory component of the composite stimulus "social interaction" is touch (taction).