Convergence of Reinforcing and Anhedonic Cocaine Effects in the Ventral Pallidum

Abstract

Addiction is a disorder of behavioral symptoms including enhanced incentive salience of drug-associated cues, but also a negative affective state. Cocaine-evoked synaptic plasticity in the reward system, particularly the nucleus accumbens (NAc), drives drug-adaptive behavior. However, how information is integrated downstream of the NAc remains unclear. Here, we identify the ventral pallidum (VP) as a site of convergence of medium spiny neurons expressing dopamine (DA) receptor type 1 (D1-MSNs) and type 2 (D2-MSNs) of the NAc. Repeated in vivo cocaine exposure potentiated output of D1-MSNs, but weakened output of D2-MSNs, occluding LTP and LTD at these synapses, respectively. Selectively restoring basal transmission at D1-MSN-to-VP synapses abolished locomotor sensitization, whereas restoring transmission at D2-MSN-to-VP synapses normalized motivational deficits. Our results support a model by which drug-evoked synaptic plasticity in the VP mediates opposing behavioral symptoms; targeting the VP may provide novel therapeutic strategies for addictive disorders.

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine

“…Strengthening of excitatory synapses in MSNs in the NAc involves the initial formation of silent synapses lacking AMPA receptors during chronic exposure to cocaine, followed by insertion of AMPA receptors into spines during withdrawal (9)(10)(11). Accumulating evidence indicates that adaptive cocaine action involves potentiation of glutamatergic afferents arising from mPFC, amygdala, and ventral hippocampus preferentially onto D1-MSNs (41-44), although D2-MSNs still contribute to certain behavioral features of cocaine action (45,46). Previous studies showed that WAVE1 is highly localized to dendritic spines (47).…”

The Ventral Pallidum: Proposed Integrator of Positive and Negative Factors in Cocaine Abuse

“…Because this subdivision of VP is predominantly innervated by the shell component of the NAc (distinct from the NAc core to dVP projections in Kupchik et al, 2015), Creed et al (2016) first confirmed that vmVP is innervated by both D1- and D2-MSNs. Retrograde tracer cholera toxin B (CTb) was injected into the vmVP of transgenic mice that expressed a reporter protein in either D1- or D2-MSNs.…”

“…This potentially places the VP in a strategic anatomical position to integrate D1- and D2-MSN activity and relay this information to key motivational circuits. In this issue of Neuron , Creed et al (2016) suggest that the VP may be a site of convergence for drug-evoked synaptic changes that contribute to both positive and negative symptoms following cocaine experience.…”

“… In this issue of Neuron , Creed et al (2016) describe how cocaine produces divergent forms of plasticity at synapses between specific neurons in nucleus accumbens and ventral pallidum, and how these changes are associated with positive and negative reward behaviors. …”

“…In their paper, Creed et al (2016) focus on the ventromedial subdivision of the VP (vmVP), as this subregion sends projections to the ventral tegmental area (VTA)—a pathway recently shown to be important for drug-seeking behavior (Mahler et al, 2014). Because this subdivision of VP is predominantly innervated by the shell component of the NAc (distinct from the NAc core to dVP projections in Kupchik et al, 2015), Creed et al (2016) first confirmed that vmVP is innervated by both D1- and D2-MSNs.…”