Abstract
Excessive alcohol consumption is a known risk factor for stroke, but the effect of stroke on alcohol intake is unknown. The dorsomedial striatum (DMS) and midbrain areas of the nigrostriatal circuit are critically associated to stroke and alcohol addiction. Here we sought to explore the influence of stroke on alcohol consumption and to uncover the underlying nigrostriatal mechanism. Rats were trained to consume alcohol using a two-bottle choice or operant self-administration procedure. Retrograde beads were infused into the DMS or midbrain to label specific neuronal types, and ischemic stroke was induced in the dorsolateral striatum (DLS). Slice electrophysiology was employed to measure excitability and synaptic transmission in DMS and midbrain neurons. We found that ischemic stroke-induced DLS infarction produced significant increases in alcohol preference, operant self-administration, and relapse. These increases were accompanied by enhanced excitability of DMS and midbrain neurons. In addition, glutamatergic inputs onto DMS D1-neurons was potentiated, whereas GABAergic inputs onto DMS-projecting midbrain dopaminergic neurons was suppressed. Importantly, systemic inhibition of dopamine D1 receptors attenuated the stroke-induced increase in operant alcohol self-administration. Our results suggest that the stroke-induced DLS infarction evoked abnormal plasticity in nigrostriatal dopaminergic neurons and DMS D1-neurons, contributing to increased post-stroke alcohol-seeking and relapse.
Highlights
Stroke is a major cause of death and adult disability[1]
We found that the amplitudes of AMPA receptor (AMPAR)-mediated miniature excitatory postsynaptic currents were increased in D1-medium spiny neurons (MSNs) on the ischemic side on post-stroke day 5 (Figs 4c and 4e left; t(26) = −2.24, p = 0.030), but not day 30 (Figs 4d and 4e right; t(22) = 1.54, p = 0.14), as compared to the non-ischemic side
We found a significant effect of stroke as early as day 5, in that the spontaneous firing rates in dorsomedial striatum (DMS)-projecting dopaminergic substantia nigra pars compacta (SNc) neurons were higher in the ipsilesional midbrain than in the equivalent contralesional region (Fig. 6b left; t(18) = −2.19, p = 0.042), which was still observed on day 30 (Fig. 6b right; Mann-Whitney U = 14.00, p = 0.0015)
Summary
Stroke is a major cause of death and adult disability[1]. In ischemic stroke, a lack of blood flow to the brain results in the damage of neurons and their connected neural circuits, leading to behavioral impairments[2]. These results suggest that ischemic stroke increases neuronal excitability without changing the resting membrane potential of DMS neurons in alcohol-drinking animals.
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