The role of endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in nicotine self-administration, reward and aversion

Abstract

Pituitary adenylyl cyclase activating polypeptide (PACAP) and its receptors (PAC1, VPAC1, and VPAC2) are localized in brain regions implicated in stress response, reward seeking and aversive responses, raising the possibility that PACAP may be involved in motivational effects of nicotine. To test this hypothesis, we used twobottle choice (TBC) and place conditioning paradigms and assessed if nicotine preference or conditioned place preference (CPP) or aversion (CPA) induced by nicotine would be altered in mice lacking PACAP compared to their wild-type controls. In the TBC paradigm, mice had access to two water bottles during the first week and then one of the water bottles was switched to nicotine solution (20, 40 and then 80 μg/mL). The volume of water and nicotine consumed was measured every day. In the place conditioning paradigm, mice were tested for baseline place preference on day 1, received conditioning with saline versus a low (0.25) or high (1 mg/kg) dose nicotine and, respectively, tested for CPP or CPA 24 h following the last conditioning. We discovered that mice lacking PACAP compared to their wild-type controls exhibited more preference for nicotine over water in the TBC paradigm, particularly at the two higher concentrations of nicotine. While the rewarding action of the low dose nicotine was not altered in mice lacking PACAP, the aversive effect of the high dose nicotine was blunted in these mice compared to their wild-type controls. The present results suggest that endogenous PACAP may play a functional role in nicotine preference and its aversive effect.

Alterations of Amphetamine Reward by Prior Nicotine and Alcohol Treatment: The Role of Age and Dopamine

“…The chambers were covered with clear flip-top lids with ventilation holes. We used an unbiased and counterbalanced place conditioning paradigm described previously [45][46][47]. We first measured the baseline preference of each mouse toward the three chambers.…”

The role of pituitary adenylyl cyclase-activating polypeptide in the motivational effects of addictive drugs

“…However, these mice showed a comparable CPP following a low dose of nicotine (0.25 mg/kg, i.p.) compared to their wildtype controls (Tseng et al, 2019). These changes are reminiscent of the differences observed in alcohol preference and ethanol-induced CPP between PACAP-deficient and their wild-type controls (Tanaka et al, 2010).…”

“…These changes are reminiscent of the differences observed in alcohol preference and ethanol-induced CPP between PACAP-deficient and their wild-type controls (Tanaka et al, 2010). We also discovered that nicotine (1 mg/kg, s.c.) induced conditioned place aversion (CPA) in wild-type mice and this response was blunted in PACAP-deficient mice compared to their wild-type controls (Tseng et al, 2019). Together, these results suggest that while the rewarding effect of nicotine was not altered in the absence of PACAP, the increased nicotine self-administration in the absence of PACAP may be due to a decrease in the aversive effect of nicotine (Tseng et al, 2019).…”

Peptides, MAbs, Molecules, Mechanisms, and More: Taking a Stab at Cluster Headache

“…The motivational effects of nicotine have been linked to these biological stress systems. Nicotine preference was increased in mice lacking PACAP, possibly due to decreased nicotine‐induced aversion 26 . This leads back to a potential relationship between gene expression alterations in PACAP in CH.…”