Effects of cocaine history on postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats

Abstract

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Stressors and stress hormones can inhibit the dorsal raphe nucleus (DRN)-5-HT system, which composes the majority of forebrain-projecting 5-HT. This inhibition is mediated via stimulation of GABA synaptic activity at DRN-5-HT neurons. Using swim stress-induced reinstatement of morphine conditioned place-preference, recent data from our laboratory indicate that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. Moreover, GABAA receptor-mediated inhibition of the serotonergic DRN is required for this reinstatement. In our current experiment, we tested the hypothesis that GABAergic sensitization of DRN-5-HT neurons is a neuroadaptation elicited by multiple classes of abused drugs across multiple models of stress-induced relapse by applying a chemical stressor (yohimbine) to induce reinstatement of previously extinguished cocaine self-administration in Sprague-Dawley rats. Whole-cell patch-clamp recordings of GABA synaptic activity in DRN-5-HT neurons were conducted after the reinstatement. Behavioral data indicate that yohimbine triggered reinstatement of cocaine self-administration. Electrophysiology data indicate that 5-HT neurons in the cocaine group exposed to yohimbine had increased amplitude of inhibitory postsynaptic currents compared to yoked-saline controls exposed to yohimbine or unstressed animals in both drug groups. These data, together with previous findings, indicate that interaction between psychostimulant or opioid history and chemical or physical stressors may increase postsynaptic GABA receptor density and/or sensitivity in DRN-5-HT neurons. Such mechanisms may result in serotonergic hypofunction and consequent dysphoric mood states which confer vulnerability to stress-induced drug reinstatement.

Inactivation of GIRK channels weakens the pre‐ and postsynaptic inhibitory activity in dorsal raphe neurons

“…; Araki et al. ; Li and Kirby ). In addition, the manipulation of 5‐HT 1A autoreceptors in the DR affects 5‐HT neuronal firing, determines the responsiveness to stress in depression‐related tasks and alters behavioral responses to antidepressant drugs in mice (Richardson‐Jones et al.…”

“…Recently, emerging evidence has shown that GABA A and GABA B receptor-mediated neurotransmissions of the DR are highly involved in drug-related stress, aggression, social avoidance, abnormal responses to social stimulation, and stress-related psychiatric disorders, such as depression (Takahashi et al 2010(Takahashi et al , 2012Challis et al 2013;Araki et al 2016;Li and Kirby 2016). In addition, the manipulation of 5-HT 1A autoreceptors in the DR affects 5-HT neuronal firing, determines the responsiveness to stress in depressionrelated tasks and alters behavioral responses to antidepressant drugs in mice (Richardson-Jones et al 2010).…”

Role of α1-GABAA receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

“…Electrophysiology. To verify the knockout of the α1-GABA A subunit and test the changes in GABA A receptors, animals were euthanized, and brain slices were prepared for electrophysiology as described previously (Kirby et al, 2008;Li and Kirby, 2016). Mice were euthanized by rapid decapitation and brains were placed into ice-cold artificial cerebrospinal fluid (ACSF) in which sucrose (248 mM) was substituted for NaCl.…”