An improved model of ethanol and nicotine co-use in female P rats: Effects of naltrexone, varenicline, and the selective nicotinic α6β2* antagonist r-bPiDI

Abstract

Background: Although pharmacotherapies are available for alcohol (EtOH) or tobacco use disorders individually, it may be possible to develop a single pharmacotherapy to treat heavy drinking tobacco smokers by capitalizing on the commonalities in their mechanisms of action. Methods: Female alcohol-preferring (P) rats were trained for EtOH drinking and nicotine self-administration in two phases: (1) EtOH alone (0 vs. 15% EtOH, 2-bottle choice) and (2) concomitant access, during which EtOH access continued with access to nicotine (0.03 mg/kg/infusion, i.v.) using a 2-lever choice procedure (active vs. inactive lever) in which the fixed ratio (FR) requirement was gradually increased to FR30. When stable co-use was obtained, rats were pretreated with varying doses of naltrexone, varenicline, or r-bPiDI, an α6β2* subtype-selective nicotinic acetylcholine receptor antagonist shown previously to reduce nicotine self-administration. Results: While EtOH intake was initially suppressed in phase 2 (co-use), pharmacologically relevant intake for both substances was achieved by raising the “price” of nicotine to FR30. In phase 2, naltrexone decreased EtOH and water consumption but not nicotine intake; in contrast, naltrexone in phase 1 (EtOH only) did not significantly alter EtOH intake. Varenicline and r-bPiDI in phase 2 both decreased nicotine self-administration and inactive lever pressing, but neither altered EtOH or water consumption. Conclusions: These results indicate that increasing the “price” of nicotine increases EtOH intake during co-use. Additionally, the efficacy of naltrexone, varenicline, and r-bPiDI was specific to either EtOH or nicotine, with no efficacy for co-use. Nevertheless, future studies on combining these treatments may reveal synergistic efficacy.

Co‐administration of ethanol and nicotine heightens sensitivity to ethanol reward within the nucleus accumbens (NAc) shell and increasing NAc shell BDNF is sufficient to enhance ethanol reward in naïve Wistar rats

“…; Tizabi et al , ; Truitt et al ). Multiple reports have indicated that naltrexone and varenicline, the pharmacological ‘gold standards’ for treating AUD and nicotine dependence, both fail to alter the concurrent co‐administration of EtOH+NIC (Van Skike et al ; Waeiss, Knight, Hauser et al ; Maggio et al ). The current results provide clear preclinical data indicating that EtOH+NIC co‐administration results in a unique neurological cascade that is not observed following comparable exposure to EtOH or NIC alone.…”

Therapeutic challenges for concurrent ethanol and nicotine consumption: naltrexone and varenicline fail to alter simultaneous ethanol and nicotine intake by female alcohol-preferring (P) rats

“…The failure of Var and Nal (and the specific α6β2* antagonist r-bPiDI) to alter concurrent EtOH (oral) +NIC (i.v.) self-administration has been replicated in a novel model that increases intake levels of both drugs (Maggio et al, 2018b). Therefore, consistent preclinical data has indicated that Var is not effective at reducing EtOH +NIC co-administration.…”

α-Conotoxin TxIB Inhibits Development of Morphine-Induced Conditioned Place Preference in Mice via Blocking α6β2* Nicotinic Acetylcholine Receptors

“…α 6 β 2* nAChRs are limitedly distributed in dopaminergic cells in the mesocorticolimbic. Previous studies have reported that α 6/ α 3 β 2 β 3 nAChRs antagonists can inhibit drug addiction such as nicotine, alcohol, and cocaine ( Brunzell et al, 2010 ; Kamens et al, 2017 ; Maggio et al, 2018 ; Avelar et al, 2019 ). However, the role of α 6β2* nAChRs in morphine addiction has not been verified so far.…”