Nicotine Modulates Alcohol‐Seeking and Relapse by Alcohol‐Preferring (P) Rats in a Time‐Dependent Manner

Abstract

Background Alcohol is frequently co-abused with smoking. In humans, nicotine use can increase alcohol craving and consumption. The objectives of the current study were to assess the acute effects of nicotine on alcohol seeking and relapse at two different time points. Method Adult female alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5 – fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hr sessions. Following 10 weeks of daily 1-hr sessions, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without EtOH or water being present for 4 sessions (Pavlovian Spontaneous Recovery [PSR]). Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (relapse). Nicotine (0, 0.1, 0.3, or 1.0 mg/kg) was injected s.c. immediately or 4-hr prior to PSR or relapse testing. Results Injections of nicotine immediately prior to testing reduced (5–10 responses PSR; 50–60 responses relapse), whereas injections of nicotine 4-hr prior to testing increased (up to 150 responses for PSR; up to 400 responses for relapse with 1.0 mg/kg dose) responses on the EtOH lever during PSR and relapse tests. Discussion The results of this study demonstrate that acute effects of nicotine on EtOH-seeking and relapse behaviors may be time-dependent, with the immediate effects being a result of nicotine possibly acting as a substitute for EtOH whereas, with a delay of 4-hr, priming effects of nicotine alterations in nicotinic receptors, and/or the effects of nicotine’s metabolites (i.e., cotinine, nornicotine) may enhance the expression of EtOH-seeking and relapse behaviors.

Nicotine and ethanol co-use in Long-Evans rats: Stimulatory effects of perinatal exposure to a fat-rich diet

“…Prior studies developing methods for administering a combination of nicotine and ethanol have involved either oral self-administration of the two drugs separately or together (Hauser, Getachew, et al, 2012; Marshall et al, 2003), IV self-administration of nicotine combined with oral self-administration of ethanol sequentially or concurrently (Hauser, Katner, et al, 2012; Lê et al, 2010, 2014), or the self-infusion of a mixture of nicotine and ethanol directly into the posterior VTA (Truitt et al, 2014). While these paradigms have been successful in getting rats to self-administer both drugs, in some cases at pharmacologically relevant levels (Hauser, Katner, et al, 2012), the results obtained relating these two drugs may in some cases be determined by their specific properties or the specific paradigms of administration.…”

“…Whereas rats trained to self-administer IV nicotine and oral ethanol sequentially show that nicotine increases subsequent ethanol self-administration and ethanol reduces nicotine self-administration (Lê, Funk, Lo, & Coen, 2014), rats trained to self-administer these drugs concurrently show no effect of nicotine on ethanol intake or of ethanol on nicotine intake (Lê et al, 2010). Further, when both drugs are given orally, outbred rats that readily drink these substances together consume them in similar amounts as when they are offered separately (Marshall, Dadmarz, Hofford, Gottheil, & Vogel, 2003), and P rats lever-press for a solution containing both nicotine and ethanol at the same level as when ethanol is provided alone (Hauser, Getachew, et al, 2012). While these studies lead one to question the phenomenon of co-use in animals, there is a recent report that allowed alcohol-preferring rats to self-administer a nicotine/ethanol mixture directly in the posterior ventral tegmental area (VTA) and obtained evidence for an interaction between the two drugs in a way that increased their co-use (Truitt et al, 2014).…”

The Role of CYP2E1 in Alcohol Metabolism and Sensitivity in the Central Nervous System

“…As noted, CYP2E1 can also be induced by nicotine (found in cigarette smoke), which can result in bioactivation of the above compounds and in increased ethanol oxidation. Indeed, Howard and colleagues (2003) determined that CYP2E1 was induced by nicotine, which offers an explanation for the increased self-administration of ethanol after exposure of rats to nicotine (Hauser, Getachew et al 2012). Induction of CYP2E1 in the CNS by nicotine likely increases the metabolism of ethanol to acetaldehyde, a result consistent with the theory that increases in CNS acetaldehyde causes reinforcement in ethanol preference.…”

Enhanced alcohol-seeking behavior by nicotine in the posterior ventral tegmental area of female alcohol-preferring (P) rats: modulation by serotonin-3 and nicotinic cholinergic receptors

“…The severity of nicotine dependency is linked to more severe levels of alcohol relapse (Abrams et al 1992; Gulliver et al 1995) and impairs the likelihood that an individual with alcohol dependence will succeed in becoming abstinent if they continue to smoke during this period (Gulliver et al 1995; Sobell et al 1995; Daeppen et al 2000). Preclinical studies have provided evidence that nicotine can enhance relapse behaviors, such as ethanol (EtOH) seeking (Le et al 2003; Hauser et al 2012a) and EtOH relapse drinking (Lopez-Moreno et al 2004; Alen et al 2009; Hauser et al 2012a). …”