Differential effects of intra-VTA ghrelin and glucagon-like peptide-1 on
the stimulatory action of amphetamine and cocaine-induced alcohol intake
Abstract
In order to further elucidate the role of mesolimbic peptides in the
expression of alcohol reward, the present study investigated the effects
of ghrelin and glucagon-like peptide-1 (GLP-1) on alcohol intake, in
addition to alcohol intake stimulated by systemic d-amphetamine or
cocaine treatment. All rats were initially habituated to a 6% alcohol
solution. We then demonstrated that intraperitoneal injections of
d-amphetamine and cocaine increased alcohol compared to the vehicle
condition. In subsequent testing we examined the effects of ventral
tegmental area (VTA) ghrelin or vehicle paired with a fixed dose of
d-amphetamine or vehicle. In separate rats we then investigated the
impact of the GLP-1 agonist exendin-4 (Ex-4), injected into the VTA, on
alcohol intake alone, or when Ex-4 was co-administered with
d-amphetamine or cocaine. Our results indicated that VTA ghrelin
significantly increased alcohol intake, and most importantly,
potentiated the effect of d-amphetamine and cocaine on alcohol
consumption. Conversely, VTA Ex-4 inhibited alcohol intake and
antagonized the stimulatory effect of d-amphetamine and cocaine on
alcohol consumption. In a final study we further demonstrated that VTA
Ex-4 treatment significantly inhibited the combined stimulatory effects
of ghrelin paired with d-amphetamine or ghrelin paired with cocaine.
Overall our findings are consistent with a critical role for both
ghrelin and GLP-1 receptor mechanisms in mesolimbic alcohol reward
circuitry. Moreover, our results further suggest that ghrelin and GLP-1
modulate the stimulatory effect of psychostimulants on alcohol intake.