Psychomotor Stimulant Effects Research Articles

Impairment of glutamate homeostasis in the nucleus accumbens core underpins cross-sensitization to cocaine following chronic restraint stress.

Though the facilitating influence of stress on drug abuse is well documented, the mechanisms underlying this interaction have yet to be fully elucidated. The present study explores the neurobiological mechanisms underpinning the sensitized response to the psychomotor-stimulating effects of cocaine following chronic restraint stress (CRS), emphasizing the differential contribution of both subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell), to this phenomenon. Adult male Wistar rats were restrained for 2 h/day for 7 days and, 2 weeks after the last stress exposure (day 21), all animals were randomly assigned to behavioral, biochemical or neurochemical tests. Our results demonstrated that the enduring CRS-induced increase in psychostimulant response to cocaine was paralleled by an increase of extracellular dopamine levels in the NAcore, but not the NAshell, greater than that observed in the non-stress group. Furthermore, we found that CRS induced an impairment of glutamate homeostasis in the NAcore, but not the NAshell. Its hallmarks were increased basal extracellular glutamate concentrations driven by a CRS-induced downregulation of GLT-1, blunted glutamate levels in response to cocaine and postsynaptic structural remodeling in pre-stressed animals. In addition, ceftriaxone, a known GLT-1 enhancer, prevented the CRS-induced GLT-1 downregulation, increased basal extracellular glutamate concentrations and changes in structural plasticity in the NAcore as well as behavioral cross-sensitization to cocaine, emphasizing the biological importance of GLT-1 in the comorbidity between chronic stress exposure and drug abuse. A future perspective concerning the paramount relevance of the stress-induced disruption of glutamate homeostasis as a vulnerability factor to the development of stress and substance use disorders during early life or adulthood of descendants is provided.

Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington's Disease.

There is a controversy about potentially positive or negative effects of caffeine consumption on onset and disease progression of neurodegenerative diseases such as Huntington’s Disease (HD). On the molecular level, the psychoactive drug caffeine targets in particular adenosine receptors (AR) as a nonselective antagonist. The aim of this study was to evaluate clinical effects of caffeine consumption in patients suffering from premanifest and motor-manifest HD. Data of the global observational study ENROLL-HD were used, in order to analyze the course of HD regarding symptoms onset, motor, functional, cognitive and psychiatric parameters, using cross-sectional and longitudinal data of up to three years. We split premanifest and manifest participants into two subgroups: consumers of >3 cups of caffeine (coffee, cola or black tea) per day (>375 mL) vs. subjects without caffeine consumption. Data were analyzed using ANCOVA-analyses for cross-sectional and repeated measures analysis of variance for longitudinal parameters in IBM SPSS Statistics V.28. Within n = 21,045 participants, we identified n = 1901 premanifest and n = 4072 manifest HD patients consuming >3 cups of caffeine/day vs. n = 841 premanifest and n = 2243 manifest subjects without consumption. Manifest HD patients consuming >3 cups exhibited a significantly better performance in a series of neuropsychological tests. They also showed at the median a later onset of symptoms (all p < 0.001), and, during follow-up, less motor, functional and cognitive impairments in the majority of tests (all p < 0.050). In contrast, there were no beneficial caffeine-related effects on neuropsychological performance in premanifest HD mutation carriers. They showed even worse cognitive performances in stroop color naming (SCNT) and stroop color reading (SWRT) tests (all p < 0.050) and revealed more anxiety, depression and irritability subscores in comparison to premanifest participants without caffeine consumption. Similarly, higher self-reported anxiety and irritability were observed in genotype negative/control group high dose caffeine drinkers, associated with a slightly better performance in some cognitive tasks (all p < 0.050). The analysis of the impact of caffeine consumption in the largest real-world cohort of HD mutation carriers revealed beneficial effects on neuropsychological performance as well as manifestation and course of disease in manifest HD patients while premanifest HD mutation carrier showed no neuropsychological improvements, but worse cognitive performances in some tasks and exhibited more severe signs of psychiatric impairment. Our data point to state-related psychomotor-stimulant effects of caffeine in HD that might be related to regulatory effects at cerebral adenosine receptors. Further studies are required to validate findings, exclude potential other unknown biasing factors such as physical activity, pharmacological interventions, gender differences or chronic habitual influences and test for dosage related effects.

Effects of adolescent Δ9-tetrahydrocannabinol exposure on the behavioral effects of cocaine in adult Sprague-Dawley rats.

Cannabis is the most popular, illegal drug used by adolescents in the United States. Exposure to cannabis and its main psychoactive ingredient, Δ9-tetrahydrocannabinol (THC), during adolescence may have long-lasting effects on the development of behavioral and neurobiological processes. This study investigated the effects of chronic adolescent exposure to THC on sensitization to the psychomotor-stimulating effects of cocaine and on the reinforcing effects of cocaine in adult male Sprague-Dawley rats. During adolescence (P28-P45), rats were given once-daily intraperitoneal injections of either vehicle or 1 mg/kg THC. On P90, the acute locomotor-stimulating effects of cocaine and sensitization to cocaine were evaluated. Also, cocaine-maintained behavior was evaluated by determining within-session cocaine dose-effect curves, acquisition of behavior maintained by a small cocaine dose (0.1 mg/kg/infusion), and breakpoints on a progressive ratio schedule of reinforcement. In general, there was no effect of adolescent THC exposure on the locomotor-stimulating effects of cocaine following acute or repeated administration. However, the reinforcing effects of cocaine were potentiated in rats treated with THC during adolescence, but this effect was only observed with small doses of cocaine. Rats exposed to THC during adolescence also more rapidly acquired self-administration behavior when a small cocaine dose was available. Together, these results demonstrate that exposure to THC during adolescence may enhance sensitivity to cocaine and/or enhance the reinforcing effects of cocaine even into adulthood under certain conditions. In conclusion, frequent exposure to THC during adolescence may produce long-lasting changes in behavior, possibly increasing susceptibility to addiction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Wheel-running exercise before and during gestation against acute and sensitized cocaine psychomotor-activation in offspring

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is displayed on addictive drugs responsiveness. This study aimed to determine whether prenatal exercise could attenuate acute cocaine reactivity and psychomotor sensitization in youth offspring. We used a split-plot factorial design where C57BL/6 J females were randomly assigned into sedentary or exercised (wheel-running) conditions before and during gestation, the wheels being removed on gestational day 18. Offspring were weaned, gendered and individually housed on 24–28 days old. At 38–42 days old, they were tested for their acute psychomotor responsiveness to 8 mg/kg cocaine and their initiation of sensitization over 8 additional once-daily administrations, the long-term expression of sensitization occurring 30 days later. Adolescent females born from exercised mothers were much less responsive to the acute psychomotor-stimulating effect of cocaine than those born from sedentary mothers (d = 0.75, p = 0.02), whereas there was no evidence for such a difference in males (d = 0.34, p = 0.17). However, we did not find sizeable attenuating effects of prenatal exercise on the initiation and the long-term expression of the psychomotor-activating effect of cocaine, in either sex (Cohen’s ds varying from −0.13 to 0.39). These results suggest that prenatal exercise may induce initial protection against cocaine responsiveness in youth females, a finding that warrants further research.

Role of nitric oxide in psychostimulant-induced neurotoxicity.

In recent decades, consumption of psychostimulants has been significantly increased all over the world, while exact mechanisms of neurochemical effects of psychomotor stimulants remained unclear. It is assumed that the neuronal messenger nitric oxide (NO) may be involved in mechanisms of neurotoxicity evoked by psychomotor stimulants. However, possible participation of NO in various pathological states is supported mainly by indirect evidence because of its short half-life in tissues. Aim of this review is to describe the involvement of NO and the contribution of lipid peroxidation (LPO) and acetylcholine (ACH) release in neurotoxic effects of psychostimulant drugs. NO was directly determined in brain structures by electron paramagnetic resonance (EPR). Both NO generation and LPO products as well as release of ACH were increased in brain structures following four injections of amphetamine (AMPH). Pretreatment of rats with the non-selective inhibitor of NO-synthase (NOS) N-nitro-L-arginine or the neuronal NOS inhibitor 7-nitroindazole significantly reduced increase of NO generation as well as the rise of ACH release induced by AMPH. Both NOS inhibitors injected prior to AMPH had no effect on enhanced levels of LPO products. Administration of the noncompetitive NMDA receptor antagonist dizocilpine abolished increase of both NO content and concentration of LPO products induced by of the psychostimulant drug. Dizocilpine also eliminated the influence of AMPH on the ACH release. Moreover, the neurochemical and neurotoxic effects of the psychostimulant drug sydnocarb were compared with those of AMPH. Single injection of AMPH showed a more pronounced increase in NO and TBARS levels than after an equimolar concentration of sydnocarb. The findings demonstrate the crucial role of NO in the development of neurotoxicity elicited by psychostimulants and underline the key role of NOS in AMPH-induced neurotoxicity.

Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes.

Females are more sensitive than males to both the acute and prolonged effects of psychomotor stimulants. In females, this is regulated by oestradiol, which enhances dopamine release in the dorsal striatum. In this study, we tested the acute effect of oestradiol on dopamine release in the nucleus accumbens (NAc) shell after cocaine administration and investigated which oestradiol receptors (ERs) contribute to sex differences in the response to cocaine. The ability of oestradiol benzoate (EB) to acutely modulate the effect of cocaine on phasic dopamine release in the NAc shell was measured by fast-scan cyclic voltammetry in anaesthetized male and female rats. The roles of ER subtypes, ERα and ERβ, was determined with selective agonists. EB acutely enhanced the effect of cocaine on stimulated dopamine release from the NAc shell in females but not in male rats only at levels of stimulation expected to optimally saturate dopamine transporters. Enhanced dopamine release after cocaine administration was also observed in females after selective activation of ERβ but not ERα. EB attenuated the effect of cocaine on NAc shell dopamine reuptake in males but not in females. Oestradiol acutely and rapidly regulates dopamine release in females and dopamine reuptake in males. In females, oestradiol rapidly enhances the effect of cocaine on dopamine release, likely via activation of ERβ. The effect of oestradiol in males is not seen with selective receptor subtype activation, a topic deserving of further study. This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

On the central noradrenergic mechanism underlying the social play-suppressant effect of methylphenidate in rats

Social play behaviour is a vigorous, highly rewarding social activity abundant in the young of most mammalian species, including humans. Social play is thought to be important for social, emotional and cognitive development, yet its neural underpinnings are incompletely understood. We have previously shown that low doses of methylphenidate suppress social play behaviour through a noradrenergic mechanism of action, and that methylphenidate exerts its effect within the prefrontal cortex, amygdala and habenula. In the present study, we sought to reveal whether these regions work in parallel or in series to mediate the play-suppressant effect of methylphenidate. To that aim, we tested whether infusion of the α2-adrenoceptor antagonist RX821002 into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala or habenula prevents the effect of methylphenidate on social play behaviour, or the psychomotor stimulant effect of methylphenidate. We found that the social play-suppressant effect of methylphenidate was not prevented by infusion of the α2-adrenoceptor antagonist into either region, or by infusion of RX821002 into both the anterior cingulate and infralimbic cortex. By contrast, RX821002 infusion into the anterior cingulate modestly enhanced social play, and infusion of the antagonist into the infralimbic cortex attenuated the psychomotor stimulant effect of methylphenidate. We conclude that there is redundancy in the neural circuitry that mediates the play-suppressant effect of methylphenidate, whereby prefrontal cortical and subcortical limbic mechanisms act in parallel. Moreover, our data support the notion that prefrontal noradrenergic mechanisms contribute to the locomotor enhancing effect of psychostimulant drugs.

Does Practice Make Perfect? Sexual Experience and Psychomotor Stimulants Influence Female Sexual Motivation Through Medial Preoptic Area Dopamine

Purpose The purpose of our review is to draw parallels between the effects of psychomotor stimulants and repeated mating encounters on sexual behavior gathered from a number of different paradigms that take into account the complexity of sexual behavior of fully receptive female rats. Animal models are useful for developing treatments for sexual dysfunction disorders; however, little progress has been made in the development of treatments specifically for women.

A Role for Sigma Receptors in Stimulant Self-Administration and Addiction.

Sigma receptors (σRs) are structurally unique proteins that function intracellularly as chaperones. Historically, σRs have been implicated as modulators of psychomotor stimulant effects and have at times been proposed as potential avenues for modifying stimulant abuse. However, the influence of ligands for σRs on the effects of stimulants, such as cocaine or methamphetamine, in various preclinical procedures related to drug abuse has been varied. The present paper reviews the effects of σR agonists and antagonists in three particularly relevant procedures: stimulant discrimination, place conditioning, and self-administration. The literature to date suggests limited σR involvement in the discriminative-stimulus effects of psychomotor stimulants, either with σR agonists substituting for the stimulant or with σR antagonists blocking stimulant effects. In contrast, studies of place conditioning suggest that administration of σR antagonists or down-regulation of σR protein can block the place conditioning induced by stimulants. Despite place conditioning results, selective σR antagonists are inactive in blocking the self-administration of stimulants. However, compounds binding to the dopamine transporter and blocking σRs can selectively decrease stimulant self-administration. Further, after self-administration of stimulants, σR agonists are self-administered, an effect not seen in subjects without that specific history. These findings suggest that stimulants induce unique changes in σR activity, and once established, the changes induced create redundant, and dopamine independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of those pathways, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

A selective D3 receptor antagonist YQA14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice.

We have reported that a selective dopamine D3 receptor antagonist YQA14 attenuates cocaine reward and relapse to drug-seeking in mice. In the present study, we investigated whether YQA14 could inhibit methamphetamine (METH)-induced locomotor sensitization and conditioned place preference (CPP) in mice. Locomotor activity was monitored in mice treated with METH (1 mg/kg, ip) daily on d 4-13, followed by a challenge with METH (0.5 mg/kg) on d 21. CPP was examined in mice that were administered METH (1 mg/kg) or saline alternately on each other day for 8 days (METH conditioning). YQA14 was injected intraperitoneally 20 min prior to METH or saline. Both repetitive (daily on d 4-13) and a single injection (on the day of challenge) of YQA14 (6.25, 12.5 and 25 mg/kg) dose-dependently inhibited the acquisition and expression of METH-induced locomotor sensitization. However, repetitive injection of YQA14 (daily during the METH conditioning) did not alter the acquisition of METH-induced CPP, whereas a single injection of YQA14 (prior to CPP test) dose-dependently attenuated the expression of METH-induced CPP. In addition, the repetitive injection of YQA14 dose-dependently facilitated the extinction and decreased the reinstatement of METH-induced CPP. Brain D3 receptors are critically involved in the reward and psychomotor-stimulating effects of METH. Thus, YQA14 deserves further study as a potential medication for METH addiction.

Individual Differences in Ethanol Locomotor Sensitization Are Associated with Dopamine D1 Receptor Intra-Cellular Signaling of DARPP-32 in the Nucleus Accumbens

In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as “sensitized” and the 33% with the lowest levels as "non-sensitized”. The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor sensitization to ethanol.

3-Methoxynaltrexone is not a selective antagonist for the acute psychomotor stimulating effects of heroin and 6-monoacetylmorphine in mice

The opioid receptor antagonist 3-methoxynaltrexone (3-MeONtx) has previously been shown in rodents to selectively reverse the analgesic actions of heroin and its metabolites 6-monoacetylmorphine (6-MAM), and morphine-6-glucuronide (M6G), but not that of morphine. Based on these and other results, a heroin/6-MAM/M6G μ-opioid receptor binding site or subreceptor mediating their analgesic activity has been proposed. It is however unknown whether this also accounts for the acute psychomotor stimulating properties of these opioids. The aim of the present study was therefore to explore if the acute psychomotor stimulating effects of heroin, 6-MAM, and morphine are mediated by distinct μ-opioid receptor binding sites or subreceptors. To address this aim, we examined how pretreatment with 3-MeONtx or naltrexone (NTX) affected the acute increase in locomotor activity induced by heroin, 6-MAM, or morphine in mice. The pharmacokinetic profiles of 3-MeONtx and NTX were also assessed in mouse brain. We found that 3-MeONtx similarly antagonized the acute increase in locomotor activity induced by equipotent doses of heroin, 6-MAM, or morphine. This antagonistic effect was comparable to the one observed following administration of NTX, and both antagonists gave similar pharmacokinetic profiles in mouse brain. Our findings do not support that different μ-opioid receptor subtypes or a distinct binding site at the μ-opioid receptor is involved in morphine-induced versus heroin/6-MAM-induced psychomotor activation. This might suggest that the opioid-induced psychomotor stimulation is mediated by different μ-opioid subreceptors than those responsible for their analgesic effects.

Relationship between ethanol-induced activity and anxiolysis in the open field, elevated plus maze, light-dark box, and ethanol intake in adolescent rats

It is yet unclear if ethanol-induced motor stimulation in the open field (OF) merely reflects psychomotor stimulating effects of the drug or if this stimulation is driven or modulated by ethanol's antianxiety properties. In the present study, adolescent rats were administered with different ethanol doses or remained untreated. They were sequentially assessed in the OF, elevated plus maze (EPM), and light-dark box (LDB) and then assessed for ethanol intake. The aims were to assess the relationship between measures of ethanol-induced activity and anxiolysis, analyze ethanol intake as a function of prior ethanol exposure, and associate behavioral responsiveness in these apparatus with ethanol intake during adolescence. The results suggested that the enhanced exploration of the OF observed after 2.5 and 3.25 g/kg ethanol reflected a motor-stimulating effect that appeared to be relatively independent of anxiolysis. The 1.25 g/kg dose induced motor stimulation in the OF and anti-anxiety effects in the EPM, but these effects were relatively independent. The 0.5 g/kg ethanol dose exerted significant anxiolytic effects in the EPM in the absence of stimulating effects in the OF. A multivariate regression analysis indicated that adolescents with a higher frequency of rearing behavior in the OF, higher percentage of open arm entries in the EPM, and lower propensity to enter the central area of the OF exhibited greater ethanol intake. These results indicate that the OF is a valid procedure for the measurement of ethanol-induced stimulation, and provide information toward characterizing subpopulations of adolescents at risk for initiating alcohol drinking.

SOME GUIDELINES FOR CONDUCTING RESEARCH IN APPLIED BEHAVIORAL PHARMACOLOGY

The Journal of Applied Behavior Analysis (JABA) has published a number of articles on the behavioral effects of psychomotor stimulant drugs in individuals with attention deficit hyperactivity disorder. Some additional JABA publications have included investigations of the behavioral effects of other drugs. However, a review of these articles revealed many methodological differences among studies, which makes it difficult to evaluate the relative contribution of each research effort to the overall database. In this context, we offer some guidelines to solidify the methodological rigor of behavior pharmacological research published in JABA.

Role of GRK6 in the addictive effect of psychostimulant drugs

The dopamine innervation of the nucleus accumbens (NAc) is the key neural substrate mediating the primary reinforcing and psychomotor stimulant effects of drugs of abuse. Psychostimulant drugs (PDS) enhance the dopamine concentration by blocking dopamine transporter and/or inducing non‐vesicular dopamine release in the brain, which increases the activity of dopamine receptors. G protein‐coupled receptor kinases (GRKs) are the key proteins regulating the signaling of G protein‐coupled receptors (GPCR) via the mechanism of homologous desensitization. The aim of the present study was to investigate the role of GRK6‐dependent GPCR desensitization in PSD addiction. Overexpression of GRK6 in NAc using lentivirus‐mediated gene transfer reduced cocaine and amphetamine‐induced conditioned place preference (CPP). The effect of down‐regulation of GRK6 in NAc on PSD‐induced CPP was also tested. To evaluate the role of GRK6 in drug craving and relapse, the drug‐induced reinstatement of CPP was performed. Our results shift the traditional focus away from receptors themselves and put the GRK/arrestin‐based receptor desensitization machinery as the main regulatory mechanisms involved in PSD reward. A pharmacological strategy based on increasing activity and/or availability of GRK6 may be a promising therapeutic approach for PSD addiction. Work supported by NIH grants NS065868 and R21DA030103.

Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non‐human primates

The objective of the present study was to further elucidate the mechanisms involved in the wake-promoting effects of psychomotor stimulants. Many previous studies have tightly linked the effects of stimulants to dopamine neurotransmission, and some studies indicate that serotonin 2A receptors modulate these effects. However, the role of dopamine in arousal is controversial, most notably because dopamine neurons do not change firing rates across arousal states. In the present study, we examined the wake-promoting effects of the dopamine-releaser amphetamine using non-invasive telemetric monitoring. These effects were evaluated in rhesus monkeys as a laboratory animal model with high translational relevance for human disorders of sleep and arousal. To evaluate the role of dopamine in the wake-promoting effects of amphetamine, we used in vivo microdialysis targeting the caudate nucleus, as this approach provides clearly interpretable measures of presynaptic dopamine release. This is beneficial in the present context because some of the inconsistencies between previous studies examining the role of dopamine in arousal may be related to differences between postsynaptic dopamine receptors. We found that amphetamine significantly and dose-dependently increased arousal at doses that engendered higher extracellular dopamine levels. Moreover, antagonism of serotonin 2A receptors attenuated the effects of amphetamine on both wakefulness and dopamine overflow. These findings further elucidate the role of dopamine and serotonin 2A receptors in arousal, and they suggest that increased dopamine neurotransmission may be necessary for the wake-promoting effects of amphetamine, and possibly other stimulants.

A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation

BackgroundCocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents.Principal FindingsConcomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors.ConclusionsThe present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine.

Behavioral inhibition in mice bred for high vs. low levels of methamphetamine consumption or sensitization

Research indicates that genetics influence methamphetamine self-administration as well as sensitization to the psychomotor-stimulating effects of methamphetamine (MA). Other studies have suggested that heightened levels of impulsivity, including low levels of behavioral inhibition, are associated with the use of drugs, including MA. The current study examined whether lines of mice selected for traits associated with a heightened risk of developing MA dependence would also exhibit low levels of drug-naïve inhibition and whether administration of MA would result in different levels of inhibition in animals selected to consume or respond more to MA. A go/no-go task was used to assess inhibition in male and female mice selected for low or high levels of MA consumption or selected for high or low levels of locomotor sensitization to repeated injections of MA. Mice selected for MA sensitization differed in false alarms, precue response rates (measures of behavioral inhibition), and also hits (measure of operant responding). Mice selected for MA consumption did not differ in measures of behavioral inhibition, though hits differed. When MA was administered prior to the task, false alarms, precue response rates, and hits decreased for mice from all selected lines. Female high drinking mice were particularly resistant to MA's effects on hits, but not precue response rate or false alarms. These data suggest a shared, but complex, genetic association between inhibition processes, general levels of operant responding, and MA sensitization or consumption.

The interplay between brain 5-hydroxytryptamine levels and cocaine addiction

Cocaine addiction is a major health problem that affects millions of people. Cocaine acts by inhibiting dopamine, noradrenaline and serotonin [5-hydroxytryptamine(5-HT)] reuptake. The dopaminergic system is generally assumed to be involved in the reinforcing aspects of the drug, but the role of 5-HT in the addictive potential of cocaine is unclear. In light of pharmacological manipulations and cocaine use-related disease states affecting brain 5-HT levels, we review studies on the effect of cocaine on central 5-HT function. In addition, the contribution of 5-HT to the rewarding, aversive, discriminative and subjective, as well as the motivational and reinforcing effects of cocaine is discussed. We specifically focus on net changes in the extracellular 5-HT levels that occur as a consequence of acute and chronic cocaine exposure and how these influence cocaine abuse-related behaviour. Overall, the data indicate that 5-HT plays a major role in the psychomotor stimulant, rewarding and discriminative stimulant effects of cocaine, but also affects the motivational and reinforcing effects of the drug. In addition, 5-HT mediates, to some extent, the aversive effects of cocaine. Difficulties with data interpretation are discussed.

Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants, including amphetamine, methamphetamine and MDMA. Previous studies have shown that in transgenic mice lacking the TAAR1 gene (TAAR1 knockout; KO) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type (WT) mice. Further, the psychostimulant effects of cocaine can be diminished by selective activation of TAAR1. These findings suggest that TAAR1 might be implicated in the rewarding properties of psychostimulants. To investigate the role of TAAR1 in the rewarding effects of drugs of abuse, the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and TAAR1 KO mice. In locomotor activity studies, both single and repeated exposure to d-amphetamine or methamphetamine generated significantly higher levels of total distance traveled in TAAR1 KO mice compared to WT mice. In conditioned place preference (CPP) studies, TAAR1 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training. In morphine-induced CPP, both WT and KO genotypes displayed similar levels of CPP. Results from locomotor activity studies suggest that TAAR1 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants. That methamphetamine-but not morphine-induced CPP was augmented in TAAR1 KO mice suggests a selective role of TAAR1 in the conditioned reinforcing effects of methamphetamine. Collectively, these findings provide support for a regulatory role of TAAR1 in methamphetamine signaling.