Acquisition Of Cocaine Self-administration Research Articles

Cognitive performance as a behavioral phenotype associated with cocaine self-administration in female and male socially housed monkeys.

Considerable research has suggested that certain cognitive domains may contribute to cocaine misuse. However, there are gaps in the literature regarding whether cognitive performance before drug exposure predicts susceptibility to cocaine self-administration and how cognitive performance relates to future cocaine intake. Thus, the present study aimed to examine cognitive performance, as measured using automated CANTAB cognitive battery, prior to and following acquisition of cocaine self-administration under a concurrent drug vs. food choice procedure in female and male socially housed cynomolgus macaques. The cognitive battery consisted of measures of associative learning (stimulus and compound discrimination tasks), behavioral flexibility (intradimensional and extradimensional tasks), and behavioral inhibition (stimulus discrimination reversal, SDR, and extra-dimensional reversal tasks). After assessing cognitive performance, monkeys were trained to self-administer cocaine (saline, 0.01-0.1 mg/kg/injection) under a concurrent cocaine vs. food schedule of reinforcement. After a history of cocaine self-administration across 3-4 years, the cognitive battery was re-assessed and compared with sensitivity to cocaine reinforcement. Results showed drug-naïve monkeys that were less accurate on the SDR task, measuring behavioral inhibition, were more sensitive to cocaine reinforcement under the concurrent cocaine vs.food choice procedure. Furthermore, following chronic cocaine self-administration, cocaine intake was a negative predictor of accuracy on the SDR behavioral inhibition task. After cocaine maintenance, monkeys with higher cocaine intakes required more trials to complete the SDR behavioral inhibition task and made more incorrect responses during these trials. No sex or social rank differences were noted. Overall, these findings suggest that cognitive performance may influence vulnerability to cocaine misuse. Also, chronic cocaine may decrease levels of behavioral inhibition as measured via the SDR task in both females and males.

β2* nAChR sensitivity modulates acquisition of cocaine self-administration in male rats

Signaling through nicotinic acetylcholine receptors (nAChRs) plays a role in cocaine reward and reinforcement, suggesting that the cholinergic system could be manipulated with therapeutics to modulate aspects of cocaine use disorder (CUD). We examined the interaction between nAChRs and cocaine reinforcement by expressing a hypersensitive β2 nAChR subunit (β2Leu9′Ser) in the ventral tegmental area of male Sprague Dawley rats. Compared to control rats, β2Leu9′Ser rats acquired (fixed ratio) intravenous cocaine self-administration faster and with greater likelihood. By contrast, β2Leu9′Ser rats were approximately equivalent to controls in their intake of cocaine on a progressive ratio schedule of reinforcement, suggesting differential effects of cholinergic signaling depending on experimental parameters. Like progressive ratio cocaine SA, β2Leu9′Ser rats and controls did not differ significantly in food SA assays, including acquisition on a fixed ratio schedule or in progressive ratio sessions. These results highlight the specific role of high-affinity, heteropentameric β2* (β2-containing) nAChRs in acquisition of cocaine SA, suggesting that mesolimbic acetylcholine signaling is active during this process.

Acquisition of cocaine reinforcement using fixed-ratio and concurrent choice schedules in socially housed female and male monkeys.

Previous studies in socially housed monkeys examining acquisition of cocaine self-administration under fixed-ratio (FR) schedules of reinforcement found that subordinate males and dominant females were more vulnerable than their counterparts. The present studies extended these findings in two ways: (1) to replicate the earlier study, in which female monkeys were studied after a relatively short period of social housing (~ 3months) using cocaine-naïve female monkeys (n = 9; 4 dominant and 5 subordinate) living in well-established social groups (~ 18months); and (2) in male monkeys (n = 3/social rank), we studied cocaine acquisition under a concurrent schedule, with an alternative, non-drug reinforcer available. In contrast to earlier findings, subordinate female monkeys acquired cocaine reinforcement (i.e., > saline reinforcement) at significantly lower cocaine doses compared with dominant monkeys. In the socially housed males, no dominant monkey acquired a cocaine preference (i.e., > 80% cocaine choice) over food, while two of three subordinate monkeys acquired cocaine reinforcement. In monkeys that did not acquire, the conditions were changed to an FR schedule with only cocaine available and after acquisition, returned to the concurrent schedule. In all monkeys, high doses of cocaine were chosen over food reinforcement. The behavioral data in females suggests that duration of social enrichment and stress can differentially impact vulnerability to cocaine reinforcement. The findings in socially housed male monkeys, using concurrent food vs. cocaine choice schedules of reinforcement, confirmed earlier social-rank differences using an FR schedule and showed that vulnerability could be modified by exposure to cocaine.

Fluoxetine potentiates methylphenidate-induced behavioral responses: Enhanced locomotion or stereotypies and facilitated acquisition of cocaine self-administration

The medical psychostimulant methylphenidate (MP) is used to treat attention-deficit hyperactivity disorder and recreationally as a “cognitive enhancer”. MP is a dopamine reuptake inhibitor, but does not affect serotonin. Serotonin contributes to addiction-related gene regulation and behavior. Previously, we showed that enhancing serotonin action by adding a selective serotonin reuptake inhibitor, fluoxetine (FLX), to MP potentiates MP-induced gene regulation in striatum and nucleus accumbens, mimicking cocaine effects. Here, we investigated the behavioral consequences of MP+FLX treatment. Young adult male rats received MP (5 mg/kg, i.p.) or MP+FLX (5 mg/kg each) daily for 6-8 days. Behavioral effects were assessed in an open-field test during the repeated treatment. Two weeks later the motor response to a cocaine challenge (25 mg/kg) and the rate of acquisition of cocaine self-administration behavior were determined. Our results demonstrate that FLX potentiates effects of MP on open-field behavior. However, we found differential behavioral responses to MP+FLX treatment, as approximately half of the rats developed high rates of focal stereotypies (termed “MP+FLX/high reactivity” group), whereas the other half did not, and only showed increased locomotion (“MP+FLX/low reactivity” group). Two weeks later, cocaine-induced locomotion and stereotypies were positively correlated with MP+FLX-induced behavior seen at the end of the repeated MP+FLX treatment. Moreover, the MP+FLX/high reactivity group, but not the low reactivity group, showed facilitated acquisition of cocaine self-administration. These results demonstrate that repeated MP+FLX treatment can facilitate subsequent cocaine taking behavior in a subpopulation of rats. These findings suggest that MP+FLX exposure in some individuals may increase the risk for psychostimulant use later in life.

Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in a panel of inbred and recombinant inbred mice

To identify addiction genes, we evaluate intravenous self-administration of cocaine or saline in 84 inbred and recombinant inbred mouse strains over 10days. We integrate the behavior data with brain RNA-seq data from 41 strains. The self-administration of cocaine and that of saline are genetically distinct. We maximize power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci are identified in the genome-wide association study. A transcriptome-wide association study highlights the Trpv2 ion channel as a key locus for cocaine self-administration as well as identifying 17 additional genes, including Arhgef26, Slc18b1, and Slco5a1. We find numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance of Trpv2, an ionotropic cannabinoid receptor, for the response to cocaine.

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Introduction: Women are more vulnerable to cocaine’s reinforcing effects and have a more rapid course to addiction after initial cocaine use as compared to men. Studies in rodents similarly indicate an enhanced sensitivity to the reinforcing effects of cocaine in females versus males. Levels of estradiol (E2) are correlated with vulnerability to the rewarding actions of cocaine. Here, we asked if sex chromosome complement (SCC) influences vulnerability to cocaine use. Methods: We used the four-core genotype mouse that produces gonadal males and females with either XX or XY SCC. Mice were gonadectomized and implanted with either an estradiol (E2) or cholesterol-filled pellet. This allowed us to determine the effects of SCC in the absence (cholesterol-treated) and presence of tonic high physiological hormone levels (estradiol). Acquisition of cocaine self-administration was determined over a 12-day period using an escalated dose procedure (0.3 mg/kg/infusion, sessions 1–6; 0.6 mg/kg/infusion, sessions 6–12). Results: Without estradiol treatment, a greater percentage of castrated XY mice acquired cocaine self-administration and did so at a faster rate than XX castrates and ovariectomized XY females. These same XY males acquired sooner, infused more cocaine, and directed more nose pokes to the rewarded nose-poke hole than XX castrates and XY males receiving E2. Conclusion: Our results suggest that in gonadal male mice, SCC and estradiol can modulate the reinforcing effects of cocaine which may influence the likelihood of cocaine use.

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.

Prelimbic Ensembles Mediate Cocaine Seeking After Behavioral Acquisition and Once Rats Are Well-Trained.

Substance use disorder (SUD) is a chronic relapsing condition characterized by continued use of drugs despite negative consequences. SUD is thought to involve disordered learning and memory wherein drug-paired cues gain increased salience, and ultimately drive craving and relapse. These types of associations are thought to be encoded within sparsely distributed sets of neurons, called neuronal ensembles, that drive encoded behaviors through synchronous activity of the participant neurons. We have previously found that Fos-expressing neuronal ensembles within the prefrontal cortex are required for well-trained cocaine seeking. However, less is known about how quickly cortical neuronal ensembles form during the initiation of cocaine seeking behavior. Here, we seek to further elucidate the role of Fos-expressing neuronal ensembles within the prelimbic cortex (PL) after the initial acquisition of cocaine self-administration (SA), or, after 10 days of additional SA training (well-trained). We trained Fos-LacZ transgenic rats to lever press for cocaine under an FR1 schedule of reinforcement. Once rats met acquisition criteria for cocaine self-administration, we ablated Fos-expressing neuronal ensembles in the PL using the Daun02 inactivation method, either 1 or 10 days after the rats met the acquisition criteria. Targeted ablation of Fos-expressing neuronal ensembles in the PL attenuated active lever pressing both 1 day and 10 days after rats acquired cocaine self-administration. Together, this suggests that Fos-expressing neuronal ensembles rapidly form in the PL and continue to mediate maintained cocaine seeking behavior.

Novelty preference does not predict trait cocaine behaviors in male rats

Heightened novelty seeking is a risk factor for the initiation of drug use and development of substance use disorders. In rats, novelty seeking can be examined by assessing preference for a novel environment. Some evidence indicates that high novelty preferring (HNP) rats have higher drug intake compared to low novelty preferring (LNP) rats, although these data are mixed. Moreover, the extent to which the HNP phenotype can predict other initial drug behaviors, including economic demand for cocaine, has not been tested. Here, we screened a cohort (n=60) of male rats for novelty preference and several subsequent cocaine behaviors, including locomotor reactivity to a cocaine priming injection, acquisition of cocaine self-administration, as well as cocaine demand using a within-session behavioral economics procedure. Novelty preference did not correlate with cocaine behaviors, nor were there any differences between HNP and LNP rats identified using a median split strategy. Moreover, regression analyses indicated that novelty preference did not have predictive utility for any of the cocaine behaviors tested. Thus, the extent to which the novelty preference trait can predict initial cocaine-related behaviors in male rats may be limited. This is in contrast to the novel locomotor reactivity phenotype, which is strongly linked with initial cocaine intake, indicating that these traits are distinct and differentially predict cocaine behaviors in rats.

Cannabidiol decreases motivation for cocaine in a behavioral economics paradigm but does not prevent incubation of craving in mice

Cocaine is a highly consumed drug worldwide which directly targets brain areas involved in reinforcement processing and motivation. Cannabidiol is a phytocannabinoid that exerts protecting effects upon cocaine-induced addictive behavior, although many questions about the mechanisms of action and the specific affected processes remain unknown. Moreover, its effects on cue-induced cocaine-craving incubation have never been addressed. The present study aimed to assess the effects of cannabidiol (20 mg/kg, i.p.) administered during the acquisition of cocaine self-administration (0.75 mg/kg/infusion) and demand task or during cocaine abstinence and craving. Moreover, we measured the alterations in expression of AMPAR subunits and ERK1/2 phosphorylation due to cannabidiol treatment or cocaine withdrawal. Our results showed that cannabidiol reduced cocaine intake when administered during the acquisition phase of the self-administration paradigm, increased behavioral elasticity and reduced motivation for cocaine in a demand task. Cannabidiol also reduced GluA1/2 ratio and increased ERK1/2 phosphorylation in amygdala. No effects over cocaine-craving incubation were found when cannabidiol was administered during abstinence. Furthermore, cocaine withdrawal induced changes in GluA1 and GluA2 protein levels in the prelimbic cortex, ventral striatum and amygdala, as well as a decrease in ERK1/2 phosphorylation in ventral striatum. Taken together, our results show that cannabidiol exerts beneficial effects attenuating the acquisition of cocaine self-administration, in which an operant learning process is required. However, cannabidiol does not affect cocaine abstinence and craving.

Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner.

BackgroundCannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown.MethodsWe exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior.ResultsTHC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females).ConclusionsAdolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner.

Individual differences in addiction-like behaviors and choice between cocaine versus food in Heterogeneous Stock rats.

Recent studies reported that when given a mutually exclusive choice between cocaine and palatable food, most rats prefer the non-drug reward over cocaine. However, these studies used rat strains with limited genetic and behavioral diversity. Here, we used a unique outbred strain of rats (Heterogeneous Stock, HS) that mimic the genetic variability of humans. We first identified individual differences in addiction-like behaviors (low and high). Next, we tested choice between cocaine and palatable food using a discrete choice procedure. We characterized the individual differences using an addiction score that incorporates key features of addiction: escalated intake, highly motivated responding (progressive ratio), and responding despite adverse consequences (footshock punishment). We assessed food versus cocaine choice at different drug-free days (without pre-choice cocaine self-administration) during acquisition of cocaine self-administration or after escalation of cocaine self-administration. We also assessed drug versus food choice immediately after 1-, 2-, or 6-h cocaine self-administration. Independent of the addiction score, without pre-choice cocaine (1 or more abstinence days), HS rats strongly preferred the palatable food over cocaine, even if the food reward was delayed or its size was reduced. However, rats with high but not low addiction score modestly increased cocaine choice immediately after 1-, 2-, or 6-h cocaine self-administration. Like other strains, HS rats strongly prefer palatable food over cocaine. Individual differences in addiction score were associated with increased drug choice in the presence but not absence (abstinence) of cocaine. The HS strain may be useful in studies on mechanisms of addiction vulnerability.

Active vaccination reduces reinforcing effects of MDPV in male Sprague-Dawley rats trained to self-administer cocaine.

3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone abused for its cocaine-like psychostimulant effects in "bath salts" products. While there are currently no pharmacotherapies for MDPV abuse, rodent studies suggest immunotherapy may offer a feasible treatment option. These studies tested the capacity of active vaccination to reduce the reinforcing effects of MDPV in Sprague-Dawley rats. Rats acquired cocaine self-administration (0.32 mg/kg/inf) on an FR1 schedule. Dose-effect functions for cocaine (0.032-1.0 mg/kg/inf) and MDPV (0.001-0.32 mg/kg/inf) were determined under an FR5 schedule. Rats in the vaccine group were immunized during cocaine self-administration. All rats transitioned to a progressive-ratio (PR) schedule to establish breakpoints for cocaine (0.1-1.0 mg/kg/inf) and MDPV (0.01-0.32 mg/kg/inf). Responding was extinguished, and cue-induced and MDPV-primed reinstatement (0.56 mg/kg, IP) were evaluated. No endpoints of cocaine self-administration differed between groups, but the ED50 for MDPV self-administration was significantly lower in control relative to vaccinated rats. Under the PR schedule, MDPV was ~ 2.5-fold more potent in maintaining responding in control than vaccinated rats, but Emax was not different between groups. Vaccination did not reduce MDPV-primed reinstatement, perhaps due to a decrease in antibody titer. Vaccination did not alter acquisition of cocaine self-administration, demonstrating pharmacological selectivity and suggesting that the vaccine did not affect learning or motivation, while effectively reducing the potency of MDPV as a reinforcer. The protective effects of the vaccine were surmounted by large unit doses of MDPV, suggesting maximal efficacy of drug-conjugate vaccines in substance abuse disorders will likely require concurrent behavior modification therapy.

Maternal immune activation is associated with a lower number of dopamine receptor 3-expressing granulocytes with no alterations in cocaine reward, resistance to extinction or cue-induced reinstatement

There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In the present work, we use a maternal immune activation model to test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine self-administration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Also, given that D3 and CB2 receptor expression in immune cells is altered in patients with schizophrenia, we examined the populations of immune cells expressing these receptors. Pregnant rats were daily injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline during pregnancy, and we tested prepulse inhibition –PPI- in the offspring. After this, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement. Finally, there were fewer D3R+ granulocytes in the LPS-offspring and an exciting trend for CB2R+ lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that D3R+ granulocytes and possibly CB2R+ lymphocytes could be potential biomarkers of schizophrenia.

P.110 Inflammasomes in “double hit” schizophrenia like-models: new perspectives in the study of psychosis

There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In the present work, we use a maternal immune activation model to test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine self-administration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Also, given that D3 and CB2 receptor expression in immune cells is altered in patients with schizophrenia, we examined the populations of immune cells expressing these receptors. Pregnant rats were daily injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline during pregnancy, and we tested prepulse inhibition –PPI- in the offspring. After this, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement. Finally, there were fewer D3R+ granulocytes in the LPS-offspring and an exciting trend for CB2R+ lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that D3R+ granulocytes and possibly CB2R+ lymphocytes could be potential biomarkers of schizophrenia.

Accelerated development of cocaine-associated dopamine transients and cocaine use vulnerability following traumatic stress.

Post-traumatic stress disorder and cocaine use disorder are highly co-morbid psychiatric conditions. The onset of post-traumatic stress disorder generally occurs prior to the development of cocaine use disorder, and thus it appears that the development of post-traumatic stress disorder drives cocaine use vulnerability. We recently characterized a rat model of post-traumatic stress disorder with segregation of rats as susceptible and resilient based on anxiety-like behavior in the elevated plus maze and context avoidance. We paired this model with in vivo fast scan cyclic voltammetry in freely moving rats to test for differences in dopamine signaling in the nucleus accumbens core at baseline, in response to a single dose of cocaine, and in response to cocaine-paired cues. Further, we examined differences in the acquisition of cocaine self-administration across groups. Results indicate that susceptibility to traumatic stress is associated with alterations in phasic dopamine signaling architecture that increase the rate at which dopamine signals entrain to cocaine-associated cues and increasethe magnitude of persistent cue-evoked dopamine signals following training. These changes in phasic dopamine signaling correspond with increases in the rate at which susceptible rats develop excessive cocaine-taking behavior. Together, our studies demonstrate that susceptibility to traumatic stress is associated with a cocaine use-vulnerable phenotype and suggests that differences in phasic dopamine signaling architecture may contribute to the process by which this vulnerability occurs.

Pitolisant and intravenous cocaine self-administration in mice

Pitolisant, a selective inverse agonist for the histamine H3 receptor, is a new treatment for adults suffering from narcolepsy. Numerous studies have shown that striatal H3 receptors can modulate the activity of the dopamine mesolimbic system, a neuronal pathway that plays a crucial role in drug addiction. Therefore, it is important to guarantee that pitolisant has no abuse potential and does not potentiate the behavioral effects of psychostimulants. The present study tested the effects of pitolisant on cocaine reinforcement in C57BL/6J mice using the intravenous self-administration technique. Mice were trained to self-administer cocaine intravenously. After the acquisition of cocaine self-administration, pitolisant was tested on cocaine self-administration under different schedules of reinforcement (fixed ratio and progressive ratio). In another group of mice, cocaine was replaced with pitolisant after the acquisition of cocaine self-administration. Finally, a group of mice was trained to self-administer pitolisant intravenously and directly compared to mice trained to self-administer cocaine under the same conditions. Our results indicate that pitolisant does not influence the reinforcing effects of cocaine under any of the experimental conditions used in this study. Moreover, pitolisant has no reinforcing properties alone when tested in the self-administration paradigm. Our results offer more evidence to support the hypothesis that pitolisant is not addictive. In addition, pitolisant does not alter the reinforcing effects of cocaine. Finally, the present study provides no evidence for a significant involvement of histamine H3 receptors in cocaine dependence.

Increased cocaine reward in offspring of females exposed to morphine during adolescence.

A growing body of evidence demonstrates that environmental exposures can impact the physiology and behavior of subsequent generations. We have previously demonstrated reduced morphine self-administration in the F1 and F2 offspring of female rats exposed to morphine during adolescence. The current study was designed to determine whether attenuated self-administration for a substance not in the opioid class is also observed in the F1 progeny of adolescent morphine exposed females. Female adolescent rats were administered morphine at increasing doses for 10days (P30-39). Females then remained drug free for at least 3weeks prior to mating with drug-naïve males. As adults, male and female offspring (F1 animals) were tested for cocaine self-administration acquisition, progressive ratio, extinction, and reinstatement. In addition, β-endorphin peptide levels were measured in the nucleus accumbens (NAc) of behaviorally experienced animals following reinstatement and in behaviorally naïve littermates after acute cocaine (0 or 10mg/kg, i.p.). Proopiomelanocortin, the polypeptide that is cleaved to produce β-endorphin, as well as β-endorphin, was examined in the arcuate nucleus of the hypothalamus and the nucleus accumbens, respectively. Finally, corticosterone was measured following acute cocaine. While no differences were observed during the cocaine acquisition phase (FR-1 and FR-5 schedules), under a PR schedule, Mor-F1 animals (both males and females) had increased motivated responding for cocaine. In addition, Mor-F1 males demonstrated enhanced reinstatement compared to Sal-F1 males. In Mor-F1 males, an acute injection of cocaine (10mg/kg, i.p.) decreased β-endorphin levels in the NAc compared to a saline injection while acute cocaine increased β-endorphin in the NAc in Sal-F1 males compared to saline injection. Following acute cocaine, Mor-F1 males had significantly lower levels of β-endorphin in the Nac compared to Sal-F1 males. Additionally, β-endorphin levels in the nucleus accumbens were negatively correlated with reinstatement behavior only in Mor-F1 males. Levels of POMC in the arcuate nucleus were elevated in Mor-F1 males compared to Sal-F1 males, a main effect driven primarily by POMC levels in the acute cocaine condition. These changes were not observed in Mor-F1 females. Finally, plasma corticosterone was increased in Mor-F1 males regardless of acute injection while Mor-F1 females displayed increased corticosterone in response to acute cocaine. These data indicate that morphine prior to conception increases the rewarding effects of cocaine in male and female offspring. In addition, sex-specific alterations in endogenous opioids and hypothalamic physiology were observed.

Effects of adolescent caffeine consumption on cocaine self-administration and reinstatement of cocaine seeking.

Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood. These experiments explore the effects of adolescent caffeine consumption on cocaine self-administration and seeking using a rodent model. Sprague-Dawley rats consumed caffeine for 28 days during the adolescent period. Following the caffeine consumption period, the caffeine solution was replaced with water for the remainder of the experiment. Age-matched control rats received water for the duration of the study. Behavioral testing in a cocaine self-administration procedure occurred during adulthood (postnatal days 62-82) to evaluate how adolescent caffeine exposure influenced the reinforcing properties of cocaine. Cocaine seeking was also tested during extinction training and reinstatement tests following cocaine self-administration. Adolescent caffeine consumption increased the acquisition of cocaine self-administration and increased performance on different schedules of reinforcement. Consumption of caffeine in adult rats did not produce similar enhancements in cocaine self-administration. Adolescent caffeine consumption also produced an upward shift in the U-shaped dose response curve on cocaine self-administration maintained on a within-session dose-response procedure. Adolescent caffeine consumption had no effect on cocaine seeking during extinction training or reinstatement of cocaine seeking by cues or cocaine. These findings suggest that caffeine consumption during adolescence may enhance the reinforcing properties of cocaine, leading to enhanced acquisition that may contribute to increased addiction vulnerability.

Optogenetic inhibition of medial prefrontal cortex projections to the nucleus accumbens core and methyl supplementation via L-Methionine attenuates cocaine-primed reinstatement.

DNA methylation has been identified as a powerful and activity-dependent regulator of changes in the brain that may underlie neuroadaptations in response to various types of stimuli, including exposure to drugs of abuse. Indeed, the medial prefrontal cortex (mPFC) projections to the nucleus accumbens (NAc) are critically important for reinstated cocaine-seeking in a rodent model of cocaine relapse. This circuitry undergoes several epigenetic modifications following cocaine exposure, including changes in DNA methylation that are associated with drug-seeking behavior. We have previously shown that methyl supplementation via L-Methionine (MET) administration attenuates cocaine-seeking behavior and reverses expression and methylation patterns of the immediate early gene c-fos, suggesting that MET may act by altering the excitability of this circuitry during cocaine reinstatement. In the current study, male rats were microinjected with an adeno-associated virus overexpressing halorhodopsin in the mPFC, optical fibers were surgically implanted into the NAc, and the rats were given injections of MET daily. Rats underwent acquisition of cocaine self-administration (0.75 mg/kg/infusion, 2-h sessions) followed by extinction training in the absence of drug-paired cues. Two reinstatement tests were conducted: cue-induced reinstatement without optogenetic manipulations and cocaine-primed reinstatement with optogenetic inhibition of mPFC-to-NAc projections. There were no group differences before the cocaine-primed reinstatement session, and all groups showed robust cue-induced reinstatement. Both rats treated with MET and rats that received mPFC-to-NAc inhibition showed an abolishment of cocaine-primed reinstatement, suggesting that systemic methyl supplementation may act through this critical circuity.