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Rationale: The adverse consequences of human addictive drug use could be the result of either addictive drug consumption resulting in punishment (e.g., incarceration) or failure to engage in negative-reinforced behaviors that might compete with drug-maintained behaviors (e.g., contingency management strategies that reset payment amounts for drug free urines)., Objective: The goal of the present study was to establish a discrete-trial cocaine-vs-negative reinforcer (S NR ) choice procedure where rats were presented with a simplified model of this conflict: choose negative reinforcement (i.e., escape or avoid foot shock) or choose an intravenous (IV) cocaine infusion followed by an inescapable shock., Methods: Responding was maintained in male and female rats by IV cocaine infusions (0.32-1.8 mg/kg/inf) and a S NR (0.1-0.7 mA shock) under a discrete-trial concurrent "choice" schedule during daily sessions. Following parametric reinforcer magnitude and response requirement experiments, the effects of 12 h extended access cocaine self-administration and acute diazepam (0.32-10 mg/kg, IP) pretreatment were determined on cocaine-vs-S NR choice., Results: Negative reinforcement was chosen over all cocaine doses. Lowering shock magnitude or increasing S NR response requirement failed to promote behavioral reallocation towards cocaine. Extended access cocaine self-administration sessions resulted in high daily cocaine intakes but failed to significantly increase cocaine choice in all (19) but one rat. Acute diazepam pretreatment also did not alter choice behavior up to doses that produced behavioral depression., Conclusions: These results suggest that S NR s may be a source of reinforcement that effectively compete with and mitigate maladaptive addictive drug-maintained behaviors in the general population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Women meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males., Objectives: The goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended access cocaine self-administration in females versus males., Methods: Motivation for cocaine, as assessed under a progressive-ratio reinforcement schedule, was determined prior to and following extended access cocaine self-administration (24 h/day, 96 infusions/day, 10 days) and after 7, 14, or 60 days of withdrawal. Compulsive use, or use despite punishment, was evaluated once progressive-ratio responding stabilized by adding histamine, an aversive stimulus, to the cocaine solutions., Results: Motivation for cocaine increased from baseline sooner during withdrawal in females than males (at 7 versus 14 days); motivation was also highest in the 60-day group. Histamine decreased progressive-ratio responding for cocaine in both sexes, although effects were greatest in males in the 7-day withdrawal group; males reached the female-level of resistance to histamine punishment by 14 days of withdrawal., Conclusions: Female rats developed addition-like features sooner during withdrawal than male rats indicating that the telescoping effect observed in humans is biologically based. Additionally, like drug-seeking/craving, motivation for cocaine and measures of compulsive use incubate over withdrawal., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: The development of addiction is accompanied by a shift in the mechanisms motivating cocaine use from nucleus accumbens (NAc) dopamine D 1 receptor (D 1 R) signaling to glutamate AMPA-kainate receptor (AMPA-R) signaling., Objective: Here, we determined whether similar shifts occur for NAc-D 2 R signaling and following systemic manipulation of D 1 R, D 2 R, and AMPA-R signaling., Methods: Male rats were given short-access (20 infusions/day) or extended-access to cocaine (24 h/day, 96 infusions/day, 10 days). Motivation for cocaine was assessed following 14 days of abstinence using a progressive-ratio schedule. Once responding stabilized, the effects of NAc-D 2 R antagonism (eticlopride; 0-10.0 μg/side) and systemic D 1 R (SCH-23390; 0-1.0 mg/kg), D 2 R (eticlopride; 0-0.1 mg/kg), and AMPA-R (CNQX; 0-1.5 mg/kg) antagonism, and NAc-dopamine-R gene expression (Drd1/2/3) were examined., Results: Motivation for cocaine was markedly higher in the extended- versus short-access group confirming the development of an addiction-like phenotype in the extended-access group. NAc-infused eticlopride decreased motivation for cocaine in both the short- and extended-access groups although low doses (0.1-0.3 μg) were more effective in the short-access group and high doses (3-10 μg/side) tended to be more effective in the extended-access group. Systemic administration of eticlopride (0.1 mg/kg) was more effective in the extended-access group, and systemic administration of CNQX was effective in the extended- but not short-access group. NAc-Drd2 expression was decreased in both the short- and extended-access groups., Conclusion: These findings indicate that in contrast to NAc-D 1 R, D 2 R remain critical for motivating cocaine use with the development of an addiction-like phenotype. These findings also indicate that shifts in the mechanisms motivating cocaine use impact the response to both site-specific and systemic pharmacological treatment.

Rationale: Epidemiological data suggest that menthol may increase vulnerability to cigarette/nicotine use and relapse. While menthol's sensory properties are often attributed as the underlying cause of the enhanced vulnerability, an alternative possibility is that they are mediated via pharmacological interactions with nicotine., Objective: This study addressed the possibility that menthol enhances nicotine intake and relapse vulnerability via pharmacological interactions with nicotine using a concurrent intravenous menthol/nicotine self-administration procedure., Methods: Following acquisition, adolescent rats were given 23-h/day access to nicotine (0.01 mg/kg/infusion), nicotine plus menthol (0.16, 0.32, or 0.64 mg/kg/infusion), or menthol alone (0.16, 0.32, 0.64 mg/kg/infusion) for a total of 10 days. Nicotine-seeking was assessed using an extinction/cue-induced reinstatement procedure following 10 days of forced abstinence. We also assessed the effect of menthol (0.32 mg/kg/infusion) on progressive ratio responding for nicotine (0.01 mg/kg/infusion)., Results: Menthol decreased PR responding for nicotine but did not affect self-administration under extended access conditions. The low dose of menthol tended to decrease subsequent extinction responding, and was not different from menthol alone, whereas the high dose decreased reinstatement responding. Although not significant, the highest levels of extinction responding were observed in a minority of rats in the moderate and high menthol-nicotine groups; rats in these groups also took longer to extinguish., Conclusions: Taken together, these results demonstrate that pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine's reinforcing effects and some measures of relapse vulnerability. Importantly, however, moderate and high menthol doses may increase some aspects of relapse vulnerability in a minority of individuals.

Rationale: Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic "crash.", Objective: The objective of this study was to determine whether individual differences in the relative value of cocaine's positive and negative effects would account for variations in subsequent drug self-administration., Methods: The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15-min postinjection) and a runway test (where animals developed approach-avoidance "retreat" behaviors about entering a goal box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration., Results: Larger place preferences were associated with faster runway start latencies (r s = -0.64), but not with retreat frequency or run times; larger place aversions predicted slower runway start times (r s = 0.62), increased run times (r s = 0.65), and increased retreats (r s = 0.62); response escalation was observed in both the 1- and 6-h self-administration groups and was associated with increased CPPs (r s = 0.58) but not CPAs, as well as with faster run times (r s = -0.60)., Conclusions: Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction.