Bi-directional effects of GABAB receptor agonists on the mesolimbic dopamine system

Abstract

The rewarding effect of drugs of abuse is mediated by activation of the mesolimbic dopamine system, which is inhibited by putative anti-craving compounds. Interestingly, different GABA(B) receptor agonists can exert similarly opposing effects on the reward pathway, but the cellular mechanisms involved are unknown. Here we found that the coupling efficacy (EC(50)) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABA(B) receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits. Consequently, in rodent VTA slices, a low concentration of the canonical agonist baclofen caused increased activity, whereas higher doses eventually inhibited dopamine neurons. At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse gamma-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons. Thus GABA(B) receptor agonists exert parallel cellular and behavioral effects due to the cell-specific expression of GIRK subunits.

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

“…The direct inhibitory influence of GABA B R and D 2 R activation on VTA DA neurons is mediated primarily by activation of G protein-gated inwardly rectifying K + (GIRK/ Kir3) channels found in the somatodendritic compartment (Beckstead et al, 2004;Cruz et al, 2004). Although GIRK1/ GIRK2 heterotetramers are considered to be the prototypical neuronal GIRK channel (Lujan et al, 2014), VTA DA neurons express a GIRK2/GIRK3 heteromer (Cruz et al, 2004).…”

“…Although GIRK1/ GIRK2 heterotetramers are considered to be the prototypical neuronal GIRK channel (Lujan et al, 2014), VTA DA neurons express a GIRK2/GIRK3 heteromer (Cruz et al, 2004). Girk2 ablation eliminates all GIRK channel activity in VTA DA neurons (Beckstead et al, 2004;Cruz et al, 2004).…”

Baclofen Toxicity Causing Acute, Reversible Dyskinesia

“…Baclofen is a gamma-amino butyric acid (GABA) derivative that acts as an agonist at the GABA B receptor inducing presynaptic motor neuron inhibition and a central antispastic response [1]. While baclofen has been used primarily to limit spasticity in spinal cord disorders, it also has been studied as an inhibitor of dopamine reward pathways to treat drug abuse [2]. Baclofen is lipophilic, readily crosses the blood-brain barrier, has an elimination half-life of approximately 2 to 6 hours, and primarily is cleared via renal excretion [1].…”

“…It has been postulated that the relative dopaminergic hypofunction produced by DBAs causes overactivity of cholinergic mechanisms [3]. With respect to GABA receptors, rodent models have shown that GABA B receptors are expressed on both dopamine neurons, as well as GABA neurons [2]. In rats exposed to baclofen, it was shown that activation of GABA B receptors inhibited both GABAergic and dopaminergic neurons, and decreased dopamine release [2].…”

“…With respect to GABA receptors, rodent models have shown that GABA B receptors are expressed on both dopamine neurons, as well as GABA neurons [2]. In rats exposed to baclofen, it was shown that activation of GABA B receptors inhibited both GABAergic and dopaminergic neurons, and decreased dopamine release [2]. Furthermore, there have been reports of baclofen neurotoxicity in patients with pre-existing cerebral lesions, which may affect receptor activity and function [1].…”