Abstract
Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.
Highlights
Alcohol use disorder (AUD) is a chronic, relapsing disorder that affects over 14 million adults in the US (Substance Abuse and Mental Health Services Administration (SAMHSA), 2019), and is estimated to be responsible for 5.3% of global deaths (Shield et al, 2020)
nucleus accumbens (NAcc) Shell AAVPAC1R KD rats drank significantly less water than associated viruses (AAV)-CTRL rats across sessions [Figure 2C, Group: F(1, 14) = 6.25, p ≤ 0.05, Group∗Session: F(13, 182) = 0.48, n.s.], and cumulatively [Figure 2D, t(14) = 2.500, p ≤ 0.05]. This decreased water drinking did not compensate for the high levels of ethanol intake by NAcc Shell PAC1R short-hairpin RNA (shRNA) knockdown rats in terms of total fluid intake, which was, increased compared to controls [Group: F(1, 14) = 9.54, p ≤ 0.001, Group∗Session: F(13, 182) = 0.85, n.s., data not shown]
The main findings of this study were that NAcc Shell PAC1R knockdown via an AAV-shRNA led to: (1) higher self-administration of, and preference for, alcohol; (2) increased motivation to drink alcohol; (3) no significant change in self-administration of the alternative reinforcer saccharin; and (4) a decrease in PAC1R+ cells as well as in virally infected cells expressing PAC1R in the NAcc Shell, as compared to a control virus infusion
Summary
Alcohol use disorder (AUD) is a chronic, relapsing disorder that affects over 14 million adults in the US (Substance Abuse and Mental Health Services Administration (SAMHSA), 2019), and is estimated to be responsible for 5.3% of global deaths (Shield et al, 2020). Both environmental and genetic factors contribute to AUD susceptibility, with the hereditability estimated at 50–60% of the total phenotypic variability (Reilly et al, 2017). PACAP has been implicated in a large variety of homeostatic systems within the body, including energy metabolism, food intake, body temperature, neuronal survival, reproduction (Gray et al, 2002; Inglott et al, 2011; Resch et al, 2011, 2014; Iemolo et al, 2015; Ross et al, 2018), as well as in the body’s response to stress and in several neuropsychiatric disorders (Hammack et al, 2009, 2010; Ressler et al, 2011; Dore et al, 2013; Mustafa et al, 2015; Seiglie et al, 2019; Ross et al, 2020; Varodayan et al, 2020, reviewed in Hammack and May, 2015; Lutfy and Shankar, 2019)
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