Cocaine Dysregulates Dynorphin Modulation of Inhibitory Neurotransmission in the Ventral Pallidum in a Cell-Type-Specific Manner

Abstract

Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, D1-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VP GABA neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VP GABA neurons, dynorphin surprisingly potentiated the inhibitory input on VP vGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VP GABA and VP vGluT2 neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VP GABA and VP vGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine.

Multimodal interrogation of ventral pallidum projections reveals projection-specific signatures and opposite roles in cocaine withdrawal

“…Slice preparation -As described before [14][15][16] . Mice were anesthetized with 150 mg/kg Ketamine-HCl and then decapitated.…”

“…From these lists, top GO terms were selected based off of highest -log10(adjusted-p-value), and top upstream regulators were selected based on the number of predicted targets DEGs. Slice preparation -As described before [14][15][16] . Mice were anesthetized with 150 mg/kg Ketamine-HCl and then decapitated.…”

Metaplasticity in the Ventral Pallidum as a Potential Marker for the Propensity to Gain Weight in Chronic High-Calorie Diet

“…Slice preparation. As described previously (Inbar et al, 2020;. Mice were anesthetized with 150 mg/kg ketamine HCl and then decapitated.…”

The ventral pallidum and relapse in alcohol seeking

“…Finally, although these roles for the VP in stress and aversion have been identified in alcohol and other drug free animals, there is emerging evidence that drug withdrawal profoundly alters neurotransmission in the VP cell types (e.g. vGlut2) essential for aversion processing (Heinsbroek et al, 2020; Inbar et al, 2020).…”