Nicotine pre-treatment reduces sensitivity to the interoceptive stimulus effects of commonly abused drugs as assessed with taste conditioning paradigms

Abstract

Background: Drug pre-exposure attenuates sensitivity to the interoceptive stimulus properties of additional subsequently administered drugs in drug-induced conditioned taste avoidance (CTA) and conditioned place preference (CPP) paradigms. Specifically, nicotine, commonly used in conjunction with other addictive substances, attenuates acquisition of ethanol and caffeine As and morphine-induced CPP. Methods: Because nicotine use is comorbid with a number of substance use disorders, we systematically examined the effects of nicotine pre-exposure on two different conditioning paradigms involving integration of the interoceptive stimulus properties of multiple commonly abused drugs, in male and female rats, designed to examine both the aversive and reinforcing properties of these drugs. Results: Nicotine dose-dependently interfered with acquisition of CTA to passively administered morphine, ethanol, and cocaine, but not lithium chloride, demonstrating that the effects of nicotine are not simply a matter of reduced orosensory processing or an inability to learn such associations. Moreover, nicotine-treated rats required higher doses of drug in order to develop CTA and did not show increased acceptance of the taste of self-administered ethanol compared with saline-treated rats. Conclusions: These data demonstrate that nicotine pre-exposure attenuates sensitivity to the stimulus effects of multiple drugs in two conditioning paradigms, in a manner which is consistent with a reduced ability to integrate the interoceptive properties of abused drugs. Through reducing these stimulus properties of drugs of abuse, concomitant nicotine use may result in a need to increase either the frequency or strength of doses during drug-taking, thus likely contributing to enhanced addiction liability in smokers.

Nicotine Produces a High‐Approach, Low‐Avoidance Phenotype in Response to Alcohol‐Associated Cues in Male Rats

“…Clinical evidence supports a bidirectional relationship between nicotine and alcohol use, with increasing use of nicotine predicting greater degree of alcohol dependence, and vice versa (Falk et al., ). In rodents, nicotine promotes operant ethanol (EtOH) self‐administration (Bito‐Onon et al., ; Doyon et al., ; Le et al., ), delays extinction of EtOH‐seeking behavior (Le et al., ), reinstates EtOH seeking (Le et al., ), and limits acquisition of EtOH‐induced conditioned taste avoidance (CTA; Bienkowski et al., ; Kunin et al., ; Loney and Meyer, ; Rinker et al., ). Alcohol‐ and nicotine‐associated stimuli (“cues”) likely play an important role in augmenting alcohol seeking.…”

“…Alcohol‐ and nicotine‐associated stimuli (“cues”) likely play an important role in augmenting alcohol seeking. Paired cues can acquire motivational properties and either spur drug seeking and self‐administration (Corbit and Janak, ; Grusser et al., ; Katner et al., ; Tomie and Sharma, ; Wiers et al., ) or elicit avoidance responses when paired with aversive doses of a given drug (Liu et al., ; Loney and Meyer, ; Loney et al., ; Verendeev and Riley, , ). Clinical models of cue‐induced alcohol craving posit that approach and avoidance inclinations develop, respectively, as a function of the reinforcing and aversive consequences of alcohol use (Breiner et al., ; Schlauch et al., ).…”

“…In preclinical models, the motivational properties of cues can be inferred using Pavlovian conditioned approach (e.g., PavCA) and avoidance paradigms (e.g., CTA), during which, respectively, an environmental cue predicts the delivery of a reward, such as a food pellet or EtOH solution (Milton and Everitt, ; Robinson and Berridge, ; Robinson et al., ) or a flavor cue predicts passive administration of concentrated EtOH (Bienkowski et al., ; Kunin et al., ; Liu et al., ; Loney and Meyer, ; Rinker et al., ). In PavCA paradigms, due to the reinforcing value of the stimulus, in response to presentations of a predictive cue, rats generally display a tendency to approach either the cue itself (“sign‐tracking”) or the reward delivery location (“goal‐tracking”), even though no response is required to receive the reward.…”

“…Conversely, nicotine interferes with the degree of avoidance of an EtOH‐paired cue in CTA paradigms (Bienkowski et al., ; Kunin et al., ; Loney and Meyer, ; Rinker et al., ). These CTA paradigms rely on the aversive interoceptive properties of a drug stimulus in order to modulate the motivational properties of a highly palatable stimulus (Loney and Meyer, ; Rinker et al., ). Thus far, the mechanisms underlying the ability for nicotine to interfere with EtOH‐induced CTA are unknown.…”

“…In this case, nicotine‐treated rats would be capable of acquiring a sufficient avoidance response relative to a saline‐treated rat; they would simply require a higher dose in order to do so. The lack of an effect of nicotine on LiCl‐induced CTA (Loney and Meyer, ) suggests this to be the case, but studies specifically testing the sensitivity of nicotine‐treated, relative to saline‐treated, rats to avoidance conditioned by a given dose of EtOH have yet to be conducted.…”