Glutamatergic Synaptic Plasticity in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons and Alcohol Use Disorder

Abstract

The dorsomedial striatum (DMS) of the basal ganglia is critically involved in drug and alcohol abuse and contains medium spiny neurons (MSNs) expressing dopamine D1 receptors (D1Rs) or D2Rs. D1-MSNs positively and D2-MSNs negatively control reward-driven behaviors. However, how different glutamatergic inputs onto distinct MSNs are altered by alcohol and how such alcohol-evoked aberrant plasticity drives reinforcement behaviors remain unclear. Thus, I first examined how excessive alcohol intake alters glutamatergic transmission at striatal synapses expressing distinct presynaptic dopamine receptors in chapter II. Then I investigated the causality between alcohol-evoked plasticity and reinforcement behaviors and whether reversal of this plasticity persistently reduced alcohol-seeking in chapter III. Lastly, I examined the selectivity of extra-striatal afferents in their innervations of D1-MSNs and D2-MSNs in chapter IV. In chapter II, I found larger excitatory postsynaptic currents at the synapses between the extra-striatal D2R-expressing afferents and D1-MSNs (D2-D1), as compared with those observed at the other tested synapses (D1-D1, D1-D2, and D2-D2). I further discovered that excessive alcohol consumption induced a long-lasting potentiation of glutamatergic transmission at the corticostriatal D2-D1 synapse. In chapter III, I found that mimicking alcohol-evoked potentiation at glutamatergic synapse between medial prefrontal cortex (mPFC) and D1-MSNs using in vivo dual-channel optogenetic self-stimulation of this synapse to induce LTP was sufficient to drive reinforcement of lever pressing in rat operant behaviors. Conversely, in vivo LTD induction at this synapse with time locked to lever presses persistently decreased alcohol-seeking behavior. In chapter IV, I discovered that pDMS D1-MSNs preferentially received inputs from orbital frontal cortex, secondary motor and visual cortex, as well as cingulate cortex, whereas D2-MSNs received primary motor, primary sensory, and thalamic inputs. Taken together, my graduate study suggests that 1) chronic alcohol exposure selectively strengthened glutamatergic transmission from cortical inputs, e.g. D2R-expressing inputs or mPFC inputs, onto DMS D1-MSNs. 2) Glutamatergic synaptic plasticity at mPFCD1-MSNs was sufficient to drive the reinforcement behavior and contributed to alcohol-seeking behavior. 3) pDMS D1-MSNs and D2-MSNs received differential innervation from extra-striatal regions. These data will enrich and help specify the understanding of how glutamatergic plasticity at striatal circuits controls alcohol-induced addictive behaviors.