Conditioned enhancement of the nicotine reinforcer.

This study was designed to assess whether nicotine can acquire additional reinforcing properties through associations with other rewards. To this end, rats self-administered nicotine-alone (0.01 mg/kg) or nicotine paired with access to sucrose during the conditioning phase. In the subsequent challenge phase, we tested the effect of nicotine-sucrose pairings on the reinforcing effects of nicotine using a progressive ratio schedule of reinforcement. Using this approach, we show that (a) rats in both paired and nicotine-alone conditions self-administered similar amounts of nicotine in the initial conditioning phase of the study when intake was limited to 10 infusions per session, (b) nicotine rapidly acquired control over goal-tracking behavior in the paired condition, (c) rats that had a history of nicotine and sucrose pairings worked harder and took more nicotine as measured on a progressive ratio using a distinct response form, and (d) conditioned goal-tracking evoked by nicotine did not show extinction when sucrose was no longer paired with nicotine over the 11 days of nicotine self-administration on a progressive ratio schedule of reinforcement. Overall, our results demonstrate that in addition to the multifaceted nature of nicotine stimulus that includes primary reinforcing effects, conditioned reinforcing effects, and reward enhancing effects, nicotine can also acquire additional reinforcing properties through associations with other rewards. This ability to acquire additional reinforcing properties through associative learning may contribute to the development and perpetuation of tobacco use disorder. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Effect of Chronotype on Sleep Quality in a Laboratory Setting.

Sleep is undoubtedly important for human health as insufficient sleep has been associated with a plethora of diseases. Adequate sleep assessment is critical in clinical and research settings, however current sleep assessment protocols fail to account for circadian rhythms, despite the fact that sleep is a well-recognized circadian process. PURPOSE: The purpose of this study was to determine if circadian parameters, such as chronotype, influence sleep quality in a sleep laboratory setting. METHODS: In order to investigate this, twenty participants (10 men and 10 women) aged 18-31 years old had their sleep recorded by electroencephalography in a sleep lab. Participants also complete surveys which provided data on chronotype, social jet lag and subjective sleep quality. Participants were allowed to self-select sleep time for the study, and sleep discrepancy, defined as the difference between reported and experienced mid-sleep, was determined. RESULTS: Interestingly, results indicated a significant correlation between self-reported sleep quality and social jet lag, with those who typically experience more social jet lag being more satisfied with their sleep during the study (r = 0.549, p = 0.012). In addition, when participants were separated into groups based on chronotype, sleep discrepancy and social jet lag, sizeable differences were noted for parameters such as sleep onset latency, number of awakenings, and percent of time spent in REM sleep. CONCLUSION: These results suggest circadian parameters serve as predictors of both subjective and objective sleep quality, and thus illuminates a necessity for these parameters to be taken into account in the assessment and research of sleep.

Alterations of acoustic features of 50 kHz vocalizations by nicotine and phencyclidine in rats.

Ultrasonic vocalizations are widely used to examine affective states in rats, yet relatively few studies explore the acoustic features of vocalizations, especially in relation to drug exposure, and no studies have explored alterations in acoustic features over time. The goal of this study was to examine nicotine- and phencyclidine-induced alterations of bandwidth, duration, and frequency of 50 kHz vocalizations. The minimum and maximum frequency, bandwidth, and duration of calls were examined after 7 days of daily subcutaneous administration of phencyclidine (2.0 mg/kg) and nicotine (0.2 and 0.4 mg/kg) in male Sprague-Dawley rats. Bandwidth was significantly decreased in rats treated with both nicotine (0.2 and 0.4 mg/kg) and phencyclidine. Maximum frequency was lowest on the first day of exposure compared with all other days and was not altered by drug exposure. Call duration was not affected by time or drug exposure. These findings suggest the importance of studying alterations in acoustic features in time, especially those induced by drug exposure.

Sex differences in nicotine intravenous self-administration: A meta-analytic review.

OBJECTIVE: This report reflects a meta-analysis that systematically reviewed the literature on intravenous self-administration (IVSA) of nicotine in female and male rats. The goal was to determine if sex differences in nicotine IVSA exist, estimate the magnitude of the effect, and identify potential moderators of the relationship between sex differences and nicotine consumption. METHODS: Extensive search procedures identified 20 studies that met the inclusion criteria of employing both female and male rats in nicotine IVSA procedures. The meta-analysis was conducted on effect size values that were calculated from mean total intake or nicotine deliveries using the Hedges' unbiased gu statistic. RESULTS: A random effects analysis revealed that overall females self-administered more nicotine than males (weighted gu=0.18, 95% CI [0.003, 0.34]). Subsequent moderator variable analyses revealed that certain procedural conditions influenced the magnitude of sex differences in nicotine IVSA. Specifically, higher reinforcement requirements (>FR1) and extended-access sessions (23h) were associated with greater nicotine IVSA in females versus males. Females also displayed higher nicotine intake than males when the experiment included a light cue that signaled nicotine delivery. Sex differences were not influenced by the diurnal phase of testing, dose of nicotine, or prior operant training. CONCLUSION: 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.

Guns, Culture or Mental Health? Framing Mass Shootings as a Public Health Crisis.

In recent years, public health scholars and policymakers have been calling for increased research on the public health implications of gun violence. However, scientific research on this issue has been stifled by a 1996 budget rider that eliminated Centers for Disease Control and Prevention's (CDC) funding for gun research. In this study, we examined newspaper coverage of three mass shootings that took place over a 20-year period before and after the passage of this budget rider. We found that sources and frames provided by news media to contextualize gun violence shifted markedly over time, progressing from episodic and individual-level frames to broader thematic societal-level concerns, with increased discussion of mental health but limited discourse explicitly related to public health.

Sex-specific attenuation of impulsive action by progesterone in a go/no-go task for cocaine in rats.

RATIONALE: Previous work indicated that progesterone (PRO) reduced impulsive choice for cocaine in female but not male rats (Smethells et al. Psychopharmacology 233:2999-3008, 2016). Impulsive action, typically measured by responding for a reinforcer during a signaled period of nonavailability of natural reinforcers, predicts initiation and escalation of drug use in animals and humans. The present study examined impulsive action for cocaine using PRO in male and female rats trained on a go/no-go task. OBJECTIVE: Rats were trained on a go/no-go task to respond for cocaine infusions (0.4 mg/kg/inf). During the "go" component, responding was reinforced on a VI 30-s schedule, whereas during the "no-go" component, withholding a response was reinforced on a differential reinforcement of other behavior (DRO) 30-s schedule. A response during the no-go component resets the DRO timer and served as a measure of impulsive action. After baseline responding was established, rats were pretreated with vehicle (VEH) or PRO (0.5 mg/kg), and DRO resets and responding during the go component for cocaine were compared in males vs. females. RESULTS: DRO resets were significantly lower following PRO treatment compared to VEH in female, but not male, rats. Response rates and overall infusions during the go component were not significantly altered by PRO in either females or males. CONCLUSION: Treatment with PRO resulted in a sex-specific reduction in impulsive action for cocaine, while not affecting cocaine self-administration.

Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus.

Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the main addictive component of tobacco products and is a moderate stimulant and a mild reinforcer. Importantly, besides its unconditional effects, nicotine also has conditioned stimulus effects that may contribute to the tenacity of the smoking habit. Because the neurobiological substrates underlying these processes are virtually unexplored, the present study investigated the functional involvement of the dorsomedial caudate putamen (dmCPu) in learning processes with nicotine as an interoceptive stimulus. Rats were trained using the discriminated goal-tracking task where nicotine injections (0.4 mg/kg; SC), on some days, were paired with intermittent (36 per session) sucrose deliveries; sucrose was not available on interspersed saline days. Pre-training excitotoxic or post-training transient lesions of anterior or posterior dmCPu were used to elucidate the role of these areas in acquisition or expression of associative learning with nicotine stimulus. Pre-training lesion of p-dmCPu inhibited acquisition while post-training lesions of p-dmCPu attenuated the expression of associative learning with the nicotine stimulus. On the other hand, post-training lesions of a-dmCPu evoked nicotine-like responding following saline treatment indicating the role of this area in disinhibition of learned motor behaviors. These results, for the first time, show functionally distinct involvement of a- and p-dmCPu in various stages of associative learning using nicotine stimulus and provide an initial account of neural plasticity underlying these learning processes.

Progesterone attenuates impulsive action in a Go/No-Go task for sucrose pellets in female and male rats.

Impulsivity, or a tendency to act without anticipation of future consequences, is associated with drug abuse. Impulsivity is typically separated into two main measures, impulsive action and impulsive choice. Given the association of impulsivity and drug abuse, treatments that reduce impulsivity have been proposed as an effective method for countering drug addiction. Progesterone has emerged as a promising treatment, as it is associated with decreased addiction-related behaviors and impulsive action. The goal of the present study was to determine the effects of progesterone (PRO) on impulsive action for food: a Go/No-Go task. Female and male rats responded for sucrose pellets during a Go component when lever pressing was reinforced on a variable-interval 30-s schedule. During the alternate No-Go component, withholding a lever press was reinforced on a differential reinforcement of other (DRO) behavior 30-s schedule, where a lever press reset the DRO timer. Impulsive action was operationally defined as the inability to withhold a response during the No-Go component (i.e. the number of DRO resets). Once Go/No-Go behavior was stable, responding between rats treated with PRO (0.5mg/kg) or vehicle was examined. Progesterone significantly decreased the total number of DRO resets in both males and females, but it did not affect VI responding for sucrose pellets. This suggests that PRO decreases motor impulsivity for sucrose pellets without affecting motivation for food. Thus, PRO may reduce motor impulsivity, a behavior underlying drug addiction.

Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone.

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 s) 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.

Sex differences in neurotensin and substance P following nicotine self-administration in rats.

Investigator-administered nicotine alters neurotensin and substance P levels in Sprague-Dawley rats. This finding suggested a role of the dopamine-related endogenous neuropeptides in nicotine addiction. We sought to extend this observation by determining the responses of neurotensin and substance P systems (assessed using radioimmunoassay) in male and female rats following nicotine self-administration (SA). Male and female Sprague-Dawley were trained to self-administer nicotine, or receive saline infusions yoked to a nicotine-administering rat during daily sessions (1-h; 21 days). Brains were extracted 3 h after the last SA session. Nicotine SA increased tissue levels of neurotensin in the males in the anterior and posterior caudate, globus pallidus, frontal cortex, nucleus accumbens core and shell, and ventral tegmental area. Nicotine SA also increased tissue levels of neurotensin in the females in the anterior caudate, globus pallidus, nucleus accumbens core and shell, but not in the posterior caudate, frontal cortex, or ventral tegmental area. There were fewer sex differences observed in the substance P systems. Nicotine SA increased tissue levels of substance P in both the males and females in the posterior caudate, globus pallidus, frontal cortex, nucleus accumbens shell, and ventral tegmental area. A sex difference was observed in the nucleus accumbens core, where nicotine SA increased tissue levels of substance P in the males, yet decreased levels in the females. The regulation of neuropeptides following nicotine SA may play a role in the susceptibility to nicotine dependence in females and males. Synapse 70:336-346, 2016. © 2016 Wiley Periodicals, Inc.

Sex differences in attenuation of nicotine reinstatement after individual and combined treatments of progesterone and varenicline.

Tobacco use is the largest cause of preventable mortality in the western world. Even after treatment, relapse rates for tobacco are high, and more effective pharmacological treatments are needed. Progesterone (PRO), a female hormone used in contraceptives, reduces stimulant use but its effects on tobacco addiction are unknown. Varenicline (VAR) is a commonly used medication that reduces tobacco use. The present study examined sex differences in the individual vs. combined effects of PRO and VAR on reinstatement of nicotine-seeking behavior in a rat model of relapse. Adult female and male Wistar rats self-administered nicotine (NIC, 0.03mg/kg/infusion) for 14days followed by 21days of extinction when no cues or drug were present. Rats were then divided into 4 treatment groups: control (VEH+SAL), PRO alone (PRO+SAL), VAR alone (VEH+VAR) and the combination (PRO+VAR). Reinstatement of nicotine-seeking behavior induced by priming injections of NIC or caffeine (CAF), presentation of cues (CUES), and the combination of drugs and cues (e.g. NIC+CUES, CAF+CUES) were tested after extinction. Male and female rats did not differ in self-administration of nicotine or extinction responding, and both showed elevated levels of responding to the CAF+CUES condition. However, males, but not females, reinstated active lever-pressing to the NIC+CUES condition, and that was attenuated by both VAR and VAR+PRO treatment. Thus, males were more sensitive to NIC+CUE-induced reinstatement than females, and VAR alone and VAR combined with PRO effectively reduced nicotine relapse.

Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase.

A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine.

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.

Effects of the phencyclidine model of schizophrenia and nicotine on total and categorized ultrasonic vocalizations in rats.

Patients with schizophrenia smoke cigarettes at a higher rate than the general population. We hypothesized that a factor in this comorbidity is sensitivity to the reinforcing and reinforcement-enhancement effects of nicotine. Phencyclidine (PCP) was used to model behavioral changes resembling negative symptoms of schizophrenia in rats. Ultrasonic vocalizations (USVs) in rats have been used to measure emotional states, with 50 kHz USVs indicating positive states and 22 kHz USVs indicating negative states. Total and categorized numbers of 22 and 50 kHz USVs and USVs during a visual stimulus (e.g. a potential measure of reinforcement-enhancement) were examined in rats following injection of PCP (2.0 mg/kg) and/or nicotine (0.2 or 0.4 mg/kg) daily for 7 days. PCP was then discontinued and all rats received nicotine (0.2 and 0.4 mg/kg) and PCP (2.0 mg/kg) on three challenge days. PCP acutely decreased 50 kHz vocalizations, whereas repeated nicotine potentiated rates of vocalizations, with similar patterns during light presentations. Rats in the PCP and nicotine combination groups made more 50 kHz vocalizations compared with rats in the control groups on challenge days. We conclude that PCP may produce a reward deficit, which is shown by decreased 50 kHz USVs, and behaviors post-PCP exposure may best model the comorbidity between schizophrenia and nicotine.

Sex differences in the acquisition and maintenance of cocaine and nicotine self-administration in rats.

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 and maintenance 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.

Effects of repeated quetiapine treatment on conditioned avoidance responding in rats.

The present study characterized the behavioral mechanisms of avoidance-disruptive effect of quetiapine in the conditioned avoidance response test under two behavioral testing (2 warning signals vs. 1 warning signal) and two drug administration conditions (subcutaneous vs. intravenous). In Experiments 1 and 2, well-trained adult male Sprague-Dawley rats were tested under the subcutaneous (s.c.) quetiapine treatment (5.0, 15.0, 25.0, 50.0mg/kg) for 7 days in a novel procedure consisting of two conditioned stimuli (CS) (white noise serving as CS1 and pure tone as CS2). Only the highest dose (50.0mg/kg) produced a persistent suppression of the avoidance response without impairing the escape response. The magnitude of suppression of the CS1 avoidance was similar to that of CS2 avoidance. No significant group difference was found in the quetiapine (15.0mg/kg, s.c.) challenge test, indicating a lack of a long-term quetiapine effect. In Experiment 3, well-trained rats were tested under the intravenous (i.v.) quetiapine treatment (3.0, 9.0, 15.0mg/kg) for 5 days and challenged with quetiapine (6.0mg/kg, i.v. followed by 9.0mg/kg, s.c.). Only the white noise was used as the CS. Similar to what was being observed in Experiments 1 and 2, intravenously administered quetiapine dose-dependently suppressed avoidance responding during the drug test days, but did not alter drug sensitivity in the challenge days. Thus, quetiapine does not appear to show a preferential inhibition of the avoidance response to a less salient stimulus; and prior quetiapine treatment (s.c. and i.v.) does not cause a sensitization or tolerance to quetiapine.

Examining the reinforcement-enhancement effects of phencyclidine and its interactions with nicotine on lever-pressing for a visual stimulus.

Nicotine is a widely-abused drug, yet its primary reinforcing effect does not seem potent as other stimulants such as cocaine. Recent research on the contributing factors toward chronic use of nicotine-containing products has implicated the role of reinforcement-enhancing effects of nicotine. The present study investigates whether phencyclidine (PCP) may also possess a reinforcement-enhancement effect and how this may interact with the reinforcement-enhancement effect of nicotine. PCP was tested for two reasons: (1) it produces discrepant results on overall reward, similar to that seen with nicotine and (2) it may elucidate how other compounds may interact with the reinforcement-enhancement of nicotine. Adult male Sprague-Dawley rats were trained to lever press for brief visual stimulus presentations under fixed-ratio (FR) schedules of reinforcement and then were tested with nicotine (0.2 or 0.4 mg/kg) and/or PCP (2.0mg/kg) over six increasing FR values. A selective increase in active lever-pressing for the visual stimulus with drug treatment was considered evidence of a reinforcement-enhancement effect. PCP and nicotine separately increased active lever pressing for a visual stimulus in a dose-dependent manner and across the different FR schedules. The addition of PCP to nicotine did not increase lever-pressing for the visual stimulus, possibly due to a ceiling effect. The effect of PCP may be driven largely by its locomotor stimulant effects, whereas the effect of nicotine was independent of locomotor stimulation. This dissociation emphasizes that distinct pharmacological properties contribute to the reinforcement-enhancement effects of substances.

Behavioral effects of phencyclidine on nicotine self-administration and reinstatement in the presence or absence of a visual stimulus in rats.

RATIONALE: Tobacco use is a serious health problem in the USA, and this problem is potentiated in patients with schizophrenia. The reward system is implicated in schizophrenia and may contribute to the high comorbidity between nicotine use and schizophrenia, but very little research has been done on the topic. The reward-enhancement effect of nicotine has been shown to be important in nicotine use, but there have been no studies on this effect in animal models of schizophrenia. OBJECTIVES: This study was designed to determine the effects of phencyclidine, used to model negative symptoms of schizophrenia, on self-administration of nicotine with or without a co-occurring sensory reinforcer [i.e., visual stimulus (VS)] in rats. METHODS: Phencyclidine (2.0 mg/kg) was administered before each of seven nicotine self-administration sessions (0.01 mg/kg/inf) after which rats (n = 8-9 per group) were given 7 days of extinction without phencyclidine pretreatment. Reinstatement using phencyclidine (2.0 mg/kg), nicotine (0.2 mg/kg), and yohimbine (1.25 mg/kg, a pharmacological stressor) was tested after extinction to determine if previous exposure to phencyclidine would alter reinstatement of active lever pressing. RESULTS: Phencyclidine initially decreased nicotine self-administration but only in the groups with a concurrent VS. This decrease in self-administration dissipated after 5 days. During reinstatement, rats that had previously received phencyclidine during self-administration with a VS were more sensitive to stress-induced reinstatement than any other group. CONCLUSIONS: These results show a transitory effect of phencyclidine on nicotine self-administration. Phencyclidine may induce a potential sensitivity to pharmacological stressors contributing to reinstatement of nicotine.

Parametric studies of antipsychotic-induced sensitization in the conditioned avoidance response model: roles of number of drug exposure, drug dose, and test-retest interval.

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.

Disentangling the nature of the nicotine stimulus.

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.