Ethanol Disinhibits Dorsolateral Striatal Medium Spiny Neurons Through Activation of A Presynaptic Delta Opioid Receptor

Abstract

The dorsolateral striatum mediates habit formation, which is expedited by exposure to alcohol. Across species, alcohol exposure disinhibits the DLS by dampening GABAergic transmission onto this structure's principal medium spiny projection neurons (MSNs), providing a potential mechanistic basis for habitual alcohol drinking. However, the molecular and circuit components underlying this disinhibition remain unknown. To examine this, we used a combination of whole-cell patch-clamp recordings and optogenetics to demonstrate that ethanol potently depresses both MSN-and fast-spiking interneuron (FSI)-MSN GABAergic synaptic transmission in the DLS. Concentrating on the powerfully inhibitory FSI-MSN synapse, we further show that acute exposure of ethanol (50 mM) to striatal slices activates delta opioid receptors that reside on FSI axon terminals and negatively couple to adenylyl cyclase to induce a long-term depression of GABA release onto both direct and indirect pathway MSNs. These findings elucidate a mechanism through which ethanol may globally disinhibit the DLS.

Critical Role for Gi/o-Protein Activity in the Dorsal Striatum in the Reduction of Voluntary Alcohol Intake in C57Bl/6 Mice

“…Furthermore, blockade of dorsal striatal G s -coupled dopamine D 1 receptors (but not blockade of G i/o -coupled dopamine D 2 ) attenuates alcohol consumption ( 8 ), suggesting indeed that inhibition of cAMP production in the dorsal striatum may contribute to reduced alcohol use. In the dorsal striatum, alcohol can induce LTD of fast spiking interneuron-medium spiny neuron synapses via a mechanism involving DORs, as this LTD was blocked by a DOR antagonist and the effect was mimicked when using the DOR agonist DPDPE ( 24 ). Moreover, the effects of DPDPE can also be blocked by activating adenylyl cyclases with forskolin ( 24 ).…”

“…In the dorsal striatum, alcohol can induce LTD of fast spiking interneuron-medium spiny neuron synapses via a mechanism involving DORs, as this LTD was blocked by a DOR antagonist and the effect was mimicked when using the DOR agonist DPDPE ( 24 ). Moreover, the effects of DPDPE can also be blocked by activating adenylyl cyclases with forskolin ( 24 ). In our hands, we find that DPDPE is relatively unbiased and thus also efficiently recruits β-arrestin ( 28 ).…”

“…Moreover, DORs are heavily expressed in the dorsal striatum presynaptically on corticostriatal glutamatergic inputs ( 19 ), both pre- and postsynaptically on interneurons within this brain region, and enriched on D 2 receptor-expressing MSNs (as compared with D 1 receptor-expressing MSNs) ( 20 – 22 ). Furthermore, direct activation ( 23 ) or indirect activation of DORs via alcohol-induced release of endogenous enkephalins ( 24 ) in the dorsal striatum induces long-term depression (LTD).…”

Persistent effects of obesity: a neuroplasticity hypothesis

“…Alcohol-induced LTD between fast-spiking interneurons and MSNs in the dorsolateral striatum is dependent on ␦-opioid receptors and was attenuated in the presence of the antagonist naloxone. 172 -Opioid receptor antagonists reversed the effects of stress on LTP of ␥ -aminobutyric acid (GABA)-ergic synapses in the VTA and prevented reinstatement of cocaine seeking. 173 Finally, stress-induced changes in hippocampal metaplasticity were prevented by administration of a -opioid receptor antagonist.…”

Titrating Tipsy Targets: The Neurobiology of Low-Dose Alcohol

“…Studies have shown that low concentrations of alcohol modulate synaptic activity in several brain regions, including the NAc [29], the central nucleus of the amygdala (CeA) [30], the lateral habenula (LHB) [31], the dorsal striatum [32], and the cerebellum [33]. For example, 5 mM alcohol inhibits spike-timing dependent long-term potentiation (tLTP) in the NAc of mouse brain slices [29].…”