Hypothalamic peptides controlling alcohol intake: Differential effects on microstructure of drinking bouts

Abstract

Different alcohol drinking patterns, involving either small and frequent drinking bouts or large and long-lasting bouts, are found to differentially affect the risk for developing alcohol-related diseases, suggesting that they have different underlying mechanisms. Such mechanisms may involve orexigenic peptides known to stimulate alcohol intake through their actions in the hypothalamic paraventricular nucleus (PVN). These include orexin (OX), which is expressed in the perifornical lateral hypothalamus, and galanin (GAL) and enkephalin (ENK), which are expressed within as well as outside the PVN. To investigate the possibility that these peptides affect different aspects of consumption, a microstructural analysis of ethanol drinking behavior was performed in male, Sprague-Dawley rats trained to drink 7% ethanol and implanted with guide shafts aimed at the PVN. While housed in specialized cages containing computerized intake monitors (BioDAQ Laboratory Intake Monitoring System, Research Diets Inc., New Brunswick, NJ) that measure bouts of ethanol drinking, these rats were given PVN injections of OX (0.9 nmol), GAL (1.0 nmol), or the ENK analog D-Ala2-met-enkephalinamide (DALA) (14.2 nmol), as compared to saline vehicle. Results revealed clear differences between the effects of these peptides. While all 3 stimulated ethanol intake, they had distinct effects on patterns of drinking, with OX increasing the number of drinking bouts, GAL increasing the size of the drinking bouts, and DALA increasing both the size and duration of the bouts. In contrast, these peptides had little impact on water or food intake. These results support the idea that different peptides can increase ethanol consumption by promoting distinct aspects of the ethanol drinking response. The stimulatory effect of OX on drinking frequency may be related to its neuronally stimulatory properties, while the stimulatory effect of GAL and ENK on bout size and duration may reflect a suppressive effect of these neuronally inhibitory peptides on the satiety-controlling PVN.

Hypothalamic neuropeptide signaling in alcohol addiction

“…Injection of GAL into the PVN of rats has been shown in a variety of paradigms to increase moderate alcohol drinking (bringing blood alcohol levels to 30-60 mg/dl) while a general GAL receptor antagonist decreases it (Chen et al, 2014a; Rada et al, 2004; Schneider et al, 2007). Notably, this stimulatory effect of GAL does not occur with injection in the LH (Schneider et al, 2007), paralleling the finding that hypothalamic GAL increases food intake only when injected into the PVN or adjacent periventricular region (Kyrkouli et al, 1990).…”

“…Peripheral injection of a GalR3 antagonist in alcohol-preferring rats reduces alcohol self-administration, breakpoint on a progressive ratio schedule, and cue-induced reinstatement of alcohol-seeking (Ash et al, 2014; Ash et al, 2011). Recent evidence in our laboratory using an episodic intake monitor has shown that GAL in the PVN acts by increasing the size but not duration of alcohol drinking bouts (Chen et al, 2014a). Thus, rats with elevated endogenous GAL appear to drink more alcohol because they consume it more quickly, similar to how hypothalamic GAL is believed to promote food intake (Koegler et al, 1999).…”

“…These results suggest that endogenously active ENK has opposite effects in the PVN compared to the adjacent LH. Using an episodic intake monitor, our laboratory has shown that, while PVN ENK is similar to GAL in promoting alcohol drinking by increasing the size of alcohol drinking bouts, it differs from GAL in also increasing the duration of those bouts (Chen et al, 2014a), suggesting that rats with endogenously elevated ENK drink alcohol for longer periods of time before they achieve satiety. Once again, this parallels results with food, which show that ENK in the PVN increases food intake by prolonging eating sessions (McLean and Hoebel, 1983).…”

“…Within the hypothalamus, injection of OX-A into the PVN or LH of rats stimulates moderate alcohol drinking (Chen et al, 2014a; Schneider et al, 2007). However, outside the hypothalamus, OX promotes excessive alcohol drinking in the NAc core but not the shell (Brown et al, 2013; Schneider et al, 2007), the ventral tegmental area but not substantia nigra (Srinivasan et al, 2012), and the anterior but not posterior paraventricular thalamus (Barson et al, 2014).…”

“…Tests in our lab using an episodic intake monitor reveal a clear difference between the effect of OX and those of GAL and ENK. Whereas the latter peptides stimulate alcohol drinking by increasing the size and duration of alcohol drinking bouts, OX in the hypothalamus stimulates alcohol drinking by increasing the number of alcohol drinking bouts (Chen et al, 2014a), suggesting that rats with elevated OX initiate more drinking responses. This parallels results with food, which show that OX promotes food intake by increasing meal frequency (Baird et al, 2009).…”