Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice

Abstract

Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use. The G-protein coupled receptor 39 (GPR39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. GPR39 encodes a Zn 2+-binding metabotropic receptor known to modulate excitatory and inhibitory neurotransmission, the balance of which is altered in AUD. These prior findings suggest that a GPR39 agonist would reduce alcohol intake. Using a drinking-in-the-dark two bottle choice (DID-2BC) model, we showed that an acute 7.5 mg/kg dose of the GPR39 agonist, TC-G 1008, reduced ethanol intake in mice without affecting total fluid intake, locomotor activity or saccharin preference. Furthermore, repeated doses of the agonist prevented ethanol escalation in an intermittent access 2BC paradigm (IA-2BC). This effect was reversible, as ethanol escalation followed agonist "wash out". As observed during the DID-2BC study, a subsequent acute agonist challenge during the IA-2BC procedure reduced ethanol intake by~47%. Finally, Gpr39 activation was associated with changes in Gpr39 and Bdnf expression, and in glutamate release in the NAcc. Together, our findings suggest that GPR39 is a promising target for the development of prevention and treatment therapies for AUD.

Zinc-mediated Neurotransmission in Alzheimer's Disease: A Potential Role of the GPR39 in Dementia

“…Our own GPR39 protein expression studies using rodent depression models corroborate the existence and the functional importance of the receptor in the murine hippocampus [73,74]. Recent findings from another group showed alterations of GPR39 protein levels in the mouse nucleus accumbens to be linked to alcohol consumption [75]. Therefore, it is highly probable that the GPR39 receptor participates in neurotransmission in at least three subcortical structures responsible for mood, memory and decisionmaking.…”

The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target

“…Later, it has been shown to activate all GPR39 inducible pathways [ 35 ]. Since its discovery, TC-G 1008 has proven to be a potent agonist and a very valuable tool in characterizing the physiological functions and therapeutic potential of GPR39 activation, published by a number of studies to date [ 30 , 31 , 32 , 35 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. However, most studies have not verified their findings in GPR39 −/− settings, which would be critical in order to confirm that the observed effects are indeed GPR39-dependent.…”

“…Intriguingly, recently GPR39 agonists were studied for the treatment of alcohol use disorder [ 61 ]. GPR39 was found to be hypermethylated and downregulated after chronic alcohol use in non-human primates, rhesus macaques.…”

“…An acute dose of TC-G 1008 reduced the ethanol preference and ethanol intake of mice drastically, and repeated doses lowered their ethanol escalation in an intermittent ethanol access model. TC-G 1008 increased excitatory neutrotransmission and Gpr39 and Bdnf expression in the nucleus accumbens core, heavily affected by ethanol intake [ 61 ]. These results suggest that further studies about TC-G 1008 in addiction disorders would be of importance and indicate GPR39 agonism to be a plausible therapeutic approach for the treatment of alcohol use disorder.…”

G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment

“…Oral administration of a GPR39 agonist, TC-G1008, inhibited liver injury marker glutamic-pyruvic transaminase expression and reduced hepatic cell necrosis in concanavalin A-induced hepatitis liver in mice[ 93 ]. Another study showed that an acute dose of TC-G1008 reduced ethanol intake in mice without affecting total fluid intake[ 94 ]. GPR40 deficiency was associated with hepatic inflammation and steatosis in low-fat diet-fed mice[ 95 ].…”