Search

Background: The appearance of stimulant-class new psychoactive substances (NPS) is a frequent and significant problem in our society. Cathinone variants are often sold illegally as 3,4-methylenedioxy methamphetamine ("ecstasy") or disguised for legal sale using misleading names such as "bath salts" and carry the risk of promoting disruptive mental states, addiction, and fatal overdose. The principal targets of these recreational drugs are monoamine transporters expressed in catecholaminergic and serotonergic neurons. Some transporter ligands can be transported into cells, where they can promote a massive release of neurotransmitters through reverse transport, and others can block uptake. A ligand's dopamine vs. serotonin transporter selectivity, potency, and activity as a substrate or blocker can help elucidate the abuse liability and subjective effects of a drug., Objectives: Here, we describe the discovery, development, and validation of an emerging methodology for compound activity assessment at monoamine transporters., Key Findings: Substrates generate inward electrical currents through transporters and can depolarize the plasma membrane, whereas blockers work as a "cork in a bottle" and function as antagonists. Voltage-gated Ca 2+ channels were co-expressed with monoamine transporters in cultured cells and used to measure fluctuations of the membrane electrical potential. In this system, substrates of monoamine transporters produce reliable dose-dependent Ca 2+ signals, while blockers hinder them., Discussion: This system constitutes a novel use of voltage-gated Ca 2+ channels as biosensors for the purpose of characterizing ligand activity at monoamine transporters using fluorimetry. This approach in combination with in vivo evaluations of drugs' abuse-related effects is a powerful strategy for anticipating potential stimulant-class NPS.

Neuropeptide Y (NPY), which is widely expressed in the central nervous system is involved in several neuropathologies including addiction. Here we comprehensively and systematically review alterations on the central NPY system induced by several drugs. We report on the effects of psychostimulants [cocaine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and nicotine], ethanol, and opioids on NPY protein levels and expression of different NPY receptors. Overall, expression and function of NPY and its receptors are changed under conditions of drug exposure, thus affecting several physiologic behaviors, such as feeding, stress and anxiety. Drugs of abuse differentially affect the components of the NPY system. For example methamphetamine and nicotine lead to a consistent increase in NPY mRNA and protein levels in different brain sites whereas ethanol and opioids decrease NPY mRNA and protein expression. Drug-induced alterations on the different NPY receptors show more complex regulation pattern. Manipulation of the NPY system can have opposing effects on reinforcing and addictive properties of drugs of abuse. NPY can produce pro-addictive effects (nicotine and heroin), but can also exert inhibitory effects on addictive behavior (AMPH, ethanol). Furthermore, NPY can act as a neuroprotective agent in chronically methamphetamine and MDMA-treated rodents. In conclusion, manipulation of the NPY system seems to be a potential target to counteract neural alterations, addiction-related behaviors and cognitive deficits induced by these drugs., (© 2015 Society for the Study of Addiction.)

Rationale: No drugs are currently validated to treat psychostimulant use disorder (PUD). Pathophysiological studies consistently highlight the contribution of cholinergic mechanisms in psychostimulant use, including the vulnerability to PUD, paving the way for potential therapeutic strategies. Objectives: The aim of this systematic review is to describe and discuss the efficacy of cholinergic agents in drug trials for patients with PUD. Methods: A systematic review was conducted on April 4, 2024 in MedLine, Embase and Cochrane Library databases on controlled clinical drug trial of cholinergic agents in humans with PUD, psychostimulant abuse or dependence and psychostimulant use in recent year. Results: Twenty-eight articles were included, twenty-one on cocaine and seven on amphetamines. Cholinergic agents used in these studies were biperiden (a muscarinic antagonist), mecamylamine (a nicotinic antagonist), nicotinic agonists, acetylcholinesterase inhibitors (AChEI), or citicoline. Two types of trials were identified. There were seventeen randomized controlled clinical trials evaluating cholinergic agents on psychostimulant use reduction in outpatients seeking treatment. Additionally, we retrieved eleven short-term «proof-of-concept» laboratory trials mainly with supervised psychostimulant administration and/or triggered craving challenges. Outpatient trials were heterogeneous and for most, inconclusive. Only two studies on galantamine (AChEI) and citicoline, reported a significant reduction of cocaine consumption. «Proof-of-concept» laboratory trials showed no evidence of efficacy on the selected outcomes, notably on craving. Conclusions: This review does not support the current prescription of cholinergic agents to treat PUD. Replication clinical trials notably on galantamine or other AChEI, and proof-of-concept trials on comedown symptoms will be necessary to identify a potential therapeutic indication for cholinergic agents in PUD. [ABSTRACT FROM AUTHOR]

Rationale : In human beings and experimental animals, maladaptive impulsivity is manifested by the acute injection of psychostimulants, such as amphetamine. Cannabinoid CB1 receptors have been implicated in the regulation of stimulant-induced impulsive action, but the role of CB1 receptors in timing-related impulsive action by amphetamine remains unknown. Methods: Male rats were used in evaluating the effects of CB1 receptor antagonist and agonist (SR141716A and WIN55,212–2, respectively) systemically administered individually and combined with d-amphetamine on a differential reinforcement of low-rate response (DRL) task, an operant behavioral test of timing and behavioral inhibition characterized as a type of timing impulsive action. Results: A distinct pattern of DRL behavioral changes was produced by acute d-amphetamine (0, 0.5, 1.0, and 1.5 mg/kg) treatment in a dose-dependent fashion, whereas no significant dose effect was detected for acute SR141716A (0, 0.3, 1, and 3 mg/kg) or WIN55,212–2 (0, 0.5, 1, and 2 mg/kg) treatment. Furthermore, DRL behavior altered by 1.5 mg/kg d-amphetamine was reversed by a noneffective dose of SR141716A (3 mg/kg) pretreatment. The minimally influenced DRL behavior by 0.5 mg/kg d-amphetamine was affected by pretreatment with a noneffective dose of WIN55,212–2 (1 mg/kg). Conclusion: These findings reveal that the activation and blockade of CB1 receptors can differentially modulate the timing impulsive action of DRL behavior induced by acute amphetamine treatment. Characterizing how CB1 receptors modulate impulsive behavior will deepen our understanding of the cannabinoid psychopharmacology of impulsivity and may be helpful in developing an optimal pharmacotherapy for reducing maladaptive impulsivity in patients with some psychiatric disorders. [ABSTRACT FROM AUTHOR]

The dopamine transporter (DAT) mediates the inactivation of released dopamine (DA) through its reuptake, and thereby plays an important homeostatic role in dopaminergic neurotransmission. Amphetamines exert their stimulant effects by targeting DAT and inducing the reverse transport of DA, leading to a dramatic increase of extracellular DA. Animal models have proven critical to investigating the molecular and cellular mechanisms underlying transporter function and its modulation by psychostimulants such as amphetamine. Here we establish a behavioral model for amphetamine action using adult Drosophila melanogaster. We use it to characterize the effects of amphetamine on sleep and sleep architecture. Our data show that amphetamine induces hyperactivity and disrupts sleep in a DA-dependent manner. Flies that do not express a functional DAT (dDAT null mutants) have been shown to be hyperactive and to exhibit significantly reduced sleep at baseline. Our data show that, in contrast to its action in control flies, amphetamine decreases the locomotor activity of dDAT null mutants and restores their sleep by modulating distinct aspects of sleep structure. To begin to explore the circuitry involved in the actions of amphetamine on sleep, we also describe the localization of dDAT throughout the fly brain, particularly in neuropils known to regulate sleep. Together, our data establish Drosophila as a robust model for studying the regulatory mechanisms that govern DAT function and psychostimulant action. [ABSTRACT FROM AUTHOR]

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models. [ABSTRACT FROM AUTHOR]

Background Among psychostimulants, the dopamine transporter ligands amphetamine and cocaine display the highest addictive potential; the adenosine receptor antagonist caffeine is most widely consumed but less addictive. Psychostimulant actions of amphetamine were correlated with its ability to orchestrate ventral tegmental dopamine neuron activity with contrasting shifts in firing after single vs repeated administration. Whether caffeine might impinge on dopamine neuron activity has remained elusive. Methods Population activity of ventral tegmental area dopamine neurons was determined by single-unit extracellular recordings and set in relation to mouse behavior in locomotion and conditioned place preference experiments, respectively. Results A single dose of caffeine reduced population activity as did amphetamine and the selective adenosine A2A antagonist KW-6002, but not the A1 antagonist DPCPX. Repeated administration of KW-6002 or amphetamine led to drug-conditioned place preference and to unaltered or even enhanced population activity. Recurrent injection of caffeine or DPCPX, in contrast, failed to cause conditioned place preference and persistently reduced population activity. Subsequent to repetitive drug administration, re-exposure to amphetamine or KW-6002, but not to caffeine or DPCPX, was able to reduce population activity. Conclusions Behavioral sensitization to amphetamine is attributed to persistent activation of ventral tegmental area dopamine neurons via the ventral hippocampus. Accordingly, a switch from acute A2A receptor-mediated reduction of dopamine neuron population activity to enduring A1 receptor-mediated suppression is correlated with tolerance rather than sensitization in response to repeated caffeine intake. [ABSTRACT FROM AUTHOR]

Objective: Psychostimulants are first-line pharmacological treatments for attention deficit hyperactivity disorder (ADHD), although symptom reduction varies widely between patients and these individual differences in treatment response are poorly understood. The authors sought to examine whether the resting-state functional connectivity within and between cingulo-opercular, striato-thalamic, and default mode networks was associated with treatment response to psychostimulant medication, and whether this relationship changed with development.Methods: Patients with ADHD (N=110; 196 observations; mean age at first observation, 10.83 years, SD=2.2) and typically developing control subjects (N=142; 330 observations; mean age at first observation, 10.49 years, SD=2.81) underwent functional neuroimaging on up to five occasions during development (age range, 6-17 years). For patients, symptoms were assessed on and off psychostimulant medication (methylphenidate-based treatments: N=132 observations, 67%; amphetamine-based treatments: N=64 observations, 33%) using the Diagnostic Interview for Children and Adolescents for parents. Linear mixed-effects models examined whether resting-state connectivity was associated with treatment response and its interaction with age. Comparisons with typically developing control subjects were performed to contextualize any significant associations.Results: Resting-state connectivity within the cingulo-opercular network was associated with a significant interaction between treatment response and age. Specifically, worse responses to treatment compared with better responses to treatment among patients and compared with typically developing control subjects were associated with an atypical increase in cingulo-opercular connectivity with increasing age from childhood to adolescence.Conclusions: This work delineates how resting-state connectivity may be associated over development with response to psychostimulants in ADHD. Functioning and development within the cingulo-opercular network may warrant further investigation as a contributor to differential response to psychostimulants. [ABSTRACT FROM AUTHOR]

Psychostimulants are a diverse range of substances that encompass cocaine and the phenylethylamines, the latter including the amphetamines, cathinones and some 'novel psychoactive substances'. This paper examines the range of pathophysiological processes, clinical presentations and treatment options involving the heart and cardiovascular system both in the acute setting and where long‐term effects of psychostimulant use have affected the cardiovascular system. A common feature of these drugs is their effect on the cardiovascular system, where their major action is that of sympathomimetic amines with short‐ and long‐term stimulation of the adrenergic system and consequent effects on blood pressure, cardiac modelling, atherogenesis and cellular calcium signalling. Cocaine additionally exhibits a variety of prothrombotic effects, effects on inflammatory mediators and alterations in myocardial gene expression. Persistent psychostimulant use results in progressive cardiovascular pathology, largely in the form of accelerated atherosclerosis, hypertension and myocardial ischaemia. Abstinence results in at least partial reversal of pathology. To a large extent, an assumption is made that treatment protocols used for cocaine‐associated cardiovascular pathology apply to the amphetamines and other phenylethylamines, but there appears to be little research in this area, despite acknowledgement that cocaine and the better‐known amphetamines have different modes of action. [ABSTRACT FROM AUTHOR]

Depersonalization and derealization symptoms are common and often transient. Recurrent, persistent symptoms can result in a diagnosis of depersonalization/derealization disorder (DDD). This is a diagnosis with little evidence available regarding effective interventions, and there are currently no pharmacological treatments for DDD approved by the United States Food and Drug Administration (FDA). Here, we reported a case of an adult female whose presentation was consistent with DDD. Her DDD symptoms notably reduced after treatment with mixed amphetamine salts. We also reviewed the limited research examining the efficacy of lamotrigine, benzodiazepines, antidepressants, naltrexone, and antipsychotics in DDD. Given the lack of evidence-based interventions for patients with DDD, additional research into the potential benefit of using psychostimulants might be warranted. [ABSTRACT FROM AUTHOR]

Psychostimulant users are typically young adults. We have conducted a narrative review of neuropsychiatric harms associated with the psychostimulants methamphetamine/amphetamine, cocaine and 3,4‐methylenedioxymethamphetamine (MDMA), focusing on epidemiological factors, common clinical presentations, underlying causal mechanisms and treatment options. The major neuropsychiatric harms of psychostimulant use are stroke, neurocognitive impairment, Parkinson's disease, seizures and psychotic illness. These arise through a combination of acute monoamine release, longer‐term neurotransmitter effects and indirect effects. These effects are moderated by factors in the individual and in the pattern of substance use. Neuropsychiatric harms associated with psychostimulant use can thus lead to severe long‐term impairment. [ABSTRACT FROM AUTHOR]

Highlights • Animal models are critical for screening new therapies. • Amphetamine-induced hyperactivity (AIH) is a screening model for mood stabilizers. • The validity of screening models depends on their response to established treatments. • We show that in ICR and black Swiss mice, chronic lithium does not ameliorate AIH. • The findings cast doubt on the validity of the model to screen mood-stabilizing drugs. Abstract Animal models are critical for the study of disease mechanisms and the screening of potential novel treatments. In the context of bipolar disorder, amphetamine-induced hyperactivity (AIH) is a frequently used screening model for antimanic effects. Yet, the utility of screening models depends on their predictive (or pharmacological) validity and it is expected that such models will respond to effective treatments. Lithium is the prototypic mood stabilizer but previous data regarding the effects of lithium in the AIH model are not clear and most data comes from studies using acute lithium administration that is not relevant to the therapeutic regimen in patients. To evaluate the pharmacological validity of AIH as a model for mania-like behavior we tested the interaction between chronic oral administration of lithium and amphetamine in ICR (CD-1®) mice and in black Swiss mice. We conducted 4 different experiments where chronic lithium was followed by an acute injection of amphetamine and one experiment where chronic amphetamine was combined with chronic lithium. The results show that amphetamine result in hyperactivity (experiments 1–4) and that lithium has no effects. Moreover, chronic amphetamine (experiment 5) result in sensitization that is not attenuated by lithium. The results clearly show that the predictive validity of the AIH model in ICR or black Swiss mice is problematic and possibly cast doubt on the utilization of the AIH as a screening model for novel mood stabilizers in other strains of mice. [ABSTRACT FROM AUTHOR]

Background: The appearance of stimulant-class new psychoactive substances (NPS) is a frequent and significant problem in our society. Cathinone variants are often sold illegally as 3,4-methylenedioxy methamphetamine ("ecstasy") or disguised for legal sale using misleading names such as "bath salts" and carry the risk of promoting disruptive mental states, addiction, and fatal overdose. The principal targets of these recreational drugs are monoamine transporters expressed in catecholaminergic and serotonergic neurons. Some transporter ligands can be transported into cells, where they can promote a massive release of neurotransmitters through reverse transport, and others can block uptake. A ligand's dopamine vs. serotonin transporter selectivity, potency, and activity as a substrate or blocker can help elucidate the abuse liability and subjective effects of a drug. Objectives: Here, we describe the discovery, development, and validation of an emerging methodology for compound activity assessment at monoamine transporters. Key findings: Substrates generate inward electrical currents through transporters and can depolarize the plasma membrane, whereas blockers work as a "cork in a bottle" and function as antagonists. Voltage-gated Ca2+ channels were co-expressed with monoamine transporters in cultured cells and used to measure fluctuations of the membrane electrical potential. In this system, substrates of monoamine transporters produce reliable dose-dependent Ca2+ signals, while blockers hinder them. Discussion: This system constitutes a novel use of voltage-gated Ca2+ channels as biosensors for the purpose of characterizing ligand activity at monoamine transporters using fluorimetry. This approach in combination with in vivo evaluations of drugs' abuse-related effects is a powerful strategy for anticipating potential stimulant-class NPS. [ABSTRACT FROM AUTHOR]

Repeated exposure to psychostimulants, such as amphetamine, causes a long-lasting enhancement in the behavioral responses to the drug, called behavioral sensitization. 1 This phenomenon involves several neuronal systems and brain areas, among which the dorsal striatum plays a key role. 2 The endocannabinoid system (ECS) has been proposed to participate in this effect, but the neuronal basis of this interaction has not been investigated. 3 In the CNS, the ECS exerts its functions mainly acting through the cannabinoid type-1 (CB 1) receptor, which is highly expressed at terminals of striatal medium spiny neurons (MSNs) belonging to both the direct and indirect pathways. 4 In this study, we show that, although striatal CB 1 receptors are not involved in the acute response to amphetamine, the behavioral sensitization and related synaptic changes require the activation of CB 1 receptors specifically located at striatopallidal MSNs (indirect pathway). These results highlight a new mechanism of psychostimulant sensitization, a phenomenon that plays a key role in the health-threatening effects of these drugs. • Striatal CB 1 receptors are required for behavioral sensitization to amphetamine • Striatopallidal synaptic impairment is associated with CB 1 -mediated sensitization • Novel mechanisms for endocannabinoid-psychostimulant interaction Mariani et al. show that repeated amphetamine exposure results in behavioral sensitization and related synaptic changes mediated by the activation of cannabinoid type-1 (CB 1) receptors. These receptors are specifically located at indirect-pathway striatal medium spiny neuron (iMSN) terminals, highlighting a new mechanism for psychostimulant sensitization. [ABSTRACT FROM AUTHOR]

Heightened distractibility is a core symptom of Attention Deficit Hyperactivity Disorder (ADHD). Effective treatment is normally with chronic orally administered psychostimulants including amphetamine. Treatment prevents worsening of symptoms but the site of therapeutic processes, and their nature, is unknown. Mounting evidence suggests that the superior colliculus (SC) is a key substrate in distractibility and a therapeutic target, so we assessed whether therapeutically-relevant changes are induced in this structure by chronic oral amphetamine. We hypothesized that amphetamine would alter visual responses and morphological measures. Six-week old healthy male rats were treated with oral amphetamine (2, 5 or 10 mg/kg) or a vehicle for one month after which local field potential and multiunit recordings were made from the superficial layers of the SC in response to whole-field light flashes in withdrawal. Rapid Golgi staining was also used to assess dendritic spines, and synaptophysin staining was used to assess synaptic integrity. Chronic amphetamine increased local field potential responses at higher doses, and increased synaptophysin expression, suggesting enhanced visual input involving presynaptic remodelling. No comparable increases in multiunit activity were found suggesting amphetamine suppresses collicular output activity, counterbalancing the increased input. We also report, for the first time, five different dendritic spine types in the superficial layers and show these to be unaffected by amphetamine, indicating that suppression does not involve gross postsynaptic structural alterations. In conclusion, we suggest that amphetamine produces changes at the collicular level that potentially stabilise the structure and may prevent the worsening of symptoms in disorders like ADHD. [ABSTRACT FROM AUTHOR]

Rationale: We have recently shown that the benzodiazepine diazepam inhibits dopamine release in the NAc and blocks the increased release of dopamine induced by DL-amphetamine. Rewarding stimuli and many drugs of abuse can induce dopamine release in the nucleus accumbens as well as 50-kHz ultrasonic vocalizations (USVs) in rats.Objectives: In the present study, we tested the hypothesis that diazepam can also block the increase in locomotor activity and USVs elicited by amphetamine.Methods: Fifty-kilohertz USVs, stereotypy, and locomotor behavior were scored in adult male Wistar rats treated with i.p. injections of saline, 3 mg/kg DL-amphetamine, 2 mg/kg diazepam, 0.2 mg/kg haloperidol, or a combination of these drugs.Results: In agreement with previous studies, amphetamine caused significant increases in the number of USV calls, stereotypies, and locomotor activity. The D2 dopamine receptor antagonist haloperidol blocked the effects of amphetamine on USVs, stereotypy, and locomotor activity. Diazepam blocked the effect of amphetamine on USV and stereotypy, but not on horizontal locomotion.Conclusions: These results suggest that diazepam blocks the rewarding effect of amphetamine. This finding is promising for basic research regarding treatments of substance use disorders and evaluation of the impact of benzodiazepines on motivation. [ABSTRACT FROM AUTHOR]

Amphetamine injection is expanding in North America and has been associated with male homosexuality among people who inject drugs (PWID). Applying subcultural evolution theory, we examined overall and gender-stratified trends in amphetamine injection and assessed sexual orientation as a gender-specific predictor of initiation among PWID in Montreal, Canada. Data were from HEPCO, an open prospective cohort of PWID. Gender and sexual orientation were self-identified at enrolment. Interviewer-administered questionnaires at three-monthly (HCV RNA-negative participants) or yearly (RNA-positive) intervals captured past three-month amphetamine injection and covariates. Annual prevalence and linear trends in amphetamine injection were estimated using GEE. Incidence was computed among naïve individuals and hazard ratios for initiation estimated using gender-stratified, time-varying Cox regression models. 803 participants contributed 8096 observations between March 2011 and December 2019. Annual prevalence of amphetamine injecting increased from 3.25% [95%CI: 2.06–4.43%] to 12.7% [9.50–16.0] (trend p<0.001). Bivariate Cox regression models suggested similar and divergent predictors of initiation by gender. Incidence was 3.27 per 100 person-years [95%CI: 2.51–4.18] among heterosexual men, 7.18 [3.50–13.2] among gay/bisexual men, 1.93 [0.78–4.02] among heterosexual women and 5.30 [1.69–12.8] among gay/bisexual women. Among men, gay/bisexual identity doubled risk of initiation after adjusting for age, ethnicity, calendar year (aHR 2.16 [1.07–4.36]) and additional covariates (2.56 [1.24–5.30]). Among women, evidence for an association with gay/bisexual identity was inconclusive (aHR 2.63 [0.62–11.2]) and sample size precluded further adjustment Prevalence of amphetamine injection among PWID increased four-fold from 2011 to 2019, with elevated risk of initiation in gay and bisexual men • Prevalence of amphetamine injecting increased four-fold among PWID in Montreal. • Gay or bisexual orientation doubled risk of initiating amphetamine injection in men. • Opioid injection and opioid agonist treatment associated with initiation in men. • Cocaine injection and sexual relations with PWID associated with initiation in women. [ABSTRACT FROM AUTHOR]

Adenosine receptors (AR) are a family of G-protein coupled receptors, comprised of four members, named A1, A2A, A2B, and A3 receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system (CNS), adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In terms of molecular pathways and second messengers involved, A1 and A3 receptors inhibit adenylyl cyclase (AC), through Gi/o proteins, while A2A and A2B receptors stimulate it through Gs proteins. In the CNS, A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2A receptors are localized mainly in the striatum and olfactory bulb, while A2B and A3 receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A1/A2A), as well as with other subtypes (e.g., A2A/D2), opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A1 receptors colocalized in heteromeric complexes with D1 receptors, and A2A receptors with D2 receptors. This review documents the present state of knowledge of the contribution of AR, particularly A1 and A2A, to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A1 agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A2A/D2 heterodimers are partly responsible for the psychomotor and reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A2A receptor is proposed as a potential therapeutic target for the treatment of drug addiction. The overall analysis of presented data provide evidence that excitatory modulation of A1 and A2A receptors constitute promising tools to counteract psychostimulants addiction.

Adenosine receptors (AR) are a family of G-protein coupled receptors, comprised of four members, named A1, A2A, A2B, and A3 receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system (CNS), adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In terms of molecular pathways and second messengers involved, A1 and A3 receptors inhibit adenylyl cyclase (AC), through Gi=o proteins, while A2A and A2B receptors stimulate it through Gs proteins. In the CNS, A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2A receptors are localized mainly in the striatum and olfactory bulb, while A2B and A3 receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A1/A2A), as well as with other subtypes (e.g., A2A/D2), opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A1 receptors colocalized in heteromeric complexes with D1 receptors, and A2A receptors with D2 receptors. This review documents the present state of knowledge of the contribution of AR, particularly A1 and A2A, to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A1 agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A2A/D2 heterodimers are partly responsible for the psychomotor and reinforcing effects of psychostimulant drugs, such as cocaine and amphetamine, and the stimulation of A2A receptor is proposed as a potential therapeutic target for the treatment of drug addiction. The overall analysis of presented data provide evidence that excitatory modulation of A1 and A2A receptors constitute promising tools to counteract psychostimulants addiction. [ABSTRACT FROM AUTHOR]

The mechanism of action of psychostimulant drugs in the treatment of Attention Deficit Hyperactivity Disorder is still largely unknown, although recent evidence suggests one possibility is that the drugs affect the superior colliculus (SC). We have previously demonstrated that systemically administered d-amphetamine attenuates/abolishes visual responses to wholefield light flashes in the superficial layers of the SC in anaesthetised rats, and the present study sought to extend this work to methylphenidate (MPH). Anaesthetised rats were administered MPH at a range of doses (or saline) and subjected to monocular wholefield light flashes at two intensities, juxta-threshold and super-threshold. In contrast to d-amphetamine, systemic MPH produced an enhancement of visual activity at both intensities. Methylphenidate was also found to produce activation of the cortical EEG in anaesthetised rats. Furthermore, cortical activation induced by electrical stimulation of the pons was found to enhance visual responses in superficial layers of the SC, and when MPH was paired with pontine-induced cortical activation, the response-enhancing effects of MPH were substantially attenuated. Taken together, the results suggest that the enhancement of visual responses in the superficial layers of the SC by MPH in the anaesthetised rat is an artefact of the drug's interaction with cortical arousal. [ABSTRACT FROM AUTHOR]

Introduction Case reports of life-threatening cardiac arrhythmias and sudden cardiac arrest (SCA) among amphetamine users have raised serious concerns about the cardiac safety of this class of drugs. This is important in light of the high prevalence of dexamphetamine (dAMPH) prescription for attention-deficit/hyperactivity disorder (ADHD), and its rising use as a recreational drug. The objective was to investigate electrocardiogram (ECG) parameters upon intravenous administration of a single dAMPH dose in habitual recreational dAMPH users (users) and healthy gender/age/ intelligence-quotient-matched controls (non-users). Methods and results ECG recordings were made in 18 users and 18 non-users during administration of dAMPH (0.3 mg/kg body weight). Baseline ECG was normal in both groups. dAMPH elicited increased heart rate and corrected QT time (QTc) prolongation in both groups (all P < 0.001, QTc = 502 in one individual). QTc prolongation was attenuated in users compared to non-users, exhibiting a significant interaction effect (P = 0.04). Conclusion SCA associated with amphetamine use may be related to its QTc prolonging effects, particularly during first-time use. These observations may provide a rationale for conducting ECG analysis immediately after the first-time use of amphetamines, as this could potentially unmask vulnerable individuals. [ABSTRACT FROM AUTHOR]

Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannabinoid use occurring prior to pregnancy can impact brain plasticity and behavior in future generations. The purpose of the present study was to determine whether adolescent exposure of female rats to Δ9-tetrahydrocannabinol (Δ9-THC) induces transgenerational effects on the reward-facilitating effects of Δ9-THC and d-amphetamine in their adult male offspring. Female Sprague-Dawley rats received Δ9-THC (0.1 or 1 mg/kg, i.p.) or vehicle during postnatal days 28-50. As adults, females were mated with drug-naïve males. We then assessed potential alterations of the Δ9-THC's (0, 0.1, 0.5, and 1 mg/kg, i.p.) and d-amphetamine's (0, 0.1, 0.5, and 1 mg/kg, i.p.) reward-modifying effects using the curve-shift variant of the intracranial self-stimulation (ICSS) procedure in their adult male F1 offspring. The reward-facilitating effect of the 0.1 mg dose of Δ9-THC was abolished in the F1 offspring of females that were exposed to Δ9-THC (0.1 or 1 mg/kg), whereas the reward-attenuating effect of the 1 mg dose of Δ9-THC remained unaltered. The reward-facilitating effects of 0.5 and 1 mg of d-amphetamine were significantly decreased in the F1 offspring of females that were exposed to Δ9-THC (1 mg/kg and 0.1 or 1 mg, respectively). The present results reveal that female Δ9-THC exposure during adolescence can diminish the reward-facilitating effects of Δ9-THC and d-amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that Δ9-THC exposure during female adolescence may affect neural mechanisms that are shaping reward-related behavioral responses in a subsequent generation, as indicated by the shifts in the reward-facilitating effects of commonly used and abused drugs. [ABSTRACT FROM AUTHOR]

Prevalence of psychostimulant use is high, and raising in several countries. Nicotine is the legal stimulant causing the most important public health impact. Cocaine ranks among the most used illicit substances after cannabis. Stimulant medications are frequently misused. Psychostimulants can lead to addiction, have physical, psychological and social health consequences and can induce a great disease burden. The aim of the present article is to provide a literature review on the health effects of stimulants as potential drugs of abuse. It will cover essentially cocaine, amphetamines and its derivatives (including methamphetamines and 3-4-methylenedioxymethamphetamine, ecstasy), nicotine, caffeine and khat, and touch upon the issues of prescribed substances (anti-depressants, weight control medications, attention-deficit hyperactivity disorder medications, hypersomniac disorder). Their pharmacology, addictive potential, health consequences and treatment will be discussed. We used Medline for the literature review from 1990 to the date of this review, and mention the findings of human and animal studies (the latter only if they are of clinical relevance).

Addiction is a multifactorial disease that comprises physiological mechanisms of learning and memory. Addict subjects have intense plasticity in cortical and limbic circuits during intoxication, abstinence or even in drug seeking behavior. Locomotor sensitization is a classic animal model of drug addiction that mimics the changes that occur in the transition from drug use to drug addiction. Several studies have demonstrated the importance of contextual associative processes in this task. However, whether the mechanisms of sensitization are maintained and precise over the time remain an open question. Thus, the aim of this study was to investigate the importance of context in the maintenance and precision of locomotor sensitization across time. For this, male c57bl/6 mice were submitted to different contexts during the acquisition phase of amphetamine-induced locomotor sensitization. We found that after 3 days of withdrawal, the expression of locomotor sensitization was context dependent, as characterized by an increased locomotion in the acquisition context (A), but not in the novel context (B). Surprisingly, when the expression of locomotor sensitization was tested after 28 days of withdrawal, mice that acquired sensitization in the context A exhibited increased locomotion in both contexts (A and B), suggesting that memories associated with amphetamine drugs generalize following long periods of abstinence. The same generalization did not occur in mice sensitized in a well-known context (home cage). These results demonstrate, for the first time, the influence of memory generalization in amphetamine-induced locomotor sensitization. The evidence that memory generalization also occurs in sensitization provides new advances in the comprehension of the mechanisms underlying memory role in addiction process. Elucidating the mechanisms of amphetamine sensitization may shed some light on understanding the transition from drug use to addiction. [ABSTRACT FROM AUTHOR]

Dopamine neurons are overstimulated by drugs of abuse and suffer molecular alterations that lead to addiction behavior. Nurr1 is a transcription factor crucial for dopamine neurons survival and dopamine production, activating the transcription of key genes like tyrosine hydroxylase (TH). Interestingly, nuclear factor-kappa B (NF-κB) has emerged as a new Nurr1 partner in response to inflammatory stimulus. In this study we evaluated the effects of single and repeated amphetamine administration in the expression of Nurr1 and the NF-κB p65 subunit in the rat ventral tegmental area (VTA). We found that acute amphetamine treatment increased Nurr1, p65 and TH protein levels in the VTA. On the other hand, chronic amphetamine treatment decreased Nurr1 and p65 protein levels, but TH was unchanged. Mammalian reporter assays in cell lines showed that p65 represses Nurr1 transcriptional activity in an artificial promoter driven by Nurr1 response elements and in the native rat TH promoter. These results indicate that Nurr1 and NF-κB p65 factors are involved in the adaptive response of dopamine neurons to psychostimulants and that both transcription factors could be regulating Nurr1-dependent transactivation in the VTA. [ABSTRACT FROM AUTHOR]

Background/aims: Methylphenidate (MPH) has been the most commonly used intravenous (i.v.) substance in Iceland in recent years. In Iceland, MPH is available in 3 forms: immediate-release (IR) tablets (MPH IR, short-acting), sustainable-release (SR) capsules (MPH SR, long-acting) and osmotic-release (OROS) tablets (MPH OROS, long-acting). The aims of the study were to compare the pattern and subjective effects of i.v. MPH use to other i.v. psychostimulants and examine whether the pattern of use differs among MPH preparations.Methods: This is a nationwide descriptive study. Information was collected from 95 i.v. substance users undergoing inpatient detoxification and reporting i.v. MPH use in the last 30 days using a semi-structured interview.Results: MPH SR was both the most commonly used (96%) and preferred i.v. psychostimulant (57%). The intensity and duration of 'euphoria' did not differ between cocaine and MPH SR. No participant reported MPH OROS as their preferred substance even though a third had used it in the past month.Conclusions: The pattern of i.v. MPH use is similar to other psychostimulants among treatment seeking patients. MPH OROS was the least preferred i.v. psychostimulant, despite having the largest market share in Iceland. The results indicate that MPH OROS has less abuse potential than other MPH preparations. [ABSTRACT FROM AUTHOR]

Repeated exposure to psychostimulants induces locomotor sensitization and leads to persistent changes in the circuitry of the mesocorticolimbic dopamine (DA) system. G-protein-gated inwardly rectifying potassium (GIRK; also known as Kir3) channels mediate a slow IPSC and control the excitability of DA neurons. Repeated 5 d exposure to psychostimulants decreases the size of the GABAB receptor (GABABR)-activated GIRK currents (IBaclofen)411 ventral tegmental area (VTA) DA neurons of mice, but the mechanism underlying this plasticity is poorly understood. Here, we show that methamphetamine-dependent attenuation of GABABR-GIRK currents in VTA DA neurons required activation of both D1R-like and D2R-like receptors. The methamphetamine-dependent decrease in GABABR-GIRK currents in VTA DA neurons did not depend on a mechanism of dephosphorylation of the GABAB R2 subunit found previously for other neurons in the reward pathway. Rather, the presence of the GIRK3 subunit appeared critical for the methamphetamine-dependent decrease of GABABR-GIRK current in VTA DA neurons. Together, these results highlight different regulatory mechanisms in the learning-evoked changes that occur in the VTA with repeated exposure to psychostimulants. [ABSTRACT FROM AUTHOR]

Background. Within the last decade, the nonmedical use of prescription drugs has raised concern, particularly among young adults. Psychostimulants, that is to say amphetamine and its derivatives, are pharmaceuticals, which contribute to what has come to be known in Canada and the United States as the “prescription drug crisis.” Research in the fields of public health, addiction studies, and neuroethics has attempted to further understand this mounting issue; however, there is a paucity of data concerning the underlying social logics related to the use of these substances.Objectives. The objective of this article is to provide an overview of the current literature related to the social context of prescription psychostimulant use among young adults, and to discuss theoretical considerations as well as implications for future research.Methods. A narrative review of the literature was performed.Results. We found that research efforts have chiefly targeted college students, yet there is a lack of knowledge concerning other social groups likely to use these pharmaceuticals nonmedically, such as persons with high strain employment. Three main emerging patterns related to prescription psychostimulant use were identified: (1) control of external stressors, (2) strategic use toward the making of the self, and (3) increasing one's performance.Conclusions. Prescription psychostimulant use among young adults is anchored in contemporary normativity and cannot be separated from the developing performance ethic within North-American and other Western societies. We suggest that pharmaceuticalization and Actor-Network Theory are useful conceptual tools to frame future research efforts. [ABSTRACT FROM PUBLISHER]

Rationale: Rate dependence refers to an orderly relationship between a baseline measure of behavior and the change in that behavior following an intervention. The most frequently observed rate-dependent effect is an inverse relationship between the baseline rate of behavior and response rates following an intervention. A previous report of rate dependence in delay discounting suggests that the discounting of delayed reinforcers, and perhaps, other impulsivity measures, may change rate dependently following acute and chronic administration of potentially therapeutic medications in both preclinical and clinical studies. Objective: The aim of the current paper was to review the effects of stimulants on delay discounting and other impulsivity tasks. Methods: All studies identified from the literature were required to include (1) an objective measure of impulsivity; (2) administration of amphetamine, methylphenidate, or modafinil; (3) presentation of a pre- and postdrug administration impulsivity measure; and (4) the report of individual drug effects or results in groups split by baseline or vehicle impulsivity. Twenty-five research reports were then reanalyzed for evidence consistent with rate dependence. Results: Of the total possible instances, 67 % produced results consistent with rate dependence. Specifically, 72, 45, and 80 % of the data sets were consistent with rate dependence following amphetamine, methylphenidate, and modafinil administration, respectively. Conclusions: These results suggest that rate dependence is a more robust phenomenon than reported in the literature. Impulsivity studies should consider this quantitative signature as a process to determine the effects of variables and as a potential prognostic tool to evaluate the effectiveness of future interventions. [ABSTRACT FROM AUTHOR]

Background: The last decade has seen a rapid and continuous growth in the availability and use of novel psychoactive substances (NPS) across the world. Although various products are labeled with warnings "not for human consumption", they are intended to mimic psychoactive effects of illicit drugs of abuse. Once some compounds become regulated, new analogues appear in order to satisfy consumers' demands and at the same time to avoid criminalization. This review presents updated information on the second generation of NPS, introduced as replacements of the already banned substances from this class, focusing on their pharmacological properties and metabolism, routes of administration, and effects in humans.Methods: Literature search, covering years 2013-2015, was performed using the following keywords alone or in combination: "novel psychoactive substances", "cathinones", "synthetic cannabinoids", "benzofurans", "phenethylamines", "2C-drugs", "NBOMe", "methoxetamine", "opioids", "toxicity", and "metabolism".Results: More than 400 NPS have been reported in Europe, with 255 detected in 2012-2014. The most popular are synthetic cannabimimetics and psychostimulant cathinones; use of psychedelics and opioids is less common. Accumulating experimental and clinical data indicate that potential harms associated with the use of second generation NPS could be even more serious than those described for the already banned drugs.Conclusions: NPS are constantly emerging on the illicit drug market and represent an important health problem. A significant amount of research is needed in order to fully quantify both the short and long term effects of the second generation NPS, and their interaction with other drugs of abuse. [ABSTRACT FROM AUTHOR]

The increasing availability, over-prescription, and misuse and abuse of ADHD psychostimulant medications in adolescent populations necessitates studies investigating the long-term effects of these drugs persisting into adulthood. Male and female C57Bl/6J mice were exposed to amphetamine (AMPH) (1.0 and 10 mg/kg), methylphenidate (MPD) (1.0 and 10 mg/kg), or cocaine (COC) (5.0 mg/kg) from postnatal day 22 to 31, which represents an early adolescent period. After an extended period of drug abstinence, adult mice were challenged with a subacute methamphetamine (METH) dose (0.5 mg/kg), to test the long-term effects of adolescent drug exposures on behavioral cross-sensitization using an open field chamber. There were no sex- or dose-specific effects on motor activity in adolescent, saline-treated controls. However, AMPH, MPD, and COC adolescent exposures induced cross-sensitization to a subacute METH dose in adulthood, which is a hallmark of addiction and a marker of long-lasting plastic changes in the brain. Of additional clinical importance, AMPH-exposed male mice demonstrated increased cross-sensitization to METH in contrast to the female-specific response observed in MPD-treated animals. There were no sex-specific effects after adolescent COC exposures. This study demonstrates differential drug, dose, and sex-specific alterations induced by early adolescent psychostimulant exposure, which leads to behavioral alterations that persist into adulthood. [ABSTRACT FROM AUTHOR]

When psychostimulant drugs like amphetamine are administered repeatedly in the presence of a contextual stimulus complex, long-lasting associations form between the unconditioned effects of the drug and the contextual stimuli. Here we assessed the role played by the proline-directed serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) in the nucleus accumbens (NAcc) on the expression of the conditioned locomotion normally observed when rats are returned to a context previously paired with amphetamine. Infusing the Cdk5 inhibitor roscovitine (40 nmol/0.5 μl/side) into the NAcc 30-min before the test for conditioning significantly enhanced the conditioned locomotor response observed in rats previously administered amphetamine in the test environment. This effect was specific to the expression of a conditioned response as inhibiting Cdk5 produced no effect in control rats previously administered saline or previously administered amphetamine elsewhere. As inhibiting Cdk5 during exposure to amphetamine has been found to block the accrual of locomotor conditioning, the present results suggest distinct roles for NAcc Cdk5 in the induction and expression of excitatory conditioning by amphetamine. [ABSTRACT FROM AUTHOR]

Intermittent systemic exposure to psychostimulants leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine-nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying the formation of conditioned associations. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density normally observed in this site following repeated cocaine. Mice lacking the Kal7 gene display similar effects. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5 μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threonine-alanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site. [ABSTRACT FROM AUTHOR]

Adults with Attention Deficit Hyperactivity Disorder (ADHD), especially teenagers and young adults, show important car driving impairments, including risky driving, accidents, fines and suspension of driver's license. We systematically reviewed the efficacy of stimulant and non-stimulant drugs on driving performance of ADHD patients. We searched several databases for randomized controlled trials (RCTs) published through March, 2013. Fifteen RCTs (the majority with crossover design) evaluated methylphenidate (MPH) immediate-release (MPH-IR), MPH osmotic-controlled oral system (MPH-OROS), MPH transdermal system (MTS), extended-release mixed amphetamine salts (MAS-XR); atomoxetine (ATX) and lisdexamfetamine (LDX). Methods varied widely; including simulators and/or cars and different courses and scenarios. Various outcomes of driving performance, including a 'composite' or 'overall' driving score were considered. In general, stimulants improved driving performance in ADHD patients (either in RCTs conducted in simulators and/or cars). MPH-OROS improved driving performance compared with MAS-XR, placebo, or no-drug conditions. Although MPH-OROS and MPH-IR produced similar improvements during the day, MPH-IR lost its efficacy in the evening. MAS-XR also improved driving performance, but worsened driving performance in the evening. MTS (one study) showed a positive effect, but drug compliance varied widely across patients. LDX had positive effect on driving (two studies with the same sample). Studies with ATX report conflicting results. Improvement was more consistent in teenagers and young adults. In general, treatment with psychostimulants or ATX in therapeutic dosages had no negative impact on driving performance of ADHD patients. To conclude, treatment with stimulants in therapeutic doses improves driving performance in ADHD patients, especially teenagers and young adults. [ABSTRACT FROM AUTHOR]

Rationale: Social play behavior is the most characteristic social behavior in young mammals. It is highly rewarding and crucial for proper neurobehavioral development. Despite the importance of genetic factors in normal and pathological social behaviors, little information is available about strain influences on social play. Objective and methods: The aim of this study was to investigate differences in social play behavior, 50-kHz ultrasonic vocalizations (USVs) and their modulation by acute morphine and amphetamine administration in two rat strains widely used in behavioral pharmacology studies, i.e., Wistar and Sprague-Dawley rats. Results: Sprague-Dawley rats showed higher levels of social play than Wistar rats. In both strains, no correlation was found between the performance of social behaviors and the emission of 50-kHz USVs. In Wistar and Sprague-Dawley rats, morphine increased and amphetamine decreased social play. The effects of morphine, however, were more pronounced in Wistar than Sprague-Dawley animals. In both strains, morphine did not affect USV emission, while amphetamine increased it during cage exploration. In Sprague-Dawley rats only, amphetamine decreased USVs during social interaction. Conclusions: Wistar and Sprague-Dawley rats differ in their absolute levels of social play behavior and 50-kHz USVs, and quantitative differences exist in their response to pharmacological manipulations of social play. The emission of 50-kHz USVs and the behavioral parameters thought to reflect rewarding social interactions in adolescent rats are dissociable. [ABSTRACT FROM AUTHOR]

Highlights: [•] Rats developed preference and relapse to amphetamine (AMPH). [•] AMPH increased intensified anxiety-like symptoms related to abstinence. [•] AMPH increased oxidative damages and modified enzymes activity in hippocampus. [•] Exercise reduced AMPH-relapse and anxiety-like symptoms after re-exposure to drug. [•] Exercise increased enzymes activity and prevented oxidative damages in hippocampus. [ABSTRACT FROM AUTHOR]

Highlights: [•] Food restriction increases the rewarding potency of drugs. [•] The MCH pathway is well located to influence reward. [•] CPP induced by amphetamine is not enhanced by food restriction in MCHR1-KO mice. [•] The MCH signaling might play a role in the effect of food restriction on drug reward. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To estimate the global prevalence of cocaine and amphetamine dependence and the burden of disease attributable to these disorders. Methods: An epidemiological model was developed using DisMod-MR, a Bayesian meta-regression tool, using epidemiological data (prevalence, incidence, remission and mortality) sourced from a multi-stage systematic review of data. Age, sex and region-specific prevalence was estimated for and multiplied by comorbidity-adjusted disability weightings to estimate years of life lost to disability (YLDs) from these disorders. Years of life lost (YLL) were estimated from cross-national vital registry data. Disability-adjusted life years (DALYs) were estimated by summing YLDs and YLLs in 21 regions, by sex and age, in 1990 and 2010. Results: In 2010, there were an estimated 24.1 million psychostimulant dependent people: 6.9 million cocaine and 17.2 million amphetamines, equating to a point prevalence of 0.10% (0.09–0.11%) for cocaine, and 0.25% (0.22–0.28%) for amphetamines. There were 37.6 amphetamine dependence DALYs (21.3–59.3) per 100,000 population in 2010 and 15.9 per 100,000 (9.3–25.0) cocaine dependence DALYs. There were clear differences between amphetamines and cocaine in the geographic distribution of crude DALYs. Over half of amphetamine dependence DALYs were in Asian regions (52%), whereas almost half of cocaine dependence DALYs were in the Americas (44%, with 23% in North America High Income). Conclusion: Dependence upon psychostimulants is a substantial contributor to global disease burden; the contribution of cocaine and amphetamines to this burden varies dramatically by geographic region. There is a need to scale up evidence-based interventions to reduce this burden. [Copyright &y& Elsevier]

he methyl-DNA binding protein MeCP2 is emerging as an important regulator of drug reinforcement processes. Psychostimulants induce phosphorylation of MeCP2 at Ser421; however, the functional significance of this posttranslational modification for addictive-like behaviors was unknown. Here we show that MeCP2 Ser421Ala knock-in mice display both a reduced threshold for the induction of locomotor sensitization by investigator-administered amphetamine and enhanced behavioral sensitivity to the reinforcing properties of self-administered cocaine. These behavioral differences were accompanied in the knock-in mice by changes in medium spiny neuron intrinsic excitability and nucleus accumbens gene expression typically observed in association with repeated exposure to these drugs. These data show that phosphorylation of MeCP2 at Ser421 functions to limit the circuit plasticities in the nucleus accumbens that underlie addictive-like behaviors. [ABSTRACT FROM AUTHOR]

Although both cocaine and amphetamine mainly target the dopamine transporter (DAT) and cause psychomotor effects, they have very different mechanisms of actions. The authors examined whether responses to cocaine and amphetamine were affected differentially by changes in DAT expression levels using transgenic mice with different DAT expression levels. In the constitutive DAT knockdown mice, reduced DAT expression enhanced cocaine's locomotor stimulatory effects and at the same time diminished amphetamine's locomotor stimulatory effects. Similar effects were observed in the inducible DAT knockdown mice, ruling out the contribution of developmental compensations in DAT knockdown mice. Extracellular dopamine levels in response to psychostimulants were assessed by in vivo microdialysis. Whereas amphetamine-induced increase in extracellular dopamine was drastically diminished in constitutive DAT knockdown mice, cocaine-induced increase in extracellular dopamine had a faster onset in knockdown mice compared with wild-type controls. Postsynaptically, D1 agonist-stimulated c-fos expression was significantly attenuated in constitutive DAT knockdown mice compared with wild-type controls. The authors propose that responses to cocaine and amphetamine depend on psychostimulant drug type, drug dose, as well as DAT expression level. DAT expression level affects presynaptic responses to psychostimulants directly and postsynaptic responses to psychostimulants indirectly via changes in receptor signaling. These data imply that individual differences in DAT expression (either genetically or pharmacologically induced) may affect susceptibility to addiction of different types of psychostimulants. [ABSTRACT FROM AUTHOR]

In psychostimulant drug addiction, relapse is the most concerning outcome to be managed, considering there is no approved treatment for this neuropsychiatric condition. Here, we investigated the effects of the CBD treatment on the relapse behavior triggered by stress, after being submitted to the amphetamine (AMPH)-induced conditioned place preference (CPP) in rats. To elucidate the mechanisms of action underlying the CBD treatment, we evaluated the neuroadaptations on dopaminergic and endocannabinoid targets in the ventral striatum (VS) and ventral tegmental area (VTA) of the brain. Animals received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the CPP paradigm for 8 days. Following the first CPP test, animals were treated with CBD (10 mg/kg, i.p.) or its vehicle for 5 days and subsequently submitted to forced swim stress protocol to induce AMPH-CPP relapse. Behavioral findings showed that CBD treatment prevented AMPH-reinstatement, also exerting anxiolytic activity. At the molecular level, in the VTA, CBD restored the CB1R levels decreased by AMPH-exposure, increased NAPE-PLD, and decreased FAAH levels. In the VS, the increase of D1R and D2R, as well as the decrease of DAT levels induced by AMPH were restored by CBD treatment. The current outcomes evidence a substantial preventive action of the CBD on the AMPH-reinstatement evoked by stress, also involving neuroadaptations in both dopaminergic and endocannabinoid systems in brain areas closely involved in the addiction. Although further studies are needed, these findings support the therapeutic potential of CBD in AMPH-relapse prevention. • Cannabidiol (CBD) treatment prevented amphetamine (AMPH) reinstatement. • CBD restored CB1 receptors levels decreased by AMPH-exposure. • CBD treatment restored the AMPH-induced increase in D1 and D2 receptor levels. • CBD acts in brain areas closely involved in addiction processes. [ABSTRACT FROM AUTHOR]

Recently, healthy individuals have been using psychostimulants for cognitive enhancement purposes. Psychostimulant medications may increase wakefulness, but as a tradeoff, they may constrict cognitive flexibility and reduce creativity in healthy individuals with no psychiatric disorders. In this perspective, the author addresses the ethical and prudential issues that arise from impairing creativity with psychostimulants. As there is a strong relationship between creativity and positive mental health, the author argues that creativity is an important character strength. Hence, reducing it with psychostimulants will impair an intrinsically and instrumentally valuable trait, which will in the long term reduce well-being and negatively impact the positive mental health of the healthy individual and the flourishing of society. The author concludes that using psychostimulants as a form of cognitive enhancement in healthy adults is imprudent and morally suspect for society. PERSPECTIVES is a special feature included in this issue of Journal of Creativity in Mental Health that provides mental health professionals with an opportunity to discuss their positions on a variety of creativity-related topics. In this article, Dr. Mohamed shares his view of the ethical and prudential issues that arise from impairing creativity with psychostimulants. Dr. Ahmed Dahir Mohamed is a chartered psychologist member of the British Psychological Society. His Ph.D., which was awarded in 2013 by the Department of Psychiatry at the University of Cambridge, was in the area of cognitive enhancement. Using modafinil as a pharmacological probe, his work explored how drugs like modafinil, Adderall, and methylphenidate (Ritalin) affect cognitive and affective functions in healthy individuals with no psychiatric disorders. His work has been published in highly regarded academic journals including the International Journal of Neuropsychopharmacology, The American Journal of Bioethics: Neuroscience, The Journal of Ethics in Mental Health, and The British Journal of Counselling and Psychotherapy. Dr. Mohamed was the previous winner of the Nuffield Science Bursary Award for outstanding research in psychology and the Wellcome Trust Doctoral Neuroscience studentship award. In 2013, Dr. Mohamed became an Elected Life Academic Member of Clare Hall at the University of Cambridge. Dr. Mohamed is currently editing an Oxford University Press handbook entitledRethinking Cognitive Enhancement: The Neuroscience and Ethics of Cognitive and Physical Enhancement. This article is based on an invited lecture given at the St. Cross Ethics Seminars at Oxford. Dr Mohamed was a visiting academic scholar at St. Cross College and a recognized DPhil student at the Oxford Centre for Neuroethics at the University of Oxford. [ABSTRACT FROM PUBLISHER]

Psychostimulants, including amphetamine (AMPH), exert robust arousal-enhancing, reinforcing and locomotor-activating effects. These behavioural actions involve drug-induced elevations in extracellular norepinephrine (NE) and dopamine (DA) within a variety of cortical and subcortical regions. The lateral hypothalamic area (LHA), including the lateral hypothalamus proper, perifornical area and adjacent dorsomedial hypothalamus, is implicated in appetitive- and arousal-related processes. The LHA is innervated by both NE and DA projections and systemically administered AMPH has been demonstrated to activate LHA neurons. Combined, these and other observations suggest the LHA may be a site of action in the behavioural effects of psychostimulants. To test this hypothesis, we examined the degree to which AMPH (10 nmol, 25 nmol) acts within the LHA to exert arousing, locomotor-activating and reinforcing actions in quietly resting/sleeping rats. Although intra-LHA AMPH robustly increased time spent awake, this occurred in the absence of pronounced locomotor activation or reinforcing actions, as measured in a conditioned place preference (CPP) paradigm. Arousing and stressful conditions or drug re-exposure can elicit relapse in humans and reinstate drug-seeking in animals. Given the LHA is also implicated in the reinstatement of drug-seeking behaviour, additional studies examined whether AMPH acts within the LHA to reinstate an extinguished CPP produced with systemic AMPH administration. Our results demonstrate that AMPH action within the LHA is sufficient to reinstate drug-seeking behaviour, as measured in this paradigm. Collectively, these observations demonstrate that psychostimulants act within the LHA to elicit affectively neutral arousal and reinstate drug-seeking behaviour. [ABSTRACT FROM AUTHOR]

Rationale: The molecular mechanisms underlying susceptibility to psychostimulant addiction remain unclear. Searching for commonalities in the effects of addictive drugs on brain gene expression is a prolific approach to determine transcriptional signatures influencing drug abuse. Objective: We explored the common transcriptional responses to the reinforcing effects of psychostimulants methamphetamine, amphetamine, and methylphenidate. We also aimed to identify transcriptional changes that may subserve abuse of these drugs. Methods: Genome-wide transcriptome profiling analyses were performed to identify common prefrontal cortical (PFC) and striatal gene expression profiles in drug-naïve (cohort 1) and stimulant-pretreated (cohort 2) rats, which showed a conditioned place preference to and self-administration of methamphetamine, amphetamine, and methylphenidate. Results: In behavioral studies, stimulant-pretreated rats showed behavioral sensitization characterized by enhanced behavioral response to the rewarding or reinforcing effects of psychostimulants. Inflammation-associated genes (e.g., Alas1, S100a8 and S100a9) were identified as the primary differentially expressed genes (DEGs) in both the PFC and the striatum of cohort 1 rats, while neuronal plasticity ( Sgk1)- and brain development (e.g., Bhlhe22, Neurod1, Nr4a2, and Msx1)-associated genes comprised the major upregulated DEGs in the striatum of cohort 2 rats. Furthermore, a meta-analysis of the common striatal DEGs in this study along with morphine-regulated striatal transcriptomes in mice (National Center for Biotechnology Information-Gene Expression Omnibus Database Accession Code GSE7762) suggested similar expression profiles of genes involved in neuronal development (e.g., Bhlhe22, Nr4a2). Conclusion: This study provides evidence that brain development-associated genes mediate the reinforcing effects of methamphetamine, amphetamine, and methylphenidate and that these transcripts may underlie susceptibility to psychostimulant addiction. [ABSTRACT FROM AUTHOR]

Objective:Methamphetamine is often perceived as a more potent drug than amphetamine, and even though this is partially supported by theoretical consideration of methamphetamine's chemistry, empirical support has been lacking. The aim of this study was to examine whether methamphetamine use was more common among people with acute psychiatric symptoms and more predictive of having such symptoms.Methods:Blood samples were obtained from two groups: 363 people admitted to two acute psychiatric wards and 735 drivers who were suspected of driving under the influence of drugs. Blood samples from both groups were analyzed at the same laboratory, using the exact same procedures, and were matched on geographical region and time the sample was collected. Differences between the two groups were analyzed and binary logistic regression was used to explore the interrelationship between the probability of being admitted to a psychiatric ward, the level of different sedating drugs, and amphetamine concentrations.Results:People admitted to psychiatric wards were more often positive for methamphetamine (73.7%; 28 of 38) compared to apprehended drivers (46.5%; 342 of 735),χ2= 9.62,df= 1,p< .01. The adjusted odds for being admitted to an acute psychiatric ward were significantly higher for those positive for methamphetamine compared to those positive only for amphetamine; B = 1.487,SE= 0.397,p< .001, adjusted odds ratio = 4.423, 95% CI [2.031–9.631].Conclusions:Methamphetamine was more often detected in people admitted to acute psychiatric wards, suggesting a possible link between methamphetamine and psychiatric symptoms that could lead to admission. [ABSTRACT FROM AUTHOR]