SUMMARY Stress is a well-known risk factor for subsequent alcohol abuse, but the neural mechanisms underlying interactions between stress and alcohol remain largely unknown. Addictive drug reinforcement and stress signaling involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to stress attenuates alcohol-induced dopamine responses and increases alcohol self-administration. The blunted dopamine signaling resulted from ethanol-induced excitation of GABA neurons in the ventral tegmental area. Excitation of GABA neurons was mediated by GABAA receptor activation and involved stress-induced functional down-regulation of the K+, Cl− cotransporter, KCC2. Blocking stress hormone receptors, enhancing KCC2 function, or preventing excitatory GABA signaling by alternative methods all prevented the attenuated alcohol-induced dopamine response and prevented the increased alcohol self-administration. These results demonstrate that stress alters the neural and behavioral responses to alcohol through a neuroendocrine signal that shifts inhibitory GABA transmission towards excitation.
SUMMARY Adolescent smoking is associated with pathological drinking later in life, but the biological basis for this vulnerability is unknown. To examine how adolescent nicotine exposure influences subsequent ethanol intake, nicotine was administered during adolescence or adulthood, and responses to alcohol were measured 1 month later. We found that adolescent, but not adult, nicotine exposure altered GABA signaling within the ventral tegmental area (VTA) and led to a long-lasting enhancement of alcohol self-administration. We detected depolarizing shifts in GABAA reversal potentials arising from impaired chloride extrusion in VTA GABA neurons. Alterations in GABA signaling were dependent on glucocorticoid receptor activation and were associated with attenuated dopaminergic neuron responses to alcohol in the lateral VTA. Importantly, enhancing chloride extrusion in adolescent nicotine-treated animals restored VTA GABA signaling and alcohol self-administration to control levels. Taken together, this work suggests that adolescent nicotine exposure increases the risk profile for increased alcohol drinking in adulthood.
Trafficking and stabilization of AMPA receptors at synapses in response to cocaine exposure is thought to be critical for expression of cocaine addiction and relapse. Glutamate receptor-interacting protein (GRIP) is a neuronal scaffolding protein that stabilizes GluA2 AMPARs at synapses but its role in cocaine addiction has not been examined. The current study demonstrates that conditional deletion of GRIP within the nucleus accumbens potentiates cue-induced reinstatement of cocaine seeking without affecting operant learning, locomotor activity, or reinstatement of natural reward seeking. This is the first study to demonstrate a role for accumbal GRIP in behavior. Electrophysiological recordings revealed increased rectification of AMPAR-mediated currents in the nucleus accumbens and increased AMPAR sensitivity to the GluA2-lacking AMPAR antagonist, 1-naphthylacetyl spermine, indicative of an increased contribution of GluA2-lacking calcium-permeable AMPARs. In addition, accumbal GRIP deletion was associated with blunted long-term depression, similar to what is seen following cocaine self-administration. Taken together, these results indicate that GRIP may modulate addictive phenotypes through its regulation of synaptic AMPARs by controlling their subunit composition and susceptibility to LTD. These effects are associated with changes in vulnerability to cocaine relapse and highlight GRIP as a novel target for the development of cocaine addiction therapeutics.
Emerging evidence indicates that type I metabotropic glutamate receptors (mGluRs) in the nucleus accumbens play a critical role in cocaine seeking. The present study sought to determine the role of accumbens core mGluR1, mGluR5 and protein kinase C (PKC) in cocaine priming-induced reinstatement of drug seeking. Here, we show that intra-accumbens core administration of the mGluR1/5 agonist DHPG (250 μM) promoted cocaine seeking in rats. Consistent with these results, administration of an mGluR1 (50.0 μM YM 298198) or mGluR5 (9.0 μM MPEP) antagonist directly into the accumbens core prior to a priming injection of cocaine (10 mg/kg) attenuated the reinstatement of drug seeking. mGluR1/5 stimulation activates a signaling cascade including PKC. Intracore microinjection of PKC inhibitors (10 μM Ro 31–8220 or 30.0 μM chelerythrine) also blunted cocaine seeking. In addition, cocaine priming-induced reinstatement of drug seeking was associated with increased phosphorylation of PKCγ, but not PKCα or PKCβII, in the core. There were no effects of pharmacological inhibition of mGluR1, mGluR5 or PKC in the accumbens core on sucrose seeking. Together, these findings indicate that mGluR1 and mGluR5 activation in the accumbens core promotes cocaine seeking and that these effects are reinforcer specific. Furthermore, stimulation of mGluR1 and mGluR5 in the accumbens core may regulate cocaine seeking, in part, through activation of PKCγ.
Stress is known to alter GABAergic signaling in the ventral tegmental area (VTA), and this inhibitory plasticity is associated with increased alcohol self-administration. In humans, serotonin 2A receptor (5-HT2AR) agonists can treat stress- and alcohol-related disorders, but the neural substrates are ill-defined. Thus, we reasoned that 5-HT2AR pharmacotherapies may ameliorate the stress-induced dysregulated inhibitory VTA circuitry that contributes to subsequent alcohol abuse. We found that acute stress exposure in mice compromised GABA-mediated inhibition of VTA GABA neurons corresponding with increased ethanol-induced GABAergic transmission. This stress-induced inhibitory plasticity was reversible by applying the 5-HT2AR agonist TCB-2 ex vivo via functional enhancement of the potassium-chloride cotransporter KCC2. The signaling pathway linking 5-HT2AR activation and normalization of KCC2 function was dependent on protein kinase C signaling and phosphorylation of KCC2 at serine 940 (S940), as mutation of S940 to alanine prevented restoration of chloride transport function by TCB-2. Through positive modulation of KCC2, TCB-2 also reduced elevated ethanol-induced GABAergic signaling after stress exposure that has previously been linked to increased ethanol consumption. Collectively, these findings provide mechanistic insights into the therapeutic action of 5-HT2AR agonists at the neuronal and circuit levels of brain reward circuitry.
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