Involvement of Accumbal Glycine Receptors in the Regulation of Voluntary Ethanol Intake in the Rat

The mechanisms of ethanol addiction are not completely understood. The mesolimbic dopaminergic system is involved in many drug-related behaviors, including ethanol self-administration. The dopaminergic neurons in this system originate in the ventral tegmental area (VTA) and are under the control of GABAergic transmission. Our previous in vitro electrophysiological data indicate that glycine receptors (GlyRs) exist on the GABAergic terminals, which make synapses on VTA dopaminergic neurons, and activation of these GlyRs reduces GABAergic transmission and increases the activity of VTA dopaminergic neurons. In the current study, we tested the hypothesis that the activation of the presynaptic GlyRs in the VTA might interfere with ethanol self-administration. Glycine and strychnine, the selective antagonist of GlyRs, were injected, either alone or in combination, into the VTA of rats. Ethanol self-administration by rats was evaluated by using three different drinking models: intermittent access, continuous access, and operant self-administration. We found that the infusion of glycine into the VTA selectively reduced the intake of ethanol but not sucrose or water in rats chronically exposed to ethanol under the intermittent-access and continuous-access procedures and decreased lever-press responding for ethanol under an operant self-administration procedure. The effects of glycine probably were mediated by strychnine-sensitive GlyRs, because the coinjection of glycine and strychnine reduced neither ethanol intake in the home cages nor lever-press responding for ethanol in the operant chambers. Thus, GlyRs in the VTA may play a critical role in ethanol self-administration in animals chronically exposed to ethanol. Therefore, drugs targeting GlyRs may be beneficial for alcoholics.

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Microinjection of Glycine into the Ventral Tegmental Area Selectively Decreases Ethanol Consumption

Li¹,

Nie²,

Bian³

et al. 2012

“…In relevance to alcohol abuse, it is now accepted that GlyRs are a major target for the intoxicating effects of ethanol as suggested by previous studies from our and other groups (Aguayo et al, 1996;Findlay et al, 2002;Molander et al, 2005Molander et al, , 2007. Therefore, the present results are relevant because we show that a small heptadecapeptide can antagonize the alcohol effect on an LGIC, opening new possibilities for the study of small organic molecules that can interfere with the intoxicating effect of ethanol, which supports previous work in relation to the development of compounds that can affect G protein activity (Davis et al, 2005;Bonacci et al, 2006).…”

Section: Discussionmentioning

confidence: 70%

Blockade of Ethanol-Induced Potentiation of Glycine Receptors by a Peptide That Interferes with Gβγ Binding

Guzmán

Moraga-Cid

Ávila³

et al. 2009

The large intracellular loop (IL) of the glycine receptor (GlyR) interacts with various signaling proteins and plays a fundamental role in trafficking and regulation of several receptor properties, including a direct interaction with G␤␥. In the present study, we found that mutation of basic residues in the N-terminal region of the IL reduced the binding of G␤␥ to 21 Ϯ 10% of control. Two basic residues in the C-terminal region, on the other hand, contributed to a smaller extent to G␤␥ binding. Using docking analysis, we found that both basic regions of the IL bind in nearby regions to the G␤␥ dimer, within an area of high density of amino acids having an electronegative character. Thereafter, we generated a 17-amino acid peptide with the N-terminal sequence of the wild-type IL (RQH) that was able to inhibit the in vitro binding of G␤␥ to GlyRs to 57 Ϯ 5% of control in glutathione Stransferase pull-down assays using purified proteins. More interestingly, when the peptide was intracellularly applied to human embryonic kidney 293 cells, it inhibited the G␤␥-mediated modulations of G protein-coupled inwardly rectifying potassium channel by baclofen (24 Ϯ 14% of control) and attenuated the GlyR potentiation by ethanol (51 Ϯ 10% versus 10 Ϯ 3%).

“…For example, bilateral infusions of glycine into the nucleus accumbens increase dopamine release and reduce ethanol drinking and preference, and injections of glycine reuptake inhibitors reduce ethanol intake and preference (Molander et al, 2005(Molander et al, , 2007Lido et al, 2011). Reduction in alcohol intake by injection of glycine appears contradictory to our results, showing that mutations that reduce alcohol potentiation of GlyR function also reduce drinking .…”

Section: Zinc and Ethanol Modulation Of Glycine Receptor Functionmentioning

confidence: 99%

Mutation of a Zinc-Binding Residue in the Glycine Receptor α1 Subunit Changes Ethanol Sensitivity In Vitro and Alcohol Consumption In Vivo

McCracken

Blednov

Trudell

et al. 2012

Ethanol is a widely used drug, yet an understanding of its sites and mechanisms of action remains incomplete. Among the protein targets of ethanol are glycine receptors (GlyRs), which are potentiated by millimolar concentrations of ethanol. In addition, zinc ions also modulate GlyR function, and recent evidence suggests that physiologic concentrations of zinc enhance ethanol potentiation of GlyRs. Here, we first built a homology model of a zinc-bound GlyR using the D80 position as a coordination site for a zinc ion. Next, we investigated in vitro the effects of zinc on ethanol action at recombinant wild-type (WT) and mutant a1 GlyRs containing the D80A substitution, which eliminates zinc potentiation. At D80A GlyRs, the effects of 50 and 200 mM ethanol were reduced as compared with WT receptors. Also, in contrast to what was seen with WT GlyRs, neither adding nor chelating zinc changed the magnitude of ethanol enhancement of mutant D80A receptors. Next, we evaluated the in vivo effects of the D80A substitution by using heterozygous Glra1(D80A) knock-in (KI) mice. The KI mice showed decreased ethanol consumption and preference, and they displayed increased startle responses compared with their WT littermates. Other behavioral tests, including ethanol-induced motor incoordination and strychnine-induced convulsions, revealed no differences between the KI and WT mice. Together, our findings indicate that zinc is critical in determining the effects of ethanol at GlyRs and suggest that zinc binding at the D80 position may be important for mediating some of the behavioral effects of ethanol action at GlyRs.