Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor variants in the transition to ethanol dependence

Joseph Robert Mazzerina

doi:10.17918/00010933

Background: Alcohol use disorder (AUD) impacts millions worldwide and leads to financial, social, and health consequences. Although many models for the motivation to consume alcohol exist, one commonly accepted model, the "dark side of addiction" hypothesis, posits that alcohol (or drug) consumption in the non-dependent state occurs because of pleasurable and hedonic experiences, but alcohol consumption in the dependent state instead occurs to avoid the negative affective experiences that result from abstinence. The nucleus accumbens (NAc) mediates motivation, including the negative affective stages of dependence. One neuropeptide that may also mediate ethanol drinking and dependence is pituitary adenylate cyclase-activating polypeptide (PACAP). Injection of PACAP in the NAc of binge-drinking rats has previously been shown to attenuate ethanol consumption in the non-dependent state. Importantly, the main receptor for PACAP, the PAC1 receptor, has two specific splice variants in the mouse, hop and short (also called null). The hypothesis of this study was that ethanol dependence would upregulate expression of the PAC1 hop receptor in the NAc, and that knockdown of the hop receptor variant in ethanol-dependent mice would result in decreased ethanol drinking. Methods: Adult, male and female C57BL/6J mice were placed on an intermittent-access two-bottle-choice paradigm for four weeks to induce binge-like drinking and then exposed to chronic intermittent ethanol (CIE) vapor or air vapor for another four weeks, to induce dependence or maintain non-dependence. After this, animals were sacrificed for examination of the PAC1 receptor variants using quantitative real-time PCR. In a second group of male and female mice that were left ethanol-naïve, a novel PAC1 hop receptor siRNA was tested for its ability to knock down expression of the hop receptor. Finally, in a third group of mice that was cannulated in the NAc and given access to ethanol drinking and then CIE or air, injections of the siRNA were made into the NAc and subsequent ethanol consumption was measured. Results: Females had higher preference and consumption for ethanol than males. After exposure to CIE, male mice had higher expression of the PAC1 hop receptor, but female mice had a small increase in expression of the PAC1 short receptor. We identified a concentration of our novel hop siRNA that effectively knocked down expression of the PAC1 hop receptor variant in the NAc. Testing of its effects on ethanol drinking are ongoing, but preliminary results indicate that it normalizes the elevated ethanol drinking of mice after CIE exposure. Conclusions: Our findings reveal that the PAC1 hop receptor may be a specific variant within the PACAP system that drives increases in ethanol consumption and, in more general terms, contributes to the transition to ethanol dependence by its upregulation in the ethanol-dependent state, which was not found in the non-dependent state. Upregulation of short receptors in ethanol-dependent females and upregulation of hop receptors in ethanol-dependent males may indicate that the PAC1 receptor variant expression is sex-regulated in response to ethanol. Ultimately, this research can provide a potential pharmacological target for treating AUD by addressing a neuropeptide system that has been implicated in the addictive process.

Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor variants in the transition to ethanol dependence

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Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor variants in the transition to ethanol dependence

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