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

Abstract

Rationale and Objectives: Simultaneous alcohol and nicotine consumption occurs in the majority of individuals with alcohol use disorder (AUD) and nicotine dependence. Varenicline (Var) is used to assist in the cessation of nicotine use, while naltrexone (Nal) is the standard treatment for AUD. Despite evidence that ethanol (EtOH) and nicotine (NIC) co-use produces unique neuroadaptations, preclinical research has focused on the effects of pharmacotherapeutics on a single reinforcer. The current experiments examined the effects of Var and Nal on EtOH, NIC, or EtOH+NIC intake. Methods: Animals were randomly assigned to 1 of 4 drinking conditions of 24-hour access to a 3-bottle choice paradigm, one of which always contained water. Drinking conditions were water only, 0.07 and 0.14 mg/mL NIC (NIC only), 15% and 30% EtOH (EtOH only), or 15% and 30% EtOH with 0.14 mg/mL NIC (EtOH+NIC). The effects of Var (0, 1, or 2 mg/kg) or Nal (0, 1, or 10 mg/kg) injections on maintenance and relapse consumption were determined during 4 consecutive days. Results: Var reduced maintenance and relapse NIC intake but had no effect on EtOH or EtOH +NIC drinking. Conversely, Nal reduced EtOH maintenance and relapse drinking, but had no effect on NIC or EtOH+NIC drinking. Discussion: The results indicate the standard pharmacological treatments for nicotine dependence and AUD were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC couse/abuse. These findings suggest that co-abuse may promote unique neuroadaptations that require models of polysubstance abuse to develop pharmacotherapeutics to treat AUD and nicotine dependence.

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.…”

Unequal interactions between alcohol and nicotine co-consumption: suppression and enhancement of concurrent drug intake

“…Varenicline (an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist) is approved for smoking cessation (Rollema et al, 2010), and naltrexone (an opioid receptor antagonist) and acamprosate (an NMDA receptor antagonist) are approved for alcohol use disorder (Franck and Jayaram-Lindström, 2013). Studies in alcohol-preferring female rats shows that varenicline reduces nicotine self-administration but has no effect on concurrent alcohol intake, and naltrexone reduces alcohol intake but has no effect on concurrent nicotine self-administration (Maggio et al, 2018;Waeiss et al, 2019), suggesting that monotherapy may be ineffective for combination alcohol and nicotine use disorder.…”

Investigating the effects of chronic perinatal alcohol and combined nicotine and alcohol exposure on dopaminergic and non-dopaminergic neurons in the VTA

“…The microarray results were validated using RT-qPCR (Supplementary Fig. S9 ) as described elsewhere 6 , 7 . All reagents and kits used for quantitative reverse transcription polymerase chain reaction (RT-qPCR) were purchased from Applied Biosystems (Thermo Fisher Scientific, Carlsbad, CA, USA) unless stated otherwise.…”

“…Their consumptions are highly linked to temporary behavioral changes, and when used together, they could result in synergistic adverse effects 4 , 5 . The rate of nicotine use has a positive correlation to the rate of alcohol use disorder (AUD) 6 – 8 . Substance use among pregnant women continues to be a major public health concern; 5% of pregnant women reported the use of one or more addictive substances during pregnancy and/or breastfeeding 9 .…”