Effects of pituitary adenylate cyclase‐activating polypeptide isoforms in nucleus accumbens subregions on ethanol drinking

Abstract

While limited research has implicated the neuropeptide, pituitary adenylate cyclase‐activating polypeptide (PACAP), in problematic alcohol use, the brain regions and isoforms involved in this effect remain to be determined. One region that has been found both to exhibit PACAP binding and, separately, to be involved in ethanol drinking is the nucleus accumbens (NAc). Thus, this study sought to characterize the effect of the PACAP isoforms in the NAc on ethanol drinking under the intermittent‐access two‐bottle‐choice paradigm, in male and female Long–Evans rats. With microinjection into the medial NAc shell, PACAP‐27 but not PACAP‐38 was found to dose‐dependently reduce binge‐like ethanol drinking. In contrast, the PACAP receptor antagonist, PACAP (6‐27), but not PACAP (6‐38), enhanced ethanol drinking. This effect of PACAP was substance specific, as neither isoform in the NAc shell affected binge‐like sucrose drinking. It was also anatomically specific, as PACAP‐38 rather than PACAP‐27 suppressed ethanol drinking when injected into the NAc core, and PACAP‐27 instead enhanced drinking when injected into the caudal third of the medial NAc shell. Finally, while PACAP‐38 in the NAc shell affected stress‐related exploratory behavior, reducing time spent in the light chamber of a light–dark box, PACAP‐27 did not significantly affect behavior in a light–dark box or open field. Together, these results, showing that PACAP‐27 in the NAc shell attenuates binge‐like ethanol drinking without affecting select stress‐related behaviors, suggest that compounds related to this PACAP isoform should be investigated as potential novel therapeutics for the treatment of alcohol use disorder.

Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats

“…As saccharin is not caloric, it is possible that the NAcc Shell shRNA PAC1R knockdown drives animals to increase caloric intake, although this seems unlikely in light of the fact that PACAP effects on hunger are mediated by hypothalamic regions (Resch et al, 2011(Resch et al, , 2014Hurley et al, 2019). Further, it has been previously reported that PACAP administration in the NAcc Shell does not affect sucrose intake (Gargiulo et al, 2021), further supporting the notion that the NAcc PACAP/PAC1R system plays a selective role in the effects of alcohol. Future studies may directly address the question of whether NAcc Shell PAC1R knockdown increases caloric intake.…”

“…PACAP modulates the hypothermic effects of alcohol ( Szabó et al, 1998 ; Tanaka et al, 2004 ), and tolerance to acute ethanol-induced ataxia ( Moore et al, 1998 ). Recent reports provide evidence that PACAP-27 and PACAP-38 administration modulate home cage alcohol drinking ( Gargiulo et al, 2021 ), and that ethanol exposure increases PACAP expression in the paraventricular nucleus of the thalamus ( Gupta et al, 2018 ) and in the bed nucleus of the stria terminalis ( Ferragud et al, 2021 ). In human studies, a single nucleotide polymorphism of the gene coding for PACAP, ADCYAP1, was linked to higher levels of alcohol intake in a Finnish population of social drinkers ( Kovanen et al, 2010 ), and a variant of PAC1R was found to be associated with problematic alcohol use in women ( Dragan et al, 2017 ).…”

Expression and Distribution of Neuropeptide-Expressing Cells Throughout the Rodent Paraventricular Nucleus of the Thalamus

“…In the nucleus accumbens shell, where this PACAP is likely released, injection of PACAP-27 in turn specifically reduces ethanol drinking, while a PACAP receptor antagonist instead increases it (Gargiulo et al, 2020b). These same injections do not affect sucrose drinking or anxiety-like behavior, as measured in a light-dark box and open field (Gargiulo et al, 2020b). These data together suggest that a major role of PACAP in the PVT is the regulation of ethanol drinking via negative feedback.…”

“…Specifically, ethanol drinking in rats leads to a significant increase in levels of PACAP-27 in individual cells across the PVT (Gupta et al, 2018). In the nucleus accumbens shell, where this PACAP is likely released, injection of PACAP-27 in turn specifically reduces ethanol drinking, while a PACAP receptor antagonist instead increases it (Gargiulo et al, 2020b). These same injections do not affect sucrose drinking or anxiety-like behavior, as measured in a light-dark box and open field (Gargiulo et al, 2020b).…”

Presence of Systemic Amyloidosis in Mice with Partial Deficiency in Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Aging

“…The splice variants of the receptor, the different signaling pathways, and the other routes of action are responsible for the very diverse actions of the peptide. Among others, PACAP has been shown to play a role in several physiological processes, such as micturition [6], cardiac excitability [7], control of body weight [8], respiration [9], pain processes [10], cartilage metabolism [11] as well as addiction and stress-related behaviors [12]. PACAP acts as a growth factor and influences the development of the nervous system as well as peripheral organs.…”