Projection-specific potentiation of ventral pallidal glutamatergic outputs after abstinence from cocaine

Abstract

The ventral pallidum (VP) is a central node in the reward system strongly implicated in reward and addiction. While the majority of VP neurons is GABAergic and encodes reward, recent studies revealed a novel glutamatergic neuronal population in the VP (VP_vGluT2), whose activation generates aversion. Withdrawal from drugs has been shown to induce drastic synaptic changes in neuronal populations associated with reward, such as the ventral tegmental area (VTA) or nucleus accumbens neurons, but less is known about cocaine-induced synaptic changes in neurons classically linked with aversion. Here we demonstrate that VP_vGluT2 neurons contact different targets with different intensities and that cocaine conditioned-place preference (CPP) training followed by abstinence selectively potentiates their synapses on targets that encode aversion. Using whole-cell patch clamp recordings combined with optogenetics in male and female transgenic mice we show that VP_vGluT2 neurons preferentially contact aversion-related neurons, such as lateral habenula neurons and VTA GABAergic neurons, with minor input to reward-related neurons like VTA dopamine and VP GABA neurons. Moreover, after cocaine CPP and abstinence the VP_vGluT2 input to the aversion-related structures is potentiated while the input to the reward-related structures is depressed. Thus, cocaine CPP followed by abstinence may allow VP_vGluT2 neurons to recruit aversion-related targets more readily and therefore be part of the mechanism underlying the aversive symptoms seen after withdrawal.

Significance statement

The biggest problem in drug addiction is the high propensity to relapse. One central driver for relapse events is the negative aversive symptoms experienced by addicts during withdrawal. In this work we propose a possible mechanism for the intensification of aversive feelings after withdrawal that involves the glutamatergic neurons of the ventral pallidum. We show that not only these neurons are most strongly connected to aversive targets such as the lateral habenula, but that after abstinence their synapses on aversive targets are strengthened while the synapses on other, rewarding, targets are weakened. These data illustrate how after abstinence from cocaine aversive pathways change in a manner that may contribute to relapse.