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

Abstract

Background: Nicotine and alcohol use are highly comorbid. Modulation of drug-paired extrinsic and intrinsic cues likely plays a role in this interaction, as cues can acquire motivational properties and augment drug seeking. The motivational properties of cues can be measured through Pavlovian conditioning paradigms, in which cues either elicit approach following pairing with the reinforcing properties of alcohol or elicit avoidance following pairing with the aversive consequences of alcohol. The present experiments tested whether nicotine would enhance the incentive properties of an appetitive ethanol (EtOH) cue and diminish the avoidance of an aversive EtOH cue in Pavlovian paradigms.Methods: In experiment 1, male Long-Evans rats with or without prior chronic intermittent access to EtOH were administered nicotine or saline injections prior to Pavlovian conditioned approach (PavCA) sessions, during which conditioned approach to the cue ("sign-tracking") or the EtOH delivery location ("goal-tracking") was measured. In experiment 2, male Long-Evans rats were administered nicotine or saline injections prior to pairing a flavor cue with increasing doses of EtOH (i.p.) in an adaptation of the conditioned taste avoidance (CTA) paradigm.Results: Results from PavCA indicate that, regardless of EtOH exposure, nicotine enhanced responding elicited by EtOH-paired cues with no effect on a similar cue not explicitly paired with EtOH. Furthermore, nicotine reduced sensitivity to EtOH-induced CTA, as indicated by a rightward shift in the dose-response curve of passively administered EtOH. The ED 50 , or the dose of EtOH that produced a 50% reduction in intake relative to baseline, was significantly higher in nicotine-treated rats compared to saline-treated rats.Conclusions: We conclude that nicotine increases the approach and diminishes the avoidance elicited by Pavlovian cues paired, respectively, with the reinforcing and aversive properties of EtOH consumption in male rats. As such, nicotine may enhance alcoholism liability by engendering an attentional bias toward cues that predict the reinforcing outcomes of drinking.

Systemic nicotine enhances opioid self-administration and modulates the formation of opioid-associated memories partly through actions within the insular cortex

“…Undoubtedly, there are likely multiple mechanisms, presumably acting in concert, through which nicotine may enhance opiate self-administration. For instance, nicotine can enhance the incentive salience of discrete drug-associated cues 19 , 24 , 25 and therefore increase the likelihood of drug intake upon presentation of said cues. In addition, nicotine can enhance dopamine dynamics in response to subsequently presented drugs 55 , including disinhibition of dopamine release from the VTA 56 , which presumably would increase the reinforcing efficacy of any subsequently administered drug.…”

“…Mnemonic representations of the past reinforcing and aversive properties of drug administration and withdrawal can be elicited by cues and contexts that were present during drug episodes and can serve to elicit either approach or avoidance 15 – 18 . Importantly, there is ample evidence for nicotine in modulating the development, strength, and recall of drug-associated memories across multiple classes of abused drugs and across multiple learning paradigms designed to measure the impact of the reinforcing and aversive effects of drug administration 19 – 23 . Specifically, acute nicotine pretreatment robustly increases the incentive properties of discrete drug-predictive cues 19 , 24 – 26 and this enhancement is likely dependent on nicotinic activity within the midbrain dopaminergic circuitry, particularly the ventral tegmental area 27 , 28 .…”

“…Importantly, there is ample evidence for nicotine in modulating the development, strength, and recall of drug-associated memories across multiple classes of abused drugs and across multiple learning paradigms designed to measure the impact of the reinforcing and aversive effects of drug administration 19 – 23 . Specifically, acute nicotine pretreatment robustly increases the incentive properties of discrete drug-predictive cues 19 , 24 – 26 and this enhancement is likely dependent on nicotinic activity within the midbrain dopaminergic circuitry, particularly the ventral tegmental area 27 , 28 . There is emerging evidence that, unlike the effects seen on discrete stimuli, nicotine pretreatment may impair the strength of drug-associated contextual memories.…”

Nicotine and Opioid Polysubstance Abuse: Enhancement of opioid self-administration by systemic nicotine and modulation of opioid-associated memories by insular nicotine

“…Undoubtedly, there are likely multiple mechanisms, presumably acting in concert, through which nicotine may enhance opiate selfadministration. For instance, nicotine can enhance the incentive salience of discrete drug-associated cues 19,24,25 and therefore increase the likelihood of drug intake upon presentation of said cues. In addition, nicotine can enhance dopamine dynamics in response to subsequently presented drugs 54 , including disinhibition of dopamine release from the VTA 55 , which presumably would increase the reinforcing efficacy of any subsequently administered drug.…”

“…Importantly, there is ample evidence for nicotine in modulating the development, strength, and recall of drug-associated memories across multiple classes of abused drugs and across multiple learning paradigms designed to measure the impact of the reinforcing and aversive effects of drug administration 19, 20 21-23 . Specifically, acute nicotine pretreatment robustly increases the incentive properties of discrete drug-predictive cues 19,[24][25][26] and this enhancement is likely dependent on nicotinic activity within the midbrain dopaminergic circuitry, particularly the ventral tegmental area 27,28 . There is emerging evidence that, unlike the effects seen on discrete stimuli, nicotine pretreatment may impair the strength of drugassociated contextual memories.…”