Low Doses Of Cocaine Research Articles

Sexual effects of commonly used recreational psychostimulants in women and the female rat model.

Recreational psychostimulants have been associated with increased sexual activity or changes in sexual function in women, but every drug in this class has not shown consistent sexual effects in scientific studies. Further, some studies in female animal models may recapitulate the effects observed in humans, while others produce conflicting results. Overall, though, published studies on the sexual effects of recreational stimulants in women are lacking. The objective of this manuscript was to review the published sexual effects of prominent recreational psychostimulants in women and in the female rat model. Literature searches for "any years" were performed through PubMed and Google Scholar. Keywords for the searches included "amphetamine," "methamphetamine," "MDMA," "ecstasy," "3,4-methylenedioxymethamphetamine," "cocaine," "caffeine," "sex," "sexual," "female," and "women." Studies in humans and using animal models were included. Older studies have shown that amphetamine produces a positive sexual effect in women, but often the sample size was too small to draw generalizable conclusions. Methamphetamine also has a positive effect on several sexual domains in women, as well as on vaginal lubrication. 3,4-Methylenedioxymethamphetamine may have a negative or positive effect on sexual activity, but often enhances the sensual aspects of sex. Though low doses of cocaine may heighten the sexual experience, most women who use cocaine experience negative sexual effects. Caffeine has been shown to enhance a physiological measure of arousal, vaginal blood flow, but based on our searches, no studies have investigated the subjective sexual effects of the drug. Different recreational psychostimulants produce varying effects on sexual behavior and responses in women and female animal models, but more research is needed to understand these effects better.

Adolescent exposure to sucrose increases cocaine-mediated behaviours in adulthood via Smad3.

Adolescence, a critical period of developmental period, is marked by neurobiological changes influenced by environmental factors. Here, we show how exposure to sucrose, which is ubiquitously available in modern diets, results in changes in behavioural response to cocaine as an adult. Rats were given daily access to either 10% sucrose or water during the adolescent period (PND28-42). Following this period, rats are left undisturbed until they reach adulthood. In adulthood, rats were tested for (i) acquisition of a low dose of cocaine, (ii) progressive ratio (PR) test, and (iii) resistance to punished cocaine taking. Sucrose exposure resulted in significant alterations in all behavioural measures. To determine the neurobiological mechanisms leading to such behavioural adaptations, we find that adolescent sucrose exposure results in an upregulation of the transcription factor Smad3 in the nucleus accumbens (NAc) when compared with water-exposed controls. Transiently blocking the active form of this transcription factor (HSV-dnSmad3) during adolescence mitigated the enhanced cocaine vulnerability-like behaviours observed in adulthood. These findings suggest that prior exposure to sucrose during adolescence can heighten the reinforcing effects of cocaine. Furthermore, they identify the TGF-beta pathway and Smad3 as playing a key role in mediating enduring and long-lasting adaptations that contribute to sucrose-induced susceptibility to cocaine. Taken together, these results have important implications for development and suggest that adolescent sucrose exposure may persistently enhance the susceptibility to substance abuse.

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking.

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, male Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an fixed-ratio 1 schedule. However, microbiome-depleted rats exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinenceand altered transcriptional regulation in the nucleus accumbens. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

Resilience to the short- and long-term behavioral effects of intermittent repeated social defeat in adolescent male mice

BackgroundExposure to intermittent repeated social defeat (IRSD) increases the sensitivity of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Some animals are resilient to this effect of IRSD, though research exploring this inconsistency in adolescent mice is scarce. Thus, our aim was to characterize the behavioral profile of mice exposed to IRSD during early adolescence and to explore a potential association with resilience to the short- and long-term effects of IRSD. MethodsThirty-six male C57BL/6 mice were exposed to IRSD during early adolescence (PND 27, 30, 33 and 36), while another 10 male mice did not undergo stress (controls). Defeated mice and controls then carried out the following battery of behavioral tests; the Elevated Plus Maze, Hole-Board and Social Interaction Test on PND 37, and the Tail Suspension and Splash tests on PND 38. Three weeks later, all the mice were submitted to the CPP paradigm with a low dose of cocaine (1.5 mg/kg). ResultsIRSD during early adolescence induced depressive-like behavior in the Social Interaction and Splash tests and increased the rewarding effects of cocaine. Mice with low levels of submissive behavior during episodes of defeat were resilient to the short- and long-term effects of IRSD. In addition, resilience to the short-term effects of IRSD on social interaction and grooming behavior predicted resilience to the long-term effects of IRSD on cocaine reward. ConclusionOur findings help to characterize the nature of resilience to the effects of social stress during adolescence.

Effects of Co‐Use of Nicotine on Cocaine‐Food Choice in Socially Housed Female and Male Cynomolgus Monkeys

Cocaine use disorder (CUD) continues to be a major public health problem worldwide with 2.0 million Americans reporting current cocaine use. At present there are no FDA‐approved pharmacotherapies for CUD. An important consideration in evaluating mechanisms of CUD and potential treatment strategies is the observation that most individuals suffering from CUD also use tobacco products. However, most preclinical studies investigating cocaine do not include co‐exposure with nicotine. For these studies, socially housed female and male monkeys (N= 5/sex) self‐administered cocaine (saline, 0.001‐0.1 mg/kg/inj) under a concurrent schedule with food (1.0‐g banana‐flavored food pellets) as the alternative reinforcer during daily 1‐hr sessions. Under these conditions, the frequency of cocaine choice increases in a dose‐dependent manner; there were individual‐subject differences in sensitivity, but when nicotine was added to the cocaine solution, we individually chose the highest cocaine dose which resulted in <20% cocaine choice for each monkey. When increasing doses of nicotine (0.01‐0.056 mg/kg/inj) were added to the cocaine solution, non‐reinforcing doses of cocaine were chosen (i.e., >80% drug choice) in 8 of the 10 monkeys; importantly, in no cases were these nicotine doses chosen over food. These data suggest that when a non‐reinforcing dose of nicotine is added to a non‐reinforcing dose of cocaine, drug choice increases to the point that the combination is chosen over the non‐drug alternative. Next, environmental manipulations were studied to determine whether the cocaine+nicotine combination was more resistant to changes than cocaine alone. For these studies, we used a delay discounting procedure similar to that described by Woolverton and colleagues (Huskinson et al., 2015, 2016). We compared the indifference point (IP; 50% choice between cocaine and food) when a preferred dose of cocaine was available vs. food and cocaine was delayed, to the IP value when a lower cocaine dose + nicotine was available vs. food. We found that in each case, the IP value was greater for the cocaine+nicotine combination compared with the cocaine alone choice. These findings suggest (1) that co‐abuse of nicotine and cocaine can potentiate the reinforcing effects of cocaine and (2) that manipulations designed to decrease cocaine choice are less effective under conditions in which co‐use of nicotine is studied. These preliminary studies did not reveal sex differences or effects of social rank. At present, it is not known how nicotine and cocaine interact. One hypothesis is that both drugs together produce entirely novel neurobiological effects compared with either one alone. The behavioral endpoints may look additive, as shown in our preliminary data, but the mechanisms are probably not simply additive. These studies may lead to a more personalized medicine approach to treating CUD.

Dose-dependent effect of retrieval-extinction on preventing reinstatement of cocaine-associated memory in mice.

As a noninvasive behavioral intervention, the retrieval-extinction (R-E) procedure has drawn much research attention for its capacity to target the reconsolidation of maladaptive memories. However, later research findings suggest that the cause and consequence of R-E may be more complicated than previously suggested. For example, the R-E procedure could increase an animal's motivation for drug-seeking under certain circumstances, and the reversed extinction-retrieval (E-R) procedure could also suppress the drug memory. Two possible mechanisms underlying the R-E procedure have been proposed: the reconsolidation-update and extinction-facilitation hypotheses. To elucidate the paradoxical prior findings and examine these two hypotheses, we systematically examined the efficacy of the extinction (E), R-E, and E-R procedures in mice's low-dose versus high-dose cocaine-induced conditioned place preference (CPP) memory. We showed that the dose of cocaine is a crucial determinant of the efficacy of the three behavioral interventions. The E procedure exerted a long-lasting suppression of the low-dose cocaine CPP memory, while the R-E procedure induced more memory defects than the E and E-R procedures in its long-term suppression of the high-dose cocaine CPP memory. It warrants further investigation of whether the R-E procedure's underlying neurochemical and molecular mechanisms differ from the E and E-R procedures.

Environmental cocaine places mussels at risk by increasing neurotransmitters

When going to the beach for a swim, probably the last thing on your mind is whether you are swimming in a thin soup of drug traces. Whether prescribed over the counter or illegal, many drugs taken by people wind up in our waterways. These drugs cannot be removed by wastewater treatment plants and thus get released back into the environment. A famous coastal region in Brazil, the Bay of All Saints (Baía de Todos os Santos in Portuguese), has been the subject of multiple environmental contaminant studies and researchers have found measurable quantities of cocaine in the seawater, sediment and mussels (Perna perna) of the bay. Although the environmental concentrations are too low to affect humans, whether cocaine at these levels has an effect on the nervous system of aquatic species that reside in the bay was unknown. So, Mayana Fontes and a team of researchers from Universidade Estadual Paulista Júlio de Mesquita Filho, Brazil, and other universities in Brazil investigated how levels of cocaine in the seawater affect the nervous system of P. perna mussels.Fontes and colleagues placed adult mussels in tanks containing seawater with two different concentrations of cocaine that were realistic for the Bay of All Saints (0.2 and 2 μg l−1) for 2, 4 or 7 days. Then, they collected the adductor muscles, which open and close the shell, and gonads of these mussels. In the adductor muscle, they measured the activity of acetylcholine esterase, an enzyme essential for a functioning nervous system. In the gonads, they measured the levels of two major neurotransmitters, serotonin and dopamine, the activity of the enzyme that breaks down these neurotransmitters, monoamine oxidase, and the activity of cyclooxygenase, an enzyme that is a sign of inflammation and is important for egg release in mussels. In addition, the authors also measured how much energy the mussels spent during the exposure to cocaine by measuring mitochondrial electron transport activity, and how much energy they set aside by measuring the level of total lipids in the gonads.The team found that mussels exposed to cocaine had a decreased acetylcholine esterase activity in the adductor muscle, which shows that cocaine disrupted the normal activity of the nervous system. They also found that mussels exposed to cocaine had raised levels of dopamine and serotonin. These neurotransmitters are essential for reproduction, and changes could lead to an unsustainable population in the wild. The mussels also increased cyclooxygenase activity in the gonads, which shows an inflammatory response to low doses of cocaine. In addition, the scientists found changes in the mitochondrial electron transport chain – which converts the energy from oxygen into ATP in the mitochondria – directly increasing the amount of energy the mussels spent after exposure to the drug, which decreases the amount of energy they can access for reproduction as energy is limited. Finally, they also found that there was an increase in levels of total lipid, which act as a convenient and easy to access energy source for the animals.Fontes and colleagues have shown that the current concentration of cocaine in the seawater around the Bay of All Saints can negatively impact the area's mussels in complex ways and this may put them at a greater risk from other chemicals that we dump into the environment.

Sex differences in cocaine-associated memory: The interplay between CB1, mGluR5, and estradiol

We know surprisingly little about the sex differences in the neurobiology of cocaine addiction, except females are more susceptible to the rewarding effects of cocaine than their male counterparts. Only a handful of recent studies have examined the neurobiology of cocaine-induced conditioned place preference (CPP) memory among female rodents. We contribute to this emerging line of research by documenting sex differences in cocaine-associated memory and illustrating the underlying signaling pathways in five experiments. Rimonabant (Rim), a cannabinoid CB1 antagonist and inverse agonist, exerted a facilitating effect for low-dose cocaine and an impairing effect for high-dose cocaine CPP memory in male mice, as in our previous study, but not in female mice. Nor did we observe the effect exist among CB1 knockout male mice, which indicated that the CB1 receptors played a mediating role. We also found that the metabotropic glutamate receptor 5 (mGluR5) was located in the same signaling pathway as CB1 in male mice. To clarify the mechanisms behind the sex differences, we used ovariectomized (OVX) female mice with estradiol benzoate (EB) replacement. In the OVX female mice, we showed that Rim-alone and EB-alone, but not Rim-and-EB-combined, facilitated the low-dose cocaine CPP memory. Moreover, 4-hydroxytamoxifen (4-OHT), an estrogen receptor (ER) antagonist, blocked Rim's and EB's facilitating effect. Finally, 2-methyl-6-(phenylethynyl)pyridine (MPEP), an mGluR5 antagonist, partially blocked EB’s facilitating effect. In sum, we identified sex-specific effects of Rim on cocaine-induced CPP memory and the respective signaling pathways: mGluR5-CB1 for male mice and ER-mGluR5-CB1 for female mice. These findings may have merits for the development of sex-specific treatment for cocaine addiction.

Delay Discounting of Cocaine‐Food Choice in Socially Housed Female and Male Cynomolgus Macaques

At present, there are no FDA-approved pharmacological treatments for cocaine use disorders (CUD). Because there is evidence of sex differences in vulnerability to cocaine abuse (O’Brien and Anthony, 2005) and treatment outcomes (Sugarman et al., 2017), research needs to include both sexes in evaluating treatment strategies. Weafer and de Wit (2014) have suggested that impulsivity is a stronger predictor of drug abuse in females compared to males and lack of inhibitory control may be a mechanism mediating the faster progression of drug use in women compared to men. The overarching goal of the present research is to utilize a “personalized medicine” approach to evaluating the role of environmental and pharmacological interventions on the reinforcing effects of cocaine. In this study, socially housed female (N=5) and male (N=6) cynomolgus monkeys, each implanted with an indwelling intravenous catheter and self-administering cocaine (0.01-0.1 mg/kg/injection) under a concurrent schedule with food (1.0-g banana-flavored pellets) as the alternative, served as subjects. Under these conditions, the frequency of cocaine choice increases in a dose-dependent manner, from <20% choice when 0.01 mg/kg/injection cocaine was available as an alternative to food, to >80% choice when 0.1 mg/kg/injection was the alternative to food; in this preliminary study, no sex or social rank differences were noted. Next, environmental manipulations were studied at both ends of the cocaine dose-response curve in order to assess whether there were sex differences in sensitivity to the reinforcing effects of cocaine. To study impulsivity, we used a delay discounting procedure similar to that described by Woolverton and colleagues (Huskinson et al., 2015, 2016). Differences in sensitivity to changes in cocaine preference when the preferred cocaine dose was available would provide information as to potential sex differences in the reinforcing strength of cocaine. In contrast, when low, non-preferred, cocaine doses were studied and food reinforcement was delayed, sex differences would provide information related to sensitivity of adverse environmental changes on vulnerability to cocaine abuse. In preliminary findings, when delays were imposed on high-dose cocaine, the indifference points (IP; 50% choice between cocaine and food) were not different between males and females (168.88 ± 75.6 seconds vs. 154.94 ± 39.1 seconds, respectively). However, when low-dose cocaine was available and food reinforcement was delayed, males were more sensitive to changes in the environment, as represented by lower IP values (46.74 ± 16.8 seconds vs. 114.39 ± 44.9 seconds, respectively). Studies are currently underway to determine if pharmacological manipulations, with and without delays, would provide additional reductions in cocaine choice, at both ends of the cocaine dose-response curve. An interesting behavioral pharmacology study would involve examine drug effects under conditions in which delayed high-dose cocaine and food-delayed low-dose cocaine produce similar behaviors (i.e., % cocaine choice).

Single Low Dose of Cocaine-Structural Brain Injury Without Metabolic and Behavioral Changes.

Chronic cocaine use has been shown to lead to neurotoxicity in rodents and humans, being associated with high morbidity and mortality rates. However, recreational use, which may lead to addictive behavior, is often neglected. This occurs, in part, due to the belief that exposure to low doses of cocaine comes with no brain damage risk. Cocaine addicts have shown glucose metabolism changes related to dopamine brain activity and reduced volume of striatal gray matter. This work aims to evaluate the morphological brain changes underlying metabolic and locomotor behavioral outcome, in response to a single low dose of cocaine in a pre-clinical study. In this context, a Balb-c mouse model has been chosen, and animals were injected with a single dose of cocaine (0.5 mg/kg). Control animals were injected with saline. A behavioral test, positron emission tomography (PET) imaging, and anatomopathological studies were conducted with this low dose of cocaine, to study functional, metabolic, and morphological brain changes, respectively. Animals exposed to this cocaine dose showed similar open field activity and brain metabolic activity as compared with controls. However, histological analysis showed alterations in the prefrontal cortex and hippocampus of mice exposed to cocaine. For the first time, it has been demonstrated that a single low dose of cocaine, which can cause no locomotor behavioral and brain metabolic changes, can induce structural damage. These brain changes must always be considered regardless of the dosage used. It is essential to alert the population even against the consumption of low doses of cocaine.

Effects of chronic treatment with bupropion on self-administration of nicotine + cocaine mixtures in nonhuman primates.

Chronic health problems associated with long-term nicotine use are the leading cause of preventable death in the United States. The use of tobacco products is 3-4 times greater among individuals with cocaine use disorder than that observed in the general population. This may reflect the propensity of nicotine to augment the reinforcing effects of cocaine. However, the mechanism of action of nicotine differs from that of cocaine, which presents a significant challenge for the development of pharmacotherapeutic interventions for the management of nicotine + cocaine polydrug abuse. Bupropion, an FDA-approved smoking cessation aid, has pharmacological actions at both monoamine transporters and nicotinic receptors, suggesting that it may be effective at decreasing nicotine + cocaine coabuse. Here, rhesus monkeys (n = 4) responded for food pellets and, separately, intravenous injections of nicotine, cocaine, or nicotine + cocaine mixtures under a second-order FR2(VR16:S) schedule of reinforcement during 7- to 10-day continuous treatment with saline or bupropion (1.0 and 1.8 mg/kg/hr). Results show that bupropion treatment dose-dependently decreased self-administration of nicotine combined with a low dose of cocaine (0.0032 mg/kg/inj); however, when the dose of cocaine in the mixture was higher (i.e., 0.01 mg/kg/inj), bupropion attenuated self-administration in only a subset of subjects. The effective dosage of bupropion increased responding for cocaine alone, nicotine alone, and for saline injections and significantly increased measures of daily activity. The apparent stimulant-like effects of bupropion at the dosage required to decrease cocaine + nicotine self-administration does not support its clinical use for the management of nicotine + cocaine polydrug abuse. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Preclinical support for the therapeutic potential of zolmitriptan as a treatment for cocaine use disorders

Serotonin 1B receptor (5-HT1BR) agonists enhance cocaine intake in rats during daily self-administration but attenuate cocaine intake after prolonged abstinence. Here we investigated whether the less selective but clinically available 5-HT1D/1BR agonist, zolmitriptan, produces similar effects. Male and free-cycling female Sprague-Dawley rats were trained to lever press for cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg pellet) reinforcement until performance rates stabilized. Rats then received zolmitriptan (3.0, 5.6, and 10 mg/kg, s.c.) prior to testing for its effects on response and reinforcement rates. Under cocaine testing conditions, rats had access to the training dose for the first hour followed by a lower cocaine dose (0.075 mg/kg, i.v.) for the second hour. Zolmitriptan decreased cocaine intake at both cocaine doses and in both sexes even without a period of abstinence and without altering sucrose intake. A separate group of rats underwent identical training procedures and were tested for effects of the selective 5-HT1B and 5-HT1D receptor antagonists, SB224289 (3.2, 5.6, and 10 mg/kg, s.c.) and BRL15572 (0.3, 1.0, and 3.0 mg/kg, i.p.), respectively, alone or in combination with zolmitriptan (5.6 mg/kg, s.c.) under identical cocaine testing procedures as above. The zolmitriptan-induced decrease in cocaine intake was reversed by SB224289 and to a lesser extent by BRL15572, suggesting that the effects of zolmitriptan involve both 5-HT1B and 5-HT1D receptors. Neither zolmitriptan, SB224289, or BRL15572 altered locomotor activity at the doses effective for modulating cocaine intake. These findings suggest that zolmitriptan has potential for repurposing as a treatment for cocaine use disorders.

Acute cocaine treatment enhances the antagonistic allosteric adenosine A2A-dopamine D2 receptor\u2013receptor interactions in rat dorsal striatum without increasing significantly extracellular dopamine levels

BackgroundAntagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor–receptor interactions have previously been demonstrated in A2AR–D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Upon cocaine self-administration, this antagonistic A2AR–D2R interaction disappeared in the dorsal striatum.MethodsIn the current experiments, it was tested whether such modifications in the antagonistic A2AR–D2R receptor–receptor interactions can develop also after an acute systemic injection of a low cocaine dose (1 mg/kg; sc).ResultsMicrodialysis experiments indicated that acute cocaine did not significantly alter the extracellular dopamine levels in the dorsal striatum of the awake Wistar rats. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R Ki, High values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Furthermore, in the dorsal striatum membrane preparation from acute cocaine-injected rats, CGS-21680 also produced significant increases in the D2R Ki, Low values (reduction of low-affinity) and in the proportion of D2Rs in the high-affinity state (RH). Such significant effects were not observed with CGS-21680 in the control group.ConclusionsThe molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR–D2R receptor–receptor interactions may be an increased formation of higher-order complexes A2AR–D2R-sigma1R in which cocaine by binding to the sigma1R protomer also allosterically enhances the inhibitory A2AR–D2R interaction in this receptor complex.

Behavioral Traits Associated With Resilience to the Effects of Repeated Social Defeat on Cocaine-Induced Conditioned Place Preference in Mice.

The relationship between stress and drug use is well demonstrated. Stress-induced by repeated social defeat (RSD) enhances the conditioned place preference (CPP) induced by cocaine in mice. The phenomenon of resilience understood as the ability of subjects to overcome the negative effects of stress is the focus of increasing interest. Our aim is to characterize the behavior of resilient animals with respect to the effects of RSD on the CPP induced by cocaine. To this end, 25 male C57BL/6 mice were exposed to stress by RSD during late adolescence, while other 15 male mice did not undergo stress (controls). On the 2 days following the last defeat, all the animals carried out the elevated plus maze (EPM) and Hole Board, Social Interaction, Tail Suspension and Splash tests. Three weeks later, all the animals performed the CPP paradigm with a low dose of cocaine (1 mg/kg). Exposure to RSD decreased all measurements related to the open arms of the EPM. It also reduced social interaction, immobility in the tail suspension test (TST) and grooming in the splash test. RSD exposure also increased the sensitivity of the mice to the rewarding effects of cocaine, since only defeated animals acquired CPP. Several behavioral traits were related to resilience to the potentiating effect of RSD on cocaine CPP. Mice that showed less submission during defeat episodes, a lower percentage of time in the open arms of the EPM, low novelty-seeking, high social interaction, greater immobility in the TST and a higher frequency of grooming were those that were resilient to the long-term effects of social defeat on cocaine reward since they behaved like controls and did not develop CPP. These results suggest that the behavioral profile of resilient defeated mice is characterized by an active coping response during episodes of defeat, a greater concern for potential dangers, less reactivity in a situation of inevitable moderate stress and fewer depressive-like symptoms after stress. Determining the neurobehavioral substrates of resilience is the first step towards developing behavioral or pharmacological interventions that increase resilience in individuals at a high risk of suffering from stress.

Social Interaction With an Alcohol-Intoxicated or Cocaine-Injected Peer Selectively Alters Social Behaviors and Drinking in Adolescent Male and Female Rats.

Drinking alcohol is facilitated by social interactions with peers, especially during adolescence. The importance of peer social influences during adolescence on alcohol and substance use has recently received more attention. We have shown that social interaction with an alcohol-intoxicated peer influences adolescent alcohol drinking differently in male and female rats using the demonstrator-observer paradigm. The present set of experiments analyzed the social interaction session to determine changes in social behaviors and subsequent alcohol drinking in adolescent male and female rats. Specifically, in Experiment 1, we determined whether specific social behaviors were altered during interaction with an alcohol-intoxicated demonstrator administered 1.5g/kg ethanol (EtOH) and assessed changes in EtOH intake in adolescent observers. Experiment 2 examined changes in voluntary saccharin consumption to determine whether social interaction with an alcohol-intoxicated demonstrator administered 1.5g/kg EtOH altered consumption of a palatable solution. In Experiment 3, we administered saline, and a low (5mg/kg) or high (20mg/kg) dose of cocaine to the demonstrator and assessed changes in the adolescent observers to determine whether social interaction with a "drugged" peer altered social behaviors and voluntary EtOH intake. We showed that social interaction with an alcohol-intoxicated demonstrator administered 1.5g/kg EtOH (i) decreased social play and increased social investigation and social contact in adolescent male and female observers, (ii) did not alter nonsocial behaviors, (iii) did not alter saccharin consumption, and (iv) increased voluntary EtOH intake in adolescent female but not male observers. When the peer was injected with cocaine, (i) social play was dose-dependently decreased, (ii) there were no changes in other social or nonsocial behaviors, and (iii) voluntary EtOH intake in adolescent male and female observers was unaffected. The present results are consistent and extend our previous work, showing that social interaction with an alcohol-intoxicated peer selectively alters social behaviors and alcohol drinking in adolescent rats. Females appear to be more sensitive to the elevating effects of social interaction on voluntary EtOH consumption.

The muscarinic agonist pilocarpine modifies cocaine-reinforced and food-reinforced responding in rats: comparison with the cholinesterase inhibitor tacrine.

Activation of muscarinic receptors in the brain antagonizes the actions of cocaine, blocking both its discriminative stimulus and reinforcing properties. Pilocarpine is a nonselective muscarinic agonist that is used clinically, but has not been well characterized for its actions during cocaine-reinforced behavior. This study evaluated its effects on cocaine-reinforced and food-reinforced behaviors in rats, using the cholinesterase inhibitor tacrine as a comparator. Intraperitoneal pilocarpine or tacrine at doses of 1.0 mg/kg or more attenuated self-administration of low-dose cocaine (0.1 mg/kg injection) but also increased oral movements. Pilocarpine was less potent than tacrine in decreasing responding supported by low or intermediate amounts of liquid food. Combined treatment with pilocarpine and tacrine was more effective than either compound alone in attenuating self-administration of intermediate-dose cocaine. At a low (0.66 mg/kg) dose which did not modify reinforced responding, pilocarpine increased nonspecific behavior (sniffing, rearing, and activity) in cocaine-reinforced but not in food-reinforced animals; with greater doses increasing cholinergic or gastrointestinal signs. These effects were most consistently correlated with changes in reinforcement in rats responding for cocaine relative to food-reinforced animals. Overall, pilocarpine exhibited modest selectivity for attenuating self-administration of low-dose cocaine without affecting a nondrug reinforcer.

The serotonin-2C agonist Lorcaserin delays intravenous choice and modifies the subjective and cardiovascular effects of cocaine: A randomized, controlled human laboratory study

BackgroundLorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR) approved for weight-loss therapy. This class can attenuate cue-induced responding and drug taking in preclinical studies, but effects in humans have not been reported. Methods and participantsWe evaluated effects of single 10 mg doses of lorcaserin on the subjective and reinforcing effects of cocaine, using a randomized, double-blind, within-subject, cross-over design. Male, non-treatment-seeking, regular cocaine users received either single doses of oral placebo (n = 9) or lorcaserin (n = 9), followed by low- or high- doses of intravenous cocaine (0.23 or 0.46 mg/kg-injection). They were then allowed to self-administer the lower dose of cocaine. ResultsCocaine was well tolerated after lorcaserin pretreatment. Oral lorcaserin did not modify the number of cocaine injections self-administered. However, it prolonged the time over which participants made intravenous choices relative to the duration of monetary (cash) decisions. Lorcaserin increased ratings of ‘high’ and ‘stimulated’ after low-dose cocaine or vehicle, but decreased craving for cocaine after intravenous vehicle. It also caused small but significant increases in heart rate following noncontingent injections of intravenous placebo or cocaine. When active cocaine was self-administered, lorcaserin decreased heart rate after selection of a monetary choice, but increased it following an intravenous choice. ConclusionsCombined treatment with cocaine and lorcaserin was safe in a limited number of subjects, but did not diminish cocaine-motivated behavior or drug-induced ‘high’. Some positive subjective effects of cocaine were enhanced by lorcaserin, and it delayed intravenous choices and decreased craving under some conditions. Effects on heart rate depended on the type of reinforcer being self-administered. Trial registrationclinicaltrials.gov Identifier, NCT02680288.

Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety.

Comorbid neuropsychiatric disorders such as addiction and anxiety could involve common underlying mechanisms. One potential mechanism involves epigenetic regulation of histone 3 dimethylation at lysine 9 residues (H3K9me2) by the histone dimethyltransferase G9a. Here we provide evidence that local AAV-RNAi-mediated knockdown of G9a expression in nucleus accumbens shell (NAcSh) of male rats reduces both addictive-related and anxiety-related behaviors. Specifically, G9a knockdown reduces sensitivity to low dose cocaine reinforcement when cocaine is freely available (fixed ratio schedule). Similarly, G9a knockdown reduces motivation for cocaine under higher effort demands (progressive ratio schedule). Following several weeks of forced abstinence, G9a knockdown attenuates extinction responding and reinstatement triggered by either cocaine-priming injections or footshock stress. This decrease in addictive behavior is associated with a long-term reduction in anxiety-like behavior as measured by the elevated plus maze (EPM). G9a knockdown also reduces basal anxiety-like behavior in EPM and marble burying tests in drug-naïve rats. These results complement our previous work showing that increased G9a expression in NAcSh enhances addictive-related and anxiety-related behaviors, indicating that G9a bi-directionally controls these responses. These results also suggest that regulation of G9a-influenced gene expression could be a common epigenetic mechanism for co-morbid anxiety and psychostimulant addiction.

Baseline prepulse inhibition of the startle reflex predicts the sensitivity to the conditioned rewarding effects of cocaine in male and female mice.

Prepulse inhibition (PPI) of the startle reflex is a model of pre-attentional inhibitory function. The dopamine baseline in the nucleus accumbens plays a key role in PPI regulation as well as in the rewarding effects of cocaine. The aim of this study was to evaluate the predictive ability of PPI to identify the more vulnerable mice of both sexes to the conditioned rewarding effects of cocaine. Male and female OF1 mice were first tested in the PPI paradigm to classify them as high or low PPI. Afterwards, they were evaluated in the conditioned place preference (CPP) paradigm induced by cocaine (1, 6 and 12mg/kg). Moreover, the D1R and D2R protein expressions in the striatum of high and low PPI animals were analysed by Western blot. Only high-PPI mice acquired CPP induced by low doses of cocaine (1 and 6mg/kg), while the low-PPI mice needed a higher dose of cocaine (12mg/kg) to acquire the CPP, but once mice were conditioned, males did not extinguish the conditioned preference and females reinstated the preference with lower doses of cocaine than their control counterparts. Low-PPI animals, especially females, showed higher basal levels of D2R than those with a higher PPI. Low-PPI mice presented a lower sensitivity to the conditioned rewarding effects of cocaine, but once they were conditioned with a higher dose, they displayed a stronger, perseverant conditioned preference. The predictive capacity of PPI to detect the more vulnerable mice to the conditioned effects of cocaine is discussed.

Vesicular acetylcholine transporter (VAChT) over-expression induces major modifications of striatal cholinergic interneuron morphology and function.

Striatal cholinergic interneurons (CIN) are pivotal for the regulation of the striatal network. Acetylcholine (ACh) released by CIN is centrally involved in reward behavior as well as locomotor or cognitive functions. Recently, BAC transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2) and displaying almost 50 extra copies of the VAChT gene were used to dissect cholinergic circuit connectivity and function using optogenetic approaches. These mice display over-expression of the vesicular acetylcholine transporter (VAChT) and increased cholinergic tone. Consequently, ChAT-ChR2 mice are a valuable model to investigate hypercholinergic phenotypes. Previous experiments established that ChAT-ChR2 mice display an increased sensitivity to amphetamine induced-locomotor activity and stereotypes. In the present report, we analyzed the impact of VAChT over-expression in the striatum of ChAT-ChR2 mice. ChAT-ChR2 mice displayed increased locomotor sensitization in response to low dose of cocaine. In addition, we observed a dramatic remodeling of the morphology of CIN in ChAT-ChR2 transgenic mice. VAChT immunolabeling was markedly enhanced in the soma and terminal of CIN from ChAT-ChR2 mice as previously shown (Crittenden etal. 2014). Interestingly, the number of cholinergic varicosities was markedly reduced (-87%) whereas their size was significantly increased (+177%). Moreover, VAChT over-expression dramatically modified its trafficking along the somatodendritic and axonal arbor. These findings demonstrate that ChAT-ChR2 mice present major alterations of CIN neuronal morphology and increased behavioral sensitization to cocaine, supporting the notion that the increased levels of VAChT observed in these mice make them fundamentally different from wild-type mice.