Dexamphetamine increased speech and visual unimodal illusions in healthy participants without affecting temporal binding window.

OBJECTIVE: Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders. METHODS: A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed. RESULTS: Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo. CONCLUSIONS: Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.

Differential effects of intra-ventral tegmental area ghrelin and glucagon-like peptide-1 on the stimulatory action of D-amphetamine and cocaine-induced ethanol intake in male Sprague Dawley rats.

In order to further elucidate the role of mesolimbic peptides in the expression of ethanol reward, the present study investigated the effects of ghrelin and glucagon-like peptide-1 (GLP-1) on ethanol intake, in addition to ethanol intake stimulated by systemic d-amphetamine or cocaine treatment. While a number of studies suggest that ghrelin plays an important role in mesolimbic reward, emerging data now indicate that GLP-1 receptor mechanisms inhibit reward signaling, possibly by directly or indirectly inhibiting ghrelinergic activity within the mesolimbic system. In the present study all rats were initially habituated to a 6% ethanol solution. We then demonstrated that intraperitoneal injections of d-amphetamine and cocaine increased ethanol intake compared to the vehicle condition. In subsequent testing we examined the effects of ventral tegmental area (VTA) ghrelin or vehicle paired with a fixed dose of d-amphetamine or vehicle. In separate rats we then investigated the impact of the GLP-1 agonist exendin-4 (Ex-4), injected into the VTA, on ethanol intake alone, or when Ex-4 was co-administered with d-amphetamine or cocaine. Our results indicated that VTA ghrelin significantly increased ethanol intake, and most importantly, potentiated the effect of d-amphetamine and cocaine on ethanol consumption. Conversely, VTA Ex-4 inhibited ethanol intake and antagonized the stimulatory effect of d-amphetamine and cocaine on ethanol consumption. In a final study we further demonstrated that VTA Ex-4 treatment significantly inhibited the combined stimulatory effects of ghrelin paired with d-amphetamine or ghrelin paired with cocaine. Overall our findings are consistent with a critical role for both ghrelin and GLP-1 receptor mechanisms in mesolimbic ethanol reward circuitry. Moreover, our results further suggest that ghrelin and GLP-1 modulate the stimulatory effect of psychostimulants on ethanol intake.

Investigating sex differences and the effect of drug exposure order in the sensory reward-enhancing effects of nicotine and d-amphetamine alone and in combination.

Nicotine enhances the rewarding effects of other environmental stimuli; this reward-enhancement encourages and maintains nicotine consumption. Nicotine use precedes other psychostimulant use, but receiving a stimulant prescription also predicts future smoking. Previously, no study has investigated effects of drug exposure order in reward-enhancement, nor with nicotine and d-amphetamine. Thus, we aimed to investigate how drug exposure order impacted the reward-enhancing effects of nicotine and d-amphetamine, alone and in combination. We used 20 male and 20 female Sprague-Dawley rats. Enhancement was investigated within-subjects by examining responding maintained by a visual stimulus reinforcer following a pre-session injection of either d-amphetamine (Sal, 0.1, 0.3, or 0.6 mg/kg) or nicotine (Sal, 0.03, 0.06, 0.1, 0.3 mg/kg). Twenty rats (10 M, 10 F) completed enhancement testing with nicotine before d-amphetamine. The other 20 rats (10 M, 10 F) completed testing with d-amphetamine before nicotine. Following these phases, rats were then given two pre-session injections: one of d-amphetamine (Sal, 0.1, 0.3, or 0.6 mg/kg) and another of nicotine (Sal, 0.03, 0.06, 0.1, or 0.3 mg/kg). Experiencing amphetamine before nicotine increased reward-enhancing effects of nicotine. Females exhibited greater effects of d-amphetamine on reward-enhancement, with no effect of exposure order. During the interaction phase, receiving nicotine before amphetamine enhanced the interaction between nicotine and d-amphetamine for females whereas amphetamine before nicotine heightened this interaction for males. From this, prior and current amphetamine use, in addition to sex, should be considered when treating nicotine dependency and when examining factors driving poly-substance use involving nicotine and d-amphetamine. Keywords: Adderall, ADHD, Dexedrine, operant, smoking, polysubstance use.

Utility of a controlled amphetamine withdrawal paradigm among adults who use methamphetamine: A pilot clinical trial.

BACKGROUND: The continued increase in prevalence of methamphetamine use in the United States has resulted in a significant increase in the number of patients entering treatment for methamphetamine use. However, no robustly efficacious pharmacologic treatment for methamphetamine use or withdrawal has been identified to date after stopping methamphetamine use. AIMS: Given the association between methamphetamine withdrawal and relapse during early treatment, this study tested a controlled d-amphetamine withdrawal paradigm among methamphetamine-using individuals. METHODS: Treatment-seeking adults who used methamphetamine (N = 34; 47% female; 100% white) were enrolled in a 4-week, randomized, double-blind, placebo-controlled trial in a residential setting, in which all participants were maintained on d-amphetamine (30 mg BID) during week 1, then half were switched to placebo during weeks 2-3. All participants received placebo during week 4. Outcomes included vital signs, withdrawal, cravings for methamphetamine, mood, and cognition. Bivariate analyses tested treatment group differences on baseline demographic and outcome variables. Repeated measures models examined main and interaction effects of treatment over time. RESULTS/OUTCOMES: Participants were successfully randomized and safely stabilized on d-amphetamine. Craving for methamphetamine increased during weeks 2-3 in the placebo group relative to those on d-amphetamine. Interactions with age and heart rate were noted. CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first double-blind, placebo-controlled trial measuring pharmacologic effects of abruptly stopping controlled d-amphetamine administration in adults who use methamphetamine. Results support the potential of this withdrawal paradigm to further examine the efficacy of pharmacologic agents in ameliorating methamphetamine withdrawal symptoms.

Medication Use in the Management of Comorbidities Among Individuals With Autism Spectrum Disorder From a Large Nationwide Insurance Database.

Importance: Although there is no pharmacological treatment for autism spectrum disorder (ASD) itself, behavioral and pharmacological therapies have been used to address its symptoms and common comorbidities. A better understanding of the medications used to manage comorbid conditions in this growing population is critical; however, most previous efforts have been limited in size, duration, and lack of broad representation. Objective: To use a nationally representative database to uncover trends in the prevalence of co-occurring conditions and medication use in the management of symptoms and comorbidities over time among US individuals with ASD. Design, Setting, and Participants: This retrospective, population-based cohort study mined a nationwide, managed health plan claims database containing more than 86 million unique members. Data from January 1, 2014, to December 31, 2019, were used to analyze prescription frequency and diagnoses of comorbidities. A total of 26 722 individuals with ASD who had been prescribed at least 1 of 24 medications most commonly prescribed to treat ASD symptoms or comorbidities during the 6-year study period were included in the analysis. Exposures: Diagnosis codes for ASD based on International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Main Outcomes and Measures: Quantitative estimates of prescription frequency for the 24 most commonly prescribed medications among the study cohort and the most common comorbidities associated with each medication in this population. Results: Among the 26 722 individuals with ASD included in the analysis (77.7% male; mean [SD] age, 14.45 [9.40] years), polypharmacy was common, ranging from 28.6% to 31.5%. Individuals' prescription regimens changed frequently within medication classes, rather than between classes. The prescription frequency of a specific medication varied considerably, depending on the coexisting diagnosis of a given comorbidity. Of the 24 medications assessed, 15 were associated with at least a 15% prevalence of a mood disorder, and 11 were associated with at least a 15% prevalence of attention-deficit/hyperactivity disorder. For patients taking antipsychotics, the 2 most common comorbidities were combined type attention-deficit/hyperactivity disorder (11.6%-17.8%) and anxiety disorder (13.1%-30.1%). Conclusions and Relevance: This study demonstrated considerable variability and transiency in the use of prescription medications by US clinicians to manage symptoms and comorbidities associated with ASD. These findings support the importance of early and ongoing surveillance of patients with ASD and co-occurring conditions and offer clinicians insight on the targeted therapies most commonly used to manage co-occurring conditions. Future research and policy efforts are critical to assess the extent to which pharmacological management of comorbidities affects quality of life and functioning in patients with ASD while continuing to optimize clinical guidelines, to ensure effective care for this growing population.

Subjective responses predict d-amphetamine choice in healthy volunteers.

BACKGROUND: It is commonly believed that drugs, including stimulants, are used recreationally because of their ability to induce pleasurable subjective effects. However, recreational drug use sometimes occurs in the absence of positive subjective effects, suggesting that other factors contribute. Here, we examine the extent to which the direct subjective effects of amphetamine, a commonly misused stimulant, predict subsequent choice of the drug vs placebo. METHODS: Healthy adults (N = 112) participated in a five-session amphetamine choice study. On the first four sessions, participants sampled either 20 mg d-amphetamine or placebo in color-coded capsules two times each. On the fifth session, they chose which color (d-amphetamine or placebo) they preferred. We examined the choice of drug vs placebo in relation to demographic characteristics, baseline mood states, personality and subjective and cardiovascular responses to acute administration of the drug. RESULTS: Eighty-one participants chose amphetamine (Choosers) while 31 chose placebo (Non-choosers). Overall, amphetamine produced typical stimulant-like effects on subjective questionnaires, and it elevated heart rate and blood pressure vs placebo. Choosers reported greater positive mood, elation and stimulant-like effects following amphetamine compared to Non-choosers. The Choosers also exhibited a greater increase in systolic blood pressure, but not heart rate. The groups did not differ on demographic characteristics, mood states before drug administration or personality. CONCLUSIONS: These findings support the idea that pleasurable subjective responses to amphetamine, including positive mood, elation, and stimulant-like effects influence behavioral choice of the drug.

GPR52 agonists attenuate ropinirole-induced preference for uncertain outcomes.

Dopamine D2/3 receptor agonists are less likely to trigger dyskinesias than L-dopa while still offering relief from the motor symptoms of Parkinson's disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful. G-protein-coupled receptor 52 (GPR52) is an orphan Gs-protein-coupled receptor that is coexpressed with striatal D2 receptors. Activating GPR52 attenuates behaviors associated with increased striatal dopamine release without altering basal function. Iatrogenic gambling disorder may be mediated, at least partly, by striatal dopamine signaling. We therefore investigated whether 2 potent small-molecule GPR52 agonists (BD442618, BD502657) could block the increase in preference for uncertain outcomes caused by acute d-amphetamine and chronic ropinirole, without altering baseline choice patterns. In the rat betting task (rBT), subjects choose between a guaranteed reward (the "wager") versus the 50:50 chance of double the wager or nothing. Although wager size varies across trial blocks, both options are constantly matched for expected value. The effects of BD442618 on the rBT were acutely assessed alone or in combination with d-amphetamine and subsequently in combination with chronic ropinirole. The latter experiment was then repeated with BD502657. BD442618 did not alter baseline decision making but attenuated the increase in preference for uncertainty caused by both acute amphetamine and chronic ropinirole administration. Similarly, BD502657 abrogated chronic ropinirole's effects. These data provide the first evidence that GPR52 agonists may be useful in treating iatrogenic gambling disorder or other conditions hallmarked by hyperdopaminergic states. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans.

Background: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood. Methods: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.0 mg/kg, i.p.) on locomotor activity and binding of the mGlu5 ligand [3H]ABP688. In a parallel study, in 19 stimulant-drug-naïve healthy human volunteers (14 female) we administered 3 doses of dextroamphetamine (0.3 mg/kg, p.o.) or placebo, followed by a fourth dose 2 weeks later. We measured [11C]ABP688 binding using positron emission tomography before and after the induction phase. We assessed psychomotor and behavioural sensitization using speech rate, eye blink rate and self-report. We measured the localization of mGlu5 relative to synaptic markers in mouse striatum using immunofluorescence. Results: We observed amphetamine-induced psychomotor sensitization in mice and humans. We did not see group differences in mGlu5 availability following 3 pre-challenge amphetamine doses, but group differences did develop in mice administered 5 doses. In mice and humans, individual differences in mGlu5 binding after repeated amphetamine administration were negatively correlated with the extent of behavioural sensitization. In drug-naïve mice, mGlu5 was expressed at 67% of excitatory synapses on dendrites of striatal medium spiny neur. Limitations: Correlational results should be interpreted as suggestive because of the limited sample size. We did not assess sex differences. Conclusion: Together, these results suggest that changes in mGlu5 availability are not part of the earliest neural adaptations in stimulant-induced behavioural sensitization, but low mGlu5 binding might identify a higher propensity for sensitization.

How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine.

Modafinil, methyphenidate (MPH) and d-amphetamine (d-amph) are putative cognitive enhancers. However, efficacy of cognitive enhancement has yet to be fully established. We examined cognitive performance in healthy non-sleep-deprived adults following modafinil, MPH, or d-amph vs placebo in 3 meta-analyses, using subgroup analysis by cognitive domain; executive functions (updating, switching, inhibitory control, access to semantic/long term memory), spatial working memory, recall, selective attention, and sustained attention. We adhered to PRISMA. We identified k = 47 studies for analysis; k = 14 studies (64 effect sizes) for modafinil, k = 24 studies (47 effect sizes) for Methylphenidate, and k = 10 (27 effect sizes) for d-amph. There was an overall effect of modafinil (SMD=0.12, p=.01). Modafinil improved memory updating (SMD=0.28, p=.03). There was an overall effect of MPH (SMD=0.21, p=.0004) driven by improvements in recall (SMD=0.43, p=.0002), sustained attention (SMD=0.42, p=.0004), and inhibitory control (SMD=0.27, p=.03). There were no effects for d-amph. MPH and modafinil show enhancing effects in specific sub-domains of cognition. However, data with these stimulants is far from positive if we consider that effects are small, in experiments that do not accurately reflect their actual use in the wider population. There is a user perception that these drugs are effective cognitive enhancers, but this is not supported by the evidence so far.

Dose Adjustment of Stimulants for Children with Attention-Deficit/Hyperactivity Disorder: A Retrospective Chart Review of the Impact of Exceeding Recommended Doses.

BACKGROUND: When children with attention-deficit/hyperactivity disorder (ADHD) are treated with stimulant medication, the dose is established clinically by dose adjustment over time. Little is known about children who are not adequately treated when they reach a designated maximum dose, or the consequences of exceeding this dose. OBJECTIVE: The aim of this study was to determine the characteristics of and side effects observed in children optimised to high dose (HD) versus regular dose (RD) stimulants. METHOD: Children treated by one paediatrician (AP) in Western Sydney, Australia with HD stimulants (n = 52) were identified using an electronic database; controls on RD stimulant (n = 118) were matched by prescription date with the cases' first HD prescription. HD was defined as methylphenidate > 2 mg/kg/day or > 108 mg/day; dexamphetamine > 1 mg/kg/day or > 50 mg/day; lisdexamfetamine > 70 mg/day. In all children, the dose was adjusted over time to optimise the clinical response. Clinical characteristics, anthropometric measures, reported side effects and reasons for dose changes were extracted from the clinical charts by LR, VS and CS. The HD and RD cohorts were compared using chi-square for categorical data and t tests for continuous data. RESULTS: The HD cohort included more boys (88% vs 75%, p = 0.041) and more oppositional defiant disorder (83% vs 55%, p = 0.001). They started stimulants younger (6.40 ± 1.67 vs 8.28 ± 2.77 years, p < 0.001) and had more growth attenuation (Δ height z-score - 0.41 ± 0.55 vs - 0.09 ± 0.58, p = 0.001; Δ weight z-score - 0.56 ± 0.82 vs - 0.18 ± 0.66, p = 0.002). The growth attenuation mainly occurred before the dose reached the HD range. Diminishing stimulant effectiveness was the commonest reason for a dose increase in either cohort, the most prominent recurring symptoms being persistent anger/aggression in the HD and poor concentration in the RD cohort. The commonest reason for dose reduction in the HD cohort was that a dose increase gave no added benefit; dose reduction or change of drug due to subdued/depressed behaviour was more frequent in RD children. Apart from growth attenuation, no serious complications were reported in the HD group. CONCLUSIONS: In this preliminary study, dose adjustment over time in some patients meant using higher doses than those generally recommended. These children experienced more growth attenuation but recorded no other significant treatment complications. Determining the dose purely on clinical grounds by careful dose adjustment over time appears reasonable, but more data on this issue is required to clarify the efficacy and tolerability of exceeding the recommended doses of stimulants when treating ADHD.

Characterisation of the pharmacodynamic effects of the P2X7 receptor antagonist JNJ-54175446 using an oral dexamphetamine challenge model in healthy males in a randomised, double-blind, placebo-controlled, multiple ascending dose trial.

BACKGROUND: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood-brain barrier penetration and a clear dose-receptor occupancy relationship was demonstrated using positron emission tomography. AIMS: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge. METHODS: Subjects (N = 64) were randomised to either JNJ-54175446 (50-450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge. RESULTS: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy. CONCLUSION: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.

Effects of exposure to chronic uncertainty and a sensitizing regimen of amphetamine injections on locomotion, decision-making, and dopamine receptors in rats.

Gambling disorder (GD) is a behavioral addiction that may be linked to alterations in dopamine (DA) systems. Gambling involves chronic exposure to uncertain reward, which can sensitize the activity of DA systems. Here we explored how combinations of Pavlovian and instrumental uncertainty impact DA sensitization and risky decision-making. Experiment 1: 40 rats underwent 66 uncertainty exposure (UE) sessions during which they responded for saccharin. Animal responding was reinforced according to a fixed or variable (FR/VR) ratio schedule that turned on a conditioned stimulus (CS; light), which predicted saccharin on 50% or 100% of trials. Animals responded under one of the four conditions: FR-CS100% (no uncertainty), VR-CS100%, FR-CS50%, and VR-CS50% (maximal uncertainty). DA sensitization was inferred from an enhanced locomotor response to d-amphetamine (d-AMPH; 0.5 mg/kg) challenge. The rat gambling task (rGT) was used to assess decision-making. Experiment 2: 24 rats received 5 weeks of sensitizing d-AMPH or saline doses, followed by locomotor activity and rGT testing. Experiment 3: Effects of UE and a sensitizing d-AMPH regimen on DA D1, D2, and D3 receptor binding were assessed in 44 rats using autoradiography. Compared to FR-CS100%, VR-CS100% and VR-CS50% rats displayed a greater locomotor response to d-AMPH, and VR-CS50% rats demonstrated riskier decision-making. Chronic d-AMPH-treated rats mirrored the effects of VR-CS50% groups on these two indices. Both VR-CS50% and d-AMPH-treated groups had increased striatal DA D2 receptor binding. These results suggest that chronic uncertainty exposure, similar to exposure to a sensitizing d-AMPH regimen, sensitized the function of DA systems and increased risky decision-making.

Clinical effects beyond cocaine use of sustained-release dexamphetamine for the treatment of cocaine dependent patients with comorbid opioid dependence: secondary analysis of a double-blind, placebo-controlled randomized trial.

BACKGROUND AND AIMS: Sustained-release (SR) formulations of dexamphetamine and mixed amphetamine salts have shown positive effects in the treatment of patients with a cocaine use disorder. We previously demonstrated the efficacy of SR-dexamphetamine for patients with cocaine dependence in terms of cocaine use reductions. In this secondary analysis, we assessed whether SR-dexamphetamine treatment also improves the health status of these patients. DESIGN: Multi-centre randomized, double-blind placebo-controlled trial. SETTING: Four supervised heroin-assisted treatment (HAT) out-patient clinics in the Netherlands. In HAT, methadone treatment-refractory opioid-dependent patients can self-administer individually titrated doses of pharmaceutical grade diacetylmorphine, coprescribed with oral methadone. PARTICIPANTS: Seventy-three cocaine-dependent patients (90% males; average age = 48.7 years), participating in HAT for their treatment-refractory comorbid opioid dependence. INTERVENTIONS: Twelve weeks pharmacotherapy with once-daily, supervised intake of two tablets of SR-dexamphetamine (2 × 30 mg/day) or two identical placebo tablets. MEASUREMENTS: Assessment every 4 weeks: cocaine use (time-line follow-back), physical health (Maudsley Addiction Profile-Health Symptoms Scale), mental health (Brief Symptom Inventory) and illegal activities (Addiction Severity Index). Primary outcome was 'overall health', a dichotomous, multi-domain response index based on physical health, mental health and social functioning. FINDINGS: Compared with placebo, SR-dexamphetamine resulted in larger increases in the number of cocaine abstinent days (P = 0.004) and the proportion of overall health treatment responders (P = 0.045) from the 4 weeks preceding baseline to the final 4 weeks of treatment. While the number of cocaine abstinent days was not associated with overall health in the total study sample, it was positively associated with overall health among patients in poor overall health at the start of SR-dexamphetamine treatment (n = 50), i.e. patients with the potential to improve on this multi-domain response index (odds ratio = 1.076; 95% confidence interval = 1.025-1.130). CONCLUSIONS: SR-dexamphetamine reduces cocaine use and may improve clinically relevant health-related outcomes in patients with cocaine dependence who are participating in heroin-assisted treatment for their comorbid heroin dependence.

Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol-dependent individuals.

Addiction has been proposed as a 'reward deficient' state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.

Effects of dopamine and serotonin synthesis inhibitors on the ketamine-, d-amphetamine-, and cocaine-induced locomotor activity of preweanling and adolescent rats: sex differences.

The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2 h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40 mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism.

Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.

Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with D-amphetamine. D-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.

Examination of the effects of SCH23390 and raclopride infused in the dorsal striatum on amphetamine-induced timing impulsivity measured on a differential reinforcement of low-rate responding (DRL) task in rats.

Although the striatal dopamine (DA) is reportedly involved in impulsive action, little is known about the DA subtype receptors of dorsal striatum (dSTR) in the impulsive control involved in differential reinforcement of low-rate-responding (DRL) behavior. We examined the receptor-specific dopaminergic modulation of d-amphetamine (AMP)-altered DRL 10 s (DRL-10 s) performance by locally infusing SCH23390 (SCH) and raclopride (RAC), DA D1 and D2 receptor antagonists, respectively, into the rat's dSTR. Systemic injection of AMP significantly affected DRL-10 s behavior by increasing total, non-reinforced, and bust responses, as well as by decreasing reinforced responses, which correspondingly caused a leftward shift of the inter-response-time distribution curve as confirmed by a profound decrease in peak time (i.e., <10 s). Neither SCH nor RAC into dSTR pharmacologically reversed the timing impulsivity produced by AMP as measured by non-reinforced responses and peak time. However, the increase in total responses and the decrease in reinforced responses by AMP were reversed by intra-dSTR SCH or RAC. These results suggest that the D1 and D2 receptors of the dSTR may be involved in behavioral components apart from the timing impulsivity produced by AMP on a DRL task, which components are distinctly different from those in other terminal areas of midbrain DA systems.

Coadministration of lithium and celecoxib reverses manic-like behavior and decreases oxidative stress in a dopaminergic model of mania induced in rats.

The present study intends to investigate the effect of lithium (Li) and celecoxib (Cel) coadministration on the behavioral status and oxidative stress parameters in a rat model of mania induced by dextroamphetamine (d-AMPH). Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on the 8th day of treatment, rats received lithium (Li), celecoxib (Cel), Li plus Cel, or water until day 14. Levels of oxidative stress parameters were evaluated in the serum, frontal cortex, and hippocampus. d-AMPH administration induced hyperlocomotion in rats, which was significantly reversed by Li and Cel coadministration. In addition, d-AMPH administration induced damage to proteins and lipids in the frontal cortex and hippocampus of rats. All these impairments were reversed by treatment with Li and/or Cel, in a way dependent on cerebral area and biochemical analysis. Li and Cel coadministration reversed the d-AMPH-induced decrease in catalase activity in cerebral structures. The activity of glutathione peroxidase was decreased in the frontal cortex of animals receiving d-AMPH, and treatment with Li, Cel, or a combination thereof reversed this alteration in this structure. Overall, data indicate hyperlocomotion and alteration in oxidative stress biomarkers in the cerebral structures of rats receiving d-AMPH. Li and Cel coadministration can mitigate these modifications, comprising a potential novel approach for BD therapy.

Nonmedical use of d-Amphetamines and Methylphenidate in Medical Students.

OBJECTIVE: The purpose of this study was to determine the prevalence of medical and nonmedical use of prescription attention deficit hyperactive disorder (ADHD) stimulant medication among medical students. MATERIALS AND METHODS: An IRB approved 19-question web survey was sent out to all students from a Puerto Rico (PR) medical school to assess use of ADHD medication. Out of the 250 stu-dents consulted there was a response of 152 surveys. Data was cross-referenced and compared with data from other studies. RESULTS/DISCUSSION: From the results gathered, the study's sample had a higher prevalence of use than the 15% reported in previous studies, reaching 47.4%. Among students who had used these drugs, 89.4% indicated using it without a prescription. 86.8% of all respondents used some form of stimulant or substance in order to cope with the academic workload of medical school, includ-ing coffee, energy drinks, cigarettes, and alcohol. The majority of students (60.5%) considered study techniques workshops and exercise programs to succeed academically. CONCLUSION: This study suggests a higher prevalence of ADHD medication use amongst the PR medical student sample compared to findings reported of US medical students, as well as a high prevalence related to nonmedical use as a means for medical students to cope with their training. The nonmedical use of stimulants in the medical school setting remains of utmost public health and clinical concern. The results of this study could help develop proper workshops and non-pharmacological techniques to help medical students cope with their workload.

Coadministration of lithium and celecoxib attenuates the behavioral alterations and inflammatory processes induced by amphetamine in an animal model of mania.

The present study evaluated the effects of the coadministration of lithium (Li) and Cel on inflammatory parameters in an animal model of mania induced by dextroamphetamine (D-amph). It was used Wistar rats 60 days old (250-350 g). The animals (n = 10 per group) received D-amph (2 mg/kg) or saline solution of NaCl 0.9% (Sal) intraperitoneally once a day for 14 days. From day eight until 14, the animals from the D-amph and Sal groups received Li (24 mg/kg), Cel (20 mg/kg), Li + Cel or water via gavage. Behavioral analyses were performed using the open-field test. The levels of IL-1ß, IL-4, IL-10, and TNF-α were evaluated. The administration of D-amph induced hyperactivity in the rats, as well increased the IL-4, IL-10, and TNF-α levels in the serum, frontal cortex, and striatum of rats compared to those of the controls, and treatment with Li plus Cel reversed these alterations. In general, the administration of Li or Cel per se did not have effects on the behavioral and biochemical parameters. However, the treatment with Cel per se decreased only the IL-10 levels in the serum of animals. Besides, the treatment with Li or Cel decreased the IL-4 levels in the serum and reversed the effects of D-amph on this parameter in the frontal cortex. The treatment with Li reversed the effects of D-amph on the TNF-α levels in all tissues evaluated, and the administration of Cel reversed this alteration only in the striatum. It can be observed that treatment with Li plus Cel was more effective against damages caused by D-amph when compared to the administration of both treatments per se, suggesting that the coadministration can be more effective to treat BD rather than Li or Cel itself. The treatment with Li plus Cel was effective against the inflammation induced by D-amph.