Dopamine Receptors Differentially Control Binge Alcohol Drinking-Mediated Synaptic Plasticity of the Core Nucleus Accumbens Direct and Indirect Pathways

Abstract

Binge alcohol drinking, a behavior characterized by rapid repeated alcohol intake, is most prevalent in young adults and is a risk factor for excessive alcohol consumption and alcohol dependence. Although the alteration of synaptic plasticity is thought to contribute to this behavior, there is currently little evidence that this is the case. We used drinking in the dark (DID) as a model of binge alcohol drinking to assess its effects on spike timing-dependent plasticity (STDP) in medium spiny neurons (MSNs) of the core nucleus accumbens (NAc) by combining patch-clamp recordings with calcium imaging and optogenetics. After 2 weeks of daily alcohol binges, synaptic plasticity was profoundly altered. STDP in MSNs expressing dopamine D1 receptors shifted from spike-timing-dependent long-term depression (tLTD), the predominant form of plasticity in naive male mice, to spike-timing-dependent long-term potentiation (tLTP) in DID mice, an effect that was totally reversed in the presence of 4 μm SCH23390, a dopamine D1 receptor antagonist. In MSNs presumably expressing dopamine D2 receptors, tLTP, the main form of plasticity in naive mice, was inhibited in DID mice. Interestingly, 1 μm sulpiride, a D2 receptor antagonist, restored tLTP. Although we observed no alterations of AMPA and NMDA receptor properties, we found that the AMPA/NMDA ratio increased at cortical and amygdaloid inputs but not at hippocampal inputs. Also, DID effects on STDP were accompanied by lower dendritic calcium transients. These data suggest that the role of dopamine in mediating the effects of binge alcohol drinking on synaptic plasticity of NAc MSNs differs markedly whether these neurons belong to the direct or indirect pathways. We examined the relationship between binge alcohol drinking and spike timing-dependent plasticity in nucleus accumbens (NAc) neurons. We found that repeated drinking bouts modulate differently synaptic plasticity in medium spiny neurons of the accumbens direct and indirect pathways. While timing-dependent long-term depression switches to long-term potentiation (LTP) in the former, timing-dependent LTP is inhibited in the latter. These effects are not accompanied by changes in AMPA and NMDA receptor properties at cortical, amygdaloid, and hippocampal synapses. Interestingly, dopamine D1 and D2 receptor antagonists have opposite effects on plasticity. Our data show that whether core NAc medium spiny neurons belong to the direct or indirect pathways determines the form of spike timing-dependent plasticity (STDP), the manner by which STDP responds to binge alcohol drinking, and its sensitivity to dopamine receptor antagonists.

Examination of the daily drinking patterns and their relationships with alcohol dependence symptoms among adult users in Burkina Faso

“…Neighbors et al concluded that time-speci c calendar events [29] and event-speci c drinking [30] were associated with increased levels of bingeing. However, neurobiological changes may occur with repetitive binge-drinking conditions [31,32], and may increase cravings [33]. Ghiţă et al reported a variability of the levels of alcohol craving in relation to the day of the week, and drinking during weekends in Spain (Friday, Saturday, or Sunday) was associated with greater craving levels in patients with alcohol use disorder [17].…”

DREADD to the Core. Commentary on Purohit et al. (2018): Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

“…The NAc exhibits substantial synaptic alterations after voluntary drinking and passive alcohol vapor exposure. In NAc MSNs of naïve male mice, postsynaptic depolarization paired with low frequency presynaptic stimulation typically leads to long‐term depression (LTD) of excitatory transmission in D1 MSNs and long‐term potentiation (LTP) (Ji et al., ) or no change in excitatory transmission in D2 MSNs (Renteria et al., ). Voluntary binge drinking shifts this plasticity to LTP in D1 MSNs and prevents LTP induction in D2 MSNs (Ji et al., ).…”

“…In NAc MSNs of naïve male mice, postsynaptic depolarization paired with low frequency presynaptic stimulation typically leads to long‐term depression (LTD) of excitatory transmission in D1 MSNs and long‐term potentiation (LTP) (Ji et al., ) or no change in excitatory transmission in D2 MSNs (Renteria et al., ). Voluntary binge drinking shifts this plasticity to LTP in D1 MSNs and prevents LTP induction in D2 MSNs (Ji et al., ). In fact, even after the first drink of alcohol, enhancements in excitatory synaptic transmission in D1 cells are detected (Beckley et al., ).…”

“…As mentioned above, binge drinking and passive alcohol vapor exposure lead to potentiation of excitatory signaling in D1 MSNs and a dampening in D2 MSNs. Interestingly, vapor exposure appears to drive this plasticity specifically in the shell (Renteria et al., , ), while binge drinking can in both shell and core (Beckley et al., ; Ji et al., ). The study by Purohit and colleagues () is consistent with recordings done in core D2 MSNs after binge drinking and suggests that selective targeting of the NAc core (or D2 MSNs specifically) could be beneficial for humans afflicted with AUDs.…”

“…Moreover, alterations in NAc circuit function are thought to underlie certain features of AUDs. Physiologic data demonstrate that alcohol exposure leads to a potentiation of excitatory transmission in D1 MSNs and weakened or unchanged excitatory transmission in D2 MSNs (Beckley et al., ; Ji et al., ; Renteria et al., , ). These data support a role for D1 MSNs in driving and D2 MSNs in inhibiting motivated behavior and suggest that synaptic modifications within NAc subcircuits might underlie escalated drinking behavior after alcohol exposure.…”