Reinforcing and adverse observable effects of nicotine and minor tobacco alkaloids in squirrel monkeys.

The most prevalent psychoactive chemical in tobacco smoke is nicotine, which has been shown to maintain tobacco consumption as well as cause acute adverse effects at high doses, like nausea and emesis. Recent studies in laboratory animals have suggested that many non-nicotine constituents of tobacco smoke (e.g., minor tobacco alkaloids) may also contribute to tobacco's overall reinforcing and adverse effects. Here, we used intravenous (IV) self-administration (n = 3) and observation (n = 4) procedures in squirrel monkeys to, respectively, compare the reinforcing and adverse observable effects of nicotine and three prominent minor tobacco alkaloids, nornicotine, anatabine, and myosmine. In self-administration studies, male squirrel monkeys were trained to respond under a second-order fixed-interval schedule of reinforcement and dose-effects functions for nicotine and each of the minor tobacco alkaloids nornicotine, anatabine, and mysomine were determined. Observation studies were conducted in a different group of male squirrel monkeys to quantify the ability of nicotine, nornicotine, anatabine, and mysomine to produce adverse overt effects, including hypersalivation, emesis, and tremors. Results show that nicotine and to a lesser extent nornicotine were readily self-administered, whereas anatabine and myosmine were not. In observation studies, all minor tobacco alkaloids produced adverse observable effects that were either comparable or more pronounced than nicotine. Collectively, the present results showing that nicotine and the minor tobacco alkaloids nornicotine, anatabine, and myosmine produce differential reinforcing and acute adverse observable effects in monkeys provides further evidence that these constituents may differently contribute to the psychopharmacological and adverse effects of tobacco consumption.

Intermittent nicotine access is as effective as continuous access in promoting nicotine seeking and taking in rats.

RATIONALE: Nicotine is a principal psychoactive agent in tobacco, contributing to tobacco's addictive potential. Preclinical studies on the effects of voluntary nicotine intake typically use self-administration procedures that provide continuous nicotine access during each self-administration session. However, many smokers consume cigarettes intermittently rather than continuously throughout each day. For drugs including cocaine and opioids, research in laboratory rats shows that intermittent intake can be more effective than continuous intake in producing patterns of drug use relevant to addiction. OBJECTIVE: We determined how intermittent versus continuous nicotine self-administration influences nicotine seeking and taking behaviours. METHODS: Female and male rats had continuous (i.e., Long Access; LgA, 6 h/day) or intermittent (IntA; 12 min ON, 60 min OFF, for 6 h/day) access to intravenous nicotine (15 µg/kg/infusion), for 12 daily sessions. We then assessed intake, responding for nicotine under a progressive ratio schedule of drug reinforcement and cue- and nicotine-induced reinstatement of drug seeking. We also estimated nicotine pharmacokinetic parameters during LgA and IntA self-administration. RESULTS: Overall, LgA rats took twice more nicotine than did IntA rats, yielding more sustained increases in estimated brain concentrations of the drug. However, the two groups showed similar motivation to seek and take nicotine, as measured using reinstatement and progressive ratio procedures, respectively. CONCLUSIONS: Intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviours, despite significantly less nicotine exposure. This has implications for modeling nicotine self-administration patterns in human smokers and resulting effects on brain and behaviour.

Associative learning: Box jellyfish learns to avoid bumps.

Operant conditioning - learning to do something for a desired outcome - has never been convincingly demonstrated in Cnidaria. A study now shows that box jellyfish, Tripedalia cystophora, can learn to avoid bumping into an obstacle based on visual cues.

Nicotine modifies cocaine responding in a concurrent self-administration model.

BACKGROUND: Preclinical models of cocaine use disorder (CUD) have not yielded any FDA-approved pharmacotherapies, potentially due to a focus on cocaine use in isolation, which may not fully translate to real-world drug taking patterns. Cocaine and nicotine are commonly used together, and clinical research suggests that nicotine may increase the potency and reinforcing strength of cocaine. In this study, we sought to determine whether and how the addition of nicotine would alter ongoing intravenous cocaine self-administration and motivation to take cocaine in rats. METHODS: Male Sprague-Dawley rats self-administered cocaine alone on a long access, Fixed Ratio one (FR1) schedule, and then switched to a combination of cocaine and nicotine. Finally, rats responded on a Progressive Ratio (PR) schedule for several doses of cocaine alone and in combination with a single dose of nicotine. RESULTS: Under long access conditions, rats co-self-administering cocaine and nicotine responded less and with decreased response rates than for cocaine alone and did not escalate responding. However, under PR conditions that test motivation to take drugs, the dose response curve for the combination was shifted upwards relative to cocaine alone. CONCLUSIONS: Together, these results suggest that nicotine may enhance the reinforcing strength of cocaine, increasing PR responding for cocaine across the dose response curve.

Experimenter administered Δ9-THC decreases nicotine self-administration in a rat model.

BACKGROUND: The co-use of nicotine and cannabis has been steadily rising in the United States. Rodent studies suggest that delta-9-tetrahydrocannabinol (THC) could increase addictive qualities of nicotine, but whether repeated THC exposure alters self-administration of nicotine has not been tested. We hypothesized that THC would increase the reinforcing effects of nicotine and alter nicotine intake. METHODS: Adult male and female Sprague-Dawley rats were treated with THC (0, 3, 30 mg/kg) daily for 14 days prior to and during training for intravenous self-administration of nicotine. Rats were allowed to self-administer nicotine for several weeks, then tested for sensitivity to nicotine dose through multiple determinations of a nicotine dose-effect curve with or without THC pretreatment. A separate set of rats were trained on fixed ratio responding for sucrose and assessed for THC effects on behavior. RESULTS: Post-session THC decreased nicotine self-administration in male and female rats throughout acquisition and maintenance and increased the latency to stable rates of nicotine intake during acquisition. Post-session THC shifted nicotine dose-effect curves downward, and pre-session THC suppressed responding at higher nicotine doses. Unlike nicotine, responding for sucrose was not affected by post-session THC. Pre-session THC decreased responding for sucrose, particularly for THC-naïve rats. CONCLUSIONS: Repeated post-session THC decreased nicotine-taking behaviors but did not alter sucrose responding. Thus, post-session THC may alter sensitivity to nicotine. Pre-session THC treatment decreased lever pressing in both sucrose and nicotine studies, indicating this effect was nonspecific. These studies show that THC modulates patterns of nicotine intake in rat models.

Effects of acute and chronic nicotine administration on probability discounting.

Nicotine use is a continuing public health concern. Smokers are more likely to make risky or maladaptive decisions compared to nonsmokers, so the relation between nicotine and risky choice warrants further investigation. Risky choice can be operationally defined as the choice for a larger, uncertain reinforcer over a smaller, certain reinforcer and can be assessed through a probability-discounting procedure. Acute nicotine administration has been shown to alter risky choice, but because the everyday smoker uses nicotine repeatedly, more research on chronic administration is needed and would allow for assessment of tolerance or sensitization of any effects. The present study examined effects of acute and repeated nicotine administration on probability discounting. Sprague-Dawley rats were used as subjects and the probability-discounting task involved discrete-trial choices between a small, certain reinforcer and a larger, uncertain reinforcer. The probability of larger-reinforcer delivery decreased across blocks within each session. Acute nicotine (0.1-1.0 mg/kg) administration dose-dependently increased risky choice, increased lose-stay ratios (a measure of response perseveration), and decreased reinforcement frequency. Tolerance to nicotine's effects on larger-reinforcer choice was observed after repeated 1.0 mg/kg nicotine administration. The results of the present study add to the existing literature that acute nicotine administration increases risky choice and demonstrates that tolerance to this effect develops after chronic exposure to the drug. Possible behavioral mechanisms behind this effect are discussed, as are suggestions for future research on nicotine and risky choice.

Role of sex hormones in the effects of sleep deprivation on methamphetamine reward memory.

Sleep deficiency is known as an important risk factor for relapse to drug abuse, especially for the powerful psychostimulant methamphetamine (METH). On the other hand, both drug addiction and sleep neurobiology are affected by sex hormones. We, therefore, aimed to examine the probable effects of sleep deprivation (SD) on methamphetamine (METH) reward memory in male and female rats. Moreover, we asked if sex hormones influence the effects of SD on METH reward memory. Adult male and female Wistar rats were divided into two main groups, sham and gonadectomized groups. Three weeks later, they were conditioned to receive METH (2 mg/kg, i.p.) in the conditioned place preference. METH reward memory was then reinstated following a 10-day extinction period. SD was induced for 72 h, either before or after extinction, in different groups. In gonadectomized animals, they daily received either subcutaneous administration of estrogen (5 µg/0.1 ml oil) or progesterone (2 mg/0.1 ml oil) or dihydrotestosterone (25 mg/0.1 ml oil) for thirteen days, from post-conditioning day to reinstatement session. We found that SD facilitated relapse to METH reward memory, depending on the time interval between SD and METH reinstatement. Furthermore, we found that estrogen and SD showed synergistic effects to facilitate METH reward memory, whereas testosterone and progesterone revealed inhibitory effects in the controls, but not in the SD, animals. Our findings would seem to suggest that sex hormones should be considered as determinant factors to manage METH abuse and relapse to METH seeking/taking behavior, especially for those with sleep deficiency.

Nicotine limits avoidance conditioning with opioids without interfering with the ability to discriminate an opioid-interoceptive state.

Approximately 90 % of individuals undergoing treatment for opioid use disorder (OUD) report comorbid use of nicotine. As such, further investigation into underlying mechanisms contributing to the extreme comorbidity between nicotine and opioid use are warranted. Nicotine administration significantly escalates self-administration of opioids and this increase in motivational efficacy persists despite contingent punishment of opioid consumption. Additionally, both systemic and intra-insular administration of nicotine produces a rightward shift in the dose-response function in both morphine-induced conditioned place preference and taste avoidance paradigms, particularly at higher doses (5-20 mg/kg). Two possible interpretations arise from these outcomes. One is that nicotine may specifically affect learning about the malaise-inducing effects of morphine thus facilitating acceptance of higher doses of morphine. Another interpretation is that it more generally reduces sensitivity to the interoceptive effects of morphine such that higher doses are needed to produce comparable effects in nicotine-treated, relative to control, rats. To further address these possibilities, we asked whether nicotine administration interfered with the ability to discriminate the morphine interoceptive state, irrespective of its hedonic evaluation, at a dose that is impacted by nicotine in avoidance conditioning paradigms. First, we demonstrated that systemic nicotine pretreatment significantly attenuates taste avoidance induced by a low dose of morphine (3 mg/kg). Next, we used an occasion setting paradigm with this same dose of morphine to test whether systemic nicotine pretreatment interferes with the ability to discriminate between saline- and morphine-induced interoceptive states. Within this task, nicotine had no effect on the ability to effectively discriminate between the interoceptive effects of morphine and saline. Collectively, these data suggest that nicotine may be specifically altering the overall hedonic assessment of morphine perhaps by interfering with learning about its deleterious consequences.

Dopamine D3 Receptor Modulates Akt/mTOR and ERK1/2 Pathways Differently during the Reinstatement of Cocaine-Seeking Behavior Induced by Psychological versus Physiological Stress.

Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK1/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK1/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK1/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK1/2 /ERK1/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist's efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK1/2 pathways in memory-processing nuclei.

Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

PURPOSE: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. METHODS: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. RESULTS: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). CONCLUSIONS: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

Anterior basolateral amygdala neurons comprise a remote fear memory engram.

Introduction: Threatening environmental cues often generate enduring fear memories, but how these are formed and stored remains actively investigated. Recall of a recent fear memory is thought to reflect reactivation of neurons, in multiple brain regions, activated during memory formation, indicating that anatomically distributed and interconnected neuronal ensembles comprise fear memory engrams. The extent to which anatomically specific activation-reactivation engrams persist during long-term fear memory recall, however, remains largely unexplored. We hypothesized that principal neurons in the anterior basolateral amygdala (aBLA), which encode negative valence, acutely reactivate during remote fear memory recall to drive fear behavior. Methods: Using adult offspring of TRAP2 and Ai14 mice, persistent tdTomato expression was used to "TRAP" aBLA neurons that underwent Fos-activation during contextual fear conditioning (electric shocks) or context only conditioning (no shocks) (n = 5/group). Three weeks later, mice were re-exposed to the same context cues for remote memory recall, then sacrificed for Fos immunohistochemistry. Results: TRAPed (tdTomato +), Fos +, and reactivated (double-labeled) neuronal ensembles were larger in fear- than context-conditioned mice, with the middle sub-region and middle/caudal dorsomedial quadrants of aBLA displaying the greatest densities of all three ensemble populations. Whereas tdTomato + ensembles were dominantly glutamatergic in context and fear groups, freezing behavior during remote memory recall was not correlated with ensemble sizes in either group. Discussion: We conclude that although an aBLA-inclusive fear memory engram forms and persists at a remote time point, plasticity impacting electrophysiological responses of engram neurons, not their population size, encodes fear memory and drives behavioral manifestations of long-term fear memory recall.

Proopiomelanocortin projections to the nucleus accumbens modulate acquisition and maintenance of operant palatable pellet administration in mice.

Obesity is a crisis in the United States, producing many co-morbid diseases that can drastically decrease quality of life. While diet is a major focus for therapeutic intervention, the need to understand underlying appetitive neurocircuitry persists. Proopiomelanocortin (POMC) peptides are well-known for their anorexigenic activity, but also mediate reward and learning. The nucleus accumbens (NAcc) is best known for its role in reward-based learning, but the contribution of POMC projections to NAcc on feeding are controversial since the two major POMC-derived peptides (ß-endorphin and α-MSH) have opposite effects on food intake. Our objective was to determine the effect of stimulating POMC projections in the NAcc on acquisition and maintenance of operant self-administration of a palatable food. Adult POMCCre mice were microinjected into the NAcc with a Cre-dependent retrograde adeno-associated viral vector expressing Gq Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Mice were trained to self-administer palatable 20-mg pellets in daily operant sessions. Acquisition of self-administration (fixed ratio 30) and baseline self-administration were measured in daily sessions, with mice receiving injections of either JHU37152 (DREADD agonist) or saline (i.p.) 15 min prior to the sessions. POMC neuron stimulation (JHU injection) before training sessions produced a significant increase in rate of acquisition and accuracy compared to the saline treated group, with no significant effect on rewards earned. Removal of POMC neuron stimulation before sessions initially reduced consumption with a gradual increase in responding for reinforcer over 3 days of saline injections. Reinstatement of POMC neuron stimulation (JHU) before the session resulted in a significant decrease in responding and rewards earned. These results suggest a complex role of POMC peptides within the NAcc that increase reward learning for a novel palatable food while decreasing consumption of the reinforcer following experience with it.

The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decrease operant responding for nicotine and food and locomotor activity in male and female rats.

BACKGROUND: The reinforcing properties of nicotine play a critical role in smoking and vaping. There is a need for treatments that decrease the reinforcing properties of nicotine and thereby improve smoking and vaping rates. Dopamine plays a role in the reinforcing properties of nicotine, but little is known about the role of dopamine D2-like receptors in nicotine intake and whether there are sex differences in the effects of dopaminergic drugs on nicotine intake. AIM: The goal of the present studies was to investigate the effects of the D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 on nicotine self-administration in male and female rats. METHODS: The effects of flupentixol and L-741626 on operant responding for nicotine and food and locomotor activity in a small open field were investigated. RESULTS: There were no sex differences in baseline nicotine intake. The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decreased operant responding for nicotine. Blockade of D1/D2-like receptors and blockade of D2-like receptors also decreased operant responding for food and decreased locomotor activity. Flupentixol induced a greater decrease in operant responding for food in males than females. However, in the other tests, there were no sex differences in the effects of the dopamine receptor antagonists. CONCLUSIONS: Blockade of D1/D2-like receptors with flupentixol and D2-like receptors with L-741626 decreases nicotine and food intake in rats of both sexes. These compounds also decrease locomotor activity which might be indicative of a sedative effect.

Nicotine Enhances Intravenous Self-administration of Cannabinoids in Adult Rats.

INTRODUCTION: Nicotine and cannabis are commonly used together, yet few studies have investigated the effects of concurrent administration. Nicotine exhibits reinforcement enhancing effects by promoting the reinforcing properties of stimuli including other drugs. As many studies of this effect used non-contingent nicotine, we implemented a dual-self-administration model where rats have simultaneous access to two drugs and choose which to self-administer throughout a session. Here, we investigated the effect of self-administered or non-contingently delivered nicotine on cannabinoid self-administration. METHODS: Adult male rats were allowed to self-administer the synthetic cannabinoid WIN 55,212-2 (WIN) intravenously, with or without subcutaneous nicotine injections before each session. A separate group of animals were allowed to self-administer WIN, nicotine, or saline using a dual-catheter procedure, where each solution was infused independently and associated with a separate operant response. A third group of male and female rats were allowed to self-administer delta-9-tetrahydrocannabinol (THC) with or without pre-session injections of nicotine. RESULTS: Nicotine injections increased self-administration of WIN and THC. During dual self-administration, nicotine availability increased saline and WIN infusions but nicotine intake was not changed by WIN or saline availability. Rats preferred nicotine over saline, but preferred nicotine and WIN equally when both were available. The effect of nicotine on cannabinoid self-administration was acute and reversible when nicotine was no longer present. CONCLUSIONS: These results expand our understanding of the ability of nicotine to enhance reinforcement of other drugs and suggest that co-use of nicotine and cannabinoids promotes cannabinoid use beyond what would be taken alone. IMPLICATIONS: This study utilizes a dual intravenous self-administration model to investigate the ability of nicotine to enhance cannabinoid intake. Our results demonstrate that the reinforcement enhancing properties of nicotine on drug use extend to include cannabinoids, but that this effect occurs specifically when nicotine is administered alongside the cannabinoid. Interestingly, cannabinoid use did not promote nicotine intake, suggesting this mechanism of reinforcement is specific to nicotine.

Glucagon-like peptide-1 receptors in nucleus accumbens, ventral hippocampus, and lateral septum reduce alcohol reinforcement in mice.

Glucagon-like peptide 1 (GLP-1) receptor agonists can decrease alcohol intake by central mechanisms that are still poorly understood. The lateral septum (LS) and the ventral/caudal part of the hippocampus are enriched in GLP-1 receptors, and activity in these regions was shown to modulate reward-related behaviors. Using microinfusions of the GLP-1 receptor agonist exendin-4 in mice trained to self-administer oral alcohol in an operant assay, we tested whether pharmacological stimulation of GLP-1 receptors in hippocampus and LS decrease alcohol self-administration. We report that infusion of exendin-4 in the ventral hippocampus or LS was sufficient to reduce alcohol self-administration with as large effect sizes as we previously reported with systemic exendin-4 administration. Infusion of exendin-4 into the nucleus accumbens also reduced alcohol self-administration, as anticipated based on earlier reports, while infusion of exendin-4 into the caudate-putamen (dorsal striatum) had little effect, consistent with lack of GLP-1 receptor expression in this region. The distribution of exendin-4 after infusion into the LS or caudate putamen was visualized using a fluorescently labeled ligand. These findings add to our understanding of the circuit-level mechanisms underlying the ability of GLP-1 receptor agonists to reduce alcohol self-administration. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The role of dorsomedial striatum adenosine 2A receptors in the loss of goal-directed behaviour.

RATIONALE: Adenosine A2A receptors (A2AR) in the dorsal striatum have been implicated in goal-directed behaviour. While activation of these receptors with several methods has resulted in an insensitivity to outcome devaluation, particular explanations for how they disrupt behaviour have not been explored. We both confirm a role for A2A receptors in goal-directed responding and evaluate additional behavioural aspects of goal-directed control to more fully understand the role of A2A receptors in instrumental behaviour. OBJECTIVES: To examine the effects of the adenosine A2A agonist CGS-21680 in the DMS on response-outcome encoding, updating representations of outcome value and on the ability to inhibit behaviour when reward is not available. METHODS: Male rats were trained to lever press for food reward. The A2AR agonist CGS-21680 was infused into the dorsomedial striatum either before an outcome devaluation test, prior to training with two distinct response-outcome associations or prior to a test of discriminative stimulus control over instrumental performance. RESULTS: Intra-DMS administration of CGS-21680 impaired sensitivity to outcome devaluation. CGS-21680 treatment did not impair acquisition of specific response-outcome associations, selective control of responding based on the presence of stimuli that signaled when reward was or was not available, discrimination between stimuli or lever choices nor did it influence the effect of devaluation on the amounts of food eaten in a consumption test. CONCLUSIONS: CGS-21680 impairs the ability to modulate responding based on recent changes to outcome value, an effect that is not accounted for by impairments in behavioural inhibition, discrimination, encoding the specific outcome of a response or the effectiveness of specific satiety.

Male and Female Sprague Dawley Rats Exhibit Equivalent Natural Reward, Nicotine Self-Administration, Extinction, and Reinstatement During Adolescent-Initiated Behaviors.

INTRODUCTION: The initiation of nicotine and tobacco use peaks during adolescence. How adolescent males and females differ based on the acquisition of nicotine use and nicotine-seeking behavior is less understood. Our current studies develop a preclinical intravenous self-administration and reinstatement paradigm in male and female Sprague Dawley rats to evaluate how sex impacts the acquisition of nicotine self-administration and nicotine-seeking, when behavior is initiated during adolescence. AIMS AND METHODS: Male and female adolescent rats were food trained under a fixed-ratio one (FR1) schedule of reinforcement and progressively increased to FR5. Animals were implanted with catheters and began nicotine self-administration (0.015 mg/kg/infusion) at FR5 during adolescence on postnatal day 34. Upon reaching stable reinforced responding, animals were tested for progressive ratio (PR) schedules of reinforcement followed by extinction via the removal of drug and associated cues for a minimum of 5 days or until responding was reduced to ≤25% of baseline. Reinstatement testing began for cue only, nicotine only, and a combination of nicotine plus cues using a Latin square design. Animals returned to extinction conditions for 2 days minimum between testing. RESULTS: No sex differences were observed for natural rewards, acquisition, and PR schedules of nicotine self-administration, days to extinction, and reinstatement condition. CONCLUSIONS: Our findings provide evidence that sex does not impact natural rewards, nicotine reinforcement, reward, and reinstatement, when behavior is initiated during adolescence. Our study offers a feasible approach for assessing nicotine-seeking in male and female Sprague Dawley rats during the unique developmental window of adolescence. IMPLICATIONS: This study demonstrates the impact of nicotine and associated cues in the reinstatement of nicotine-seeking in male and female rats when behavior is initiated during adolescence. Findings support the equivalent impact of nicotine and the nonpharmacological stimuli of cues between male and female adolescent rats that began nicotine self-administration during adolescence.

Effects of isoflurane anesthesia on addictive behaviors in rats.

RATIONALE: Recently, it has been suggested that isoflurane might reduce dopamine release from rat midbrain dopaminergic neurons, the neurobiological substrate implicated in the reinforcing effects of abused drugs and nondrug rewards. However, little is known about effects of isoflurane on neurobehavioral activity associated with chronic exposure to psychoactive substances. OBJECTIVE: The present study was designed to investigate the effects of isoflurane on cocaine-reinforced behavior. Using behavioral paradigm in rats, we evaluated the effects of isoflurane on cocaine self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. We also tested the effects of isoflurane on lever responding by nondrug reinforcers (sucrose and food) in drug-naive rats to control for the nonselective effects of isoflurane on cocaine- and nicotine-taking behavior. To further assess the ability of isoflurane to modulate the motivation for taking a drug, we evaluated the effects of isoflurane on nicotine self-administration. Using different groups of rats, the effects of isoflurane on the locomotor activity induced by a single intraperitoneal injection of cocaine (15 mg/kg) were also examined. RESULTS: Isoflurane significantly suppressed the self-administration of cocaine and nicotine without affecting food consumption. Unlike food-reinforced responding, responding for sucrose reinforcement was decreased by isoflurane. Isoflurane reduced breaking points under a PR schedule of reinforcement in a dose-dependent manner, indicating its efficacy in decreasing the incentive value of cocaine. Isoflurane also attenuated acute cocaine-induced hyperlocomotion. CONCLUSIONS: The results provided evidence that isoflurane decreases cocaine- and nicotine-reinforced responses, while isoflurane effect is not selective for cocaine- and nicotine-maintained responding. These results suggest that isoflurane inhibitions of cocaine- and nicotine-maintenance responses may be related to decreased effects of dopamine, and further investigation will need to elucidate this relationship.

Relapse to cotinine seeking in rats: differential effects of sex.

Relapse is a defining feature of smoking and a significant challenge in cessation management. Elucidation of novel factors underlying relapse may inform future treatments. Cotinine, the major metabolite of nicotine, has been shown to support intravenous self-administration in rats, implicating it as one potential factor contributing to nicotine reinforcement. However, it remains unknown whether cotinine would induce relapse-like behaviors. The current study investigated relapse to cotinine seeking in two relapse models, the reinstatement of drug seeking and incubation of drug craving models. In the reinstatement model, rats were trained to self-administer cotinine, underwent extinction of cotinine-associated responses, and were tested for cue-, drug-, or stress-induced reinstatement. Conditioned cues associated with cotinine self-administration, cotinine (1-2 mg/kg), or the pharmacological stressor yohimbine (1.25-2.5 mg/kg) induced reinstatement of cotinine seeking. Female rats displayed more pronounced cue-induced, but not drug- or stress-induced reinstatement than male rats. In the incubation of the craving model, rats were trained to self-administer cotinine and underwent forced withdrawal in home cages. Rats were tested for cue-induced cotinine-seeking on both withdrawal day 1 and withdrawal day 18. Rats exhibited greater cue-induced cotinine-seeking on withdrawal day 18 compared to withdrawal day 1, with no difference between male and female rats. These findings indicate that cotinine induces sex-specific relapse to drug seeking in rats, suggesting that cotinine may contribute to relapse.

Dopamine D1-like receptor blockade and stimulation decreases operant responding for nicotine and food in male and female rats.

Dopamine has been implicated in the reinforcing effects of smoking. However, there remains a need for a better understanding of the effects of dopamine D1-like receptor agonists on nicotine intake and the role of sex differences in the effects of dopaminergic drugs on behavior. This work studied the effects of D1-like receptor stimulation and blockade on operant responding for nicotine and food and locomotor activity in male and female rats. The effects of the D1-like receptor antagonist SCH 23390 (0.003, 0.01, 0.03 mg/kg) and the D1-like receptor agonist A77636 (0.1, 0.3, 1 mg/kg) on responding for nicotine and food, and locomotor activity were investigated. The effects of SCH 23390 were investigated 15 min and 24 h after treatment, and the effects of the long-acting drug A77636 were investigated 15 min, 24 h, and 48 h after treatment. Operant responding for nicotine and food and locomotor activity were decreased immediately after treatment with SCH 23390. Treatment with SCH 23390 did not have any long-term effects. Operant responding for nicotine was still decreased 48 h after treatment with A77636, and food responding was decreased up to 24 h after treatment. Treatment with A77636 only decreased locomotor activity at the 48 h time point. There were no sex differences in the effects of SCH 23390 or A77636. In conclusion, the D1-like receptor antagonist SCH 23390 reduces nicotine intake and causes sedation in rats. Stimulation of D1-like receptors with A77636 decreases nicotine intake at time points that the drug does not cause sedation.