Repeated haloperidol and olanzapine treatment produces an enhanced disruption of avoidance responding, a validated measure of antipsychotic activity. Experimental parameters affecting this sensitization-like effect have not been thoroughly examined. The present study investigated the role of three parameters (number of injections, dose, and interval between initial exposure and challenge) in antipsychotic sensitization in the conditioned avoidance response paradigm. Well-trained Sprague–Dawley rats received different numbers of drug treatment (1–5 days) or different doses of haloperidol (0.025–0.10 mg/kg, subcutaneously) or olanzapine (0.5–2.0 mg/kg, subcutaneously). After certain time intervals (4, 10 or 17 days), they were tested for the expression of haloperidol or olanzapine sensitization in a challenge test in which all rats were injected with a lower dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg). Throughout the drug-treatment period, both haloperidol and olanzapine dose-dependently enhanced their disruption of avoidance responding. Three days later, the sensitization induced by a low dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg) was only apparent in rats that received treatment for 5 days, but not in those that received treatment for 1–4 days. The sensitization induced by the medium and high doses of haloperidol (0.05 and 0.10 mg/kg) or olanzapine (1.0 and 2.0 mg/kg) was still robust even with only 3 days of treatment. The sensitization induced by a 3-day haloperidol (0.10 mg/kg) and olanzapine (2.0 mg/kg) treatment was long-lasting, still detectable 17 days after the last drug treatment. This study suggests that antipsychotic sensitization is a robust behavioral phenomenon. Its induction and expression are strongly influenced by parameters such as number of drug exposures, drug dose, and test–retest interval. Given the importance of antipsychotic sensitization in the maintenance of antipsychotic effects in the clinic, this study introduces a paradigm that can be used to investigate the behavioral and neurobiological mechanisms underlying antipsychotic sensitization.

Rationale Impulsive choice, or an inability to delay immediate gratification, has been strongly linked to the development and persistence of drug abuse. Indeed, delaying drug use itself may underlie drug addiction and relapse. Thus, employing treatments that are efficacious in reducing impulsive choice (atomoxetine; ATO) or drug-seeking behavior (progesterone; PRO) may be an effective means of treating drug addiction. Objective The current study assessed sex differences in the effects of PRO, ATO and their combination in a delay discounting paradigm for cocaine and for sucrose pellets. Method Male and female rats chose between a small-immediate or a large-delayed (0, 7.5, 15, 30, 60 sec) outcome in an impulsive choice procedure for sucrose pellets (1 vs 3 pellets) or for iv cocaine infusions (0.3 vs 0.9 mg/kg). Following baseline assessment of impulsive choice, rats received daily treatment of vehicle (VEH), PRO (0.5 mg/kg), ATO (1.5 mg/kg) or a combination (PRO + ATO) until a second assessment of impulsive choice was determined. Results Compared to the VEH group, females were less impulsive for cocaine following PRO or the PRO + ATO combined treatment, whereas males were less impulsive for cocaine following ATO. No treatment effects were observed on impulsive choice for sucrose pellets. Conclusions The present results indicate that impulsive choice for cocaine is reduced by PRO in females and by ATO in males. These findings suggest both treatments may be an effective intervention in treating cocaine abuse, but that their effectiveness differs by sex.

Rationale Consistent sex differences are observed in human drug addiction, with females often exceeding males on drug intake. However, there is still a need for animal models for some aspects of addiction such as acquisition of drug self-administration and the subsequent development of drug-seeking. Objectives The present study examined sex differences in the acquisition of self-administration of two widely used stimulants, cocaine and nicotine. Methods Male and female rats self-administered cocaine (0.4 mg/kg/infusion) or nicotine (0.03 mg/kg/infusion) daily under a fixed-ratio 1 (FR 1) schedule until acquisition criteria were met (maximum of 30 sessions). The self-administration criterion for cocaine was ≥20 infusions in a 2 h session and ≥5 infusions in a 1 h session for nicotine. Sex differences were assessed by examining the percentage of rats that met acquisition criteria, the number of sessions to meet criteria and the number of infusions earned during the maintenance phase. Results A significantly higher percentage of male rats acquired both cocaine and nicotine self-administration than females, and males met acquisition criteria in fewer sessions. However, after criteria were met, females self-administered more cocaine than males during the first 5 days of maintenance. There were no sex differences in nicotine infusions post acquisition. Conclusions Differences in acquisition amongst sexes can reveal factors that are integral to initiation of drug use, an often overlooked phase of drug addiction.

Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using “standard” testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more “standard” testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli.

Overall, the results revealed that female rats display higher levels of nicotine IVSA than males, suggesting that the strong reinforcing effects of nicotine promote tobacco use in women.