Psychostimulant Use Research Articles

Comorbid ADHD and schizophrenia and the use of psychostimulants: a scoping review protocol

IntroductionSchizophrenia and attention deficit hyperactivity disorder (ADHD) are psychiatric disorders that have a profound impact on patients and healthcare systems globally. There is preliminary evidence suggesting a potential association between...

Exploring the efficacy of cholinergic agents for the treatment of psychostimulant use disorder: a systematic review.

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. The aim of this systematic review is to describe and discuss the efficacy of cholinergic agents in drug trials for patients with PUD. 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. 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. 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.

Environmental enrichment and sex, but not n-acetylcysteine, alter extended-access amphetamine self-administration and cue-seeking

There are no approved therapeutics for psychostimulant use and recurrence of psychostimulant use. However, in preclinical rodent models environmental enrichment can decrease psychostimulant self-administration of low unit doses and cue-induced amphetamine seeking. We have previously demonstrated that glutamate-dependent therapeutics are able to alter amphetamine seeking to amphetamine-associated cues only in enriched rats. In the current experiment, we will determine if enrichment can attenuate responding and cue-induced amphetamine seeking during extended access to a high dose of intravenous amphetamine. We will also determine if N-acetylcysteine (NAC), a glutamate dependent therapeutic, can attenuate amphetamine seeking in differentially reared rats. Female and male Sprague-Dawley rats were reared in enriched, isolated, or standard conditions from postnatal day 21–51. Rats were trained to self-administer intravenous amphetamine (0.1 mg/kg/infusion) during twelve 6-hour sessions. During the abstinence period, NAC (100 mg/kg) or saline was administered daily. Following a cue-induced amphetamine-seeking test, astrocyte densities within regions of the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb) were quantified using immunohistochemistry. Environmental enrichment decreased responding for amphetamine and during the cue-induced amphetamine-seeking test. NAC did not attenuate cue-induced amphetamine seeking or alter astrocyte density. Across all groups, female rats self-administered less amphetamine but responded more during cue-induced amphetamine seeking than male rats. While amphetamine increased astrocyte densities within the ACb and mPFC, it did not alter mPFC astrocyte densities in female rats. The results suggest that enrichment can attenuate responding during extended access to a high dose of amphetamine and the associated cues. Sex alters amphetamine-induced changes to astrocyte densities in a regionally specific matter.

The Effects of Chronic Psychostimulant Administration on Bone Health: A Review.

(1) Background: Methylphenidate (MP) and amphetamine (AMP) are psychostimulants that are widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. In recent years, 6.1 million children received an ADHD diagnosis, and nearly 2/3 of these children were prescribed psychostimulants for treatment. The purpose of this review is to summarize the current literature on psychostimulant use and the resulting effects on bone homeostasis, biomechanical properties, and functional integrity. (2) Methods: Literature searches were conducted from Medline/PubMed electronic databases utilizing the search terms "methylphenidate" OR "amphetamine" OR "methylphenidate" AND "bone health" AND "bone remodeling" AND "osteoclast" AND "osteoblast" AND "dopamine" from 01/1985 to 04/2023. (3) Results: Of the 550 publications found, 44 met the inclusion criteria. Data from identified studies demonstrate that the use of MP and AMP results in decreases in specific bone properties and biomechanical integrity via downstream effects on osteoblasts and osteoclast-related genes. (4) Conclusions: The chronic use of psychostimulants negatively affects bone integrity and strength as a result of increased osteoclast activity. These data support the need to take this into consideration when planning the treatment type and duration for bone fractures.

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit that acts as a gatekeeper of cocaine-induced behavioral plasticity. However, the molecular and circuit mechanisms underlying this function are unknown. Here, we show that GPe parvalbumin-positive (GPePV) cells mediate cocaine responses by selectively modulating ventral tegmental area dopamine (VTADA) cells projecting to the dorsomedial striatum (DMS). Interestingly, GPePV cell activity in cocaine-naive mice is correlated with behavioral responses following cocaine, effectively predicting cocaine sensitivity. Expression of the voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability following cocaine was downregulated, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its therapeutic potential to counteract psychostimulant use disorder.

Psychotropic drug use among children and adolescents in the Nordic countries: a systematic review.

The Nordic countries have rather homogenous populations and similar health care systems, and one could therefore expect comparable levels of psychopathology and psychotropic drug use. However, recent studies show pronounced variations in psychotropic drug use among children and adolescents from different Nordic countries. Therefore, we aimed to conduct a systematic review of the literature examining the use of psychotropic drugs among children and adolescents in the Nordic countries. This review followed PRISMA guidelines. We searched PsycINFO, EMBASE and MEDLINE for population-based studies published 2010 or later that investigated prevalent or incident use of antidepressants, psychostimulants, antipsychotics, hypnotics, anxiolytics, and mood stabilizers among 0-19-year-olds in the Nordic countries. Two reviewers assessed all studies. Twenty-two out of 2142 eligible studies were included in the final review covering data collected from 1995 to 2018. The use of psychotropic drugs, except for anxiolytics, increased in most of the Nordic countries, but at different rates. Prevalent use of antidepressants was two to four times higher among Swedish children and adolescents compared to Danish and Norwegian peers. Prevalent use of psychostimulants, on the other hand, was two to sixfold higher in Iceland compared to the other Nordic countries. Finally, the prevalence of antipsychotic use was threefold higher in Finland compared to Sweden, Denmark, and Norway. This systematic review provides a thorough overview of psychotropic treatment of youths in the Nordic countries. We demonstrate a pronounced national variation in use of psychotropics that should be addressed further to facilitate rational pharmacotherapy in youths with psychiatric disorders.

Effects of an elimination diet and a healthy diet in children with Attention‐Deficit/Hyperactivity Disorder: 1‐Year prospective follow‐up of a two‐arm randomized, controlled study (TRACE study)

AbstractBackgroundAn Elimination Diet (ED) or Healthy Diet (HD) may be effective in reducing symptoms of Attention‐Deficit/Hyperactivity Disorder (ADHD), but long‐term maintenance effects and feasibility have never been examined.MethodsOne‐year prospective follow‐up of a sample of 165 children (5–12 years) with ADHD randomized (unblinded; 1:1) to 5 weeks treatment with either ED (N = 84) or HD (N = 81) and a non‐randomized comparator arm including 58 children being treated with Care as Usual (CAU). Dietary participants were allowed to add or switch to CAU treatment after 5 weeks. The primary outcome was a 5‐point ordinal measure of improvement based on both parent and teacher ratings on ADHD and dysregulation problems, determined after 1 year prospective follow‐up. Ordinal regression analyses and linear mixed models analyses were conducted on an intention to treat basis. In addition, as‐treated analyses were performed. The trial is closed and registered in the Dutch trial registry, number NL5324.ResultsAt 1 year follow‐up, 24% of the participants still complied with the ED and 37% still complied with the HD. In the ED (+CAU) trajectory, fewer participants showed (partial) improvement after 1‐year prospective follow‐up compared to the HD (+CAU) trajectory (47% vs. 64%, χ2 (4, N = 152) = 11.97, p = 0.018). The HD (+CAU) ‐ but not ED (+CAU) ‐ trajectory had comparable 1‐year outcomes compared to the non‐randomized CAU‐trajectory. Results for secondary outcomes (e.g. health, parental stress) did not differ between the ED (+CAU) and HD (+CAU) trajectories. The prevalence of psychostimulant use was lower in the ED (+CAU) and HD (+CAU) trajectories compared to the non‐randomized CAU‐trajectory (38%, 45%, 78%, respectively). Predictors for long‐term benefit from dietary treatments included high initial severity of ADHD problems, low severity of emotional problems and sufficient parental mental resources.ConclusionsIn line with the short‐term effects, prospective 1‐year follow‐up outcomes are in favor of treatment with HD and not ED. Initial 5‐week treatment with HD and if needed/preferred followed by CAU may reduce psychostimulant use without negatively impacting 1‐year outcomes.

Prescription psychostimulant use, admissions and treatment initiation and retention in pregnant people with opioid use disorder

Prescription psychostimulant use, admissions and treatment initiation and retention in pregnant people with opioid use disorder

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe PV ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe PV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr GABA ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA DA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe PV cells is the indirect pathway of the dorsomedial striatum (DMS D 2 ), which receives DAergic innervation from collaterals of VTA DA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS D 2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe PV cells, closing the loop. Interestingly, the level of GPe PV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe PV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe PV cells following a single cocaine exposure, contributing to the elevation in GPe PV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPe PV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

Prescribed psychostimulants and other pro-cognitive medications in bipolar disorder: A systematic review and meta-analysis of recurrence of manic symptoms.

Clinicians are often hesitant to prescribe psychostimulants in bipolar disorder (BD) due to concerns of inducing (hypo)mania, despite limited published evidence on associations between prescribed psychostimulant use and recurrence of mood episodes in BD. The current systematic review and meta-analysis evaluated the emergence of (hypo)manic symptoms in patients with BD receiving prescribed psychostimulants or other pro-cognitive medications in euthymic or depressive states. A systematic search was performed of MEDLINE, Embase, and PsychINFO from inception to April 5, 2023 and search of Clinicaltrials.gov and Clinicaltrialsregister.eu for unpublished data. References of included studies were hand-searched. Randomized trials and prospective longitudinal studies that evaluated psychostimulants and non-stimulant medications recommended for the treatment of ADHD by the Canadian ADHD practice guidelines were included. The review was reported in line with PRISMA guidelines and was preregistered on PROSPERO (CRD42022358588). After screening 414 unique records, we included 27 studies, of which five reported data that was quantitatively synthesized (n = 1653). The use of psychostimulants in BD was not associated with increased scores on the Young Mania Rating Scale in patients who were in a euthymic or depressed state (SMD IV -0.17; 95% CI, -0.40 to 0.06) compared to placebo. There was a high degree of study-level heterogeneity (I2 = 80%). A qualitative synthesis of studies revealed a limited risk of medication-induced manic symptoms. Our review provides preliminary evidence to suggest psychostimulants and non-stimulant ADHD medications have a limited risk of precipitating (hypo)mania symptoms. More extensive studies evaluating the safety and efficacy of these medications are warranted.

The selective D3Receptor antagonist VK4-116 reverses loss of insight caused by self-administration of cocaine in rats

Chronic psychostimulant use causes long-lasting changes to neural and cognitive function that persist after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism and striatal D2/D3-receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3-receptor (D3R) antagonists and partial agonists, has shown promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder. However, much less attention has been paid to treating the loss of insight, operationalized as the inability to infer likely outcomes, associated with chronic psychostimulant use. Here we tested the selective D3R antagonist VK4-116 as a treatment for this loss in rats with a prior history of cocaine use. Male and female rats were first trained to self-administer cocaine or a sucrose liquid for 2 weeks. After 4 weeks of abstinence, performance was assessed using a sensory preconditioning (SPC) learning paradigm. Rats were given VK4-116 (15 mg/kg, i.p.) or vehicle 30 min prior to each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) showed normal sensory preconditioning, whereas cocaine use (cocaine-vehicle) selectively disrupted responding to the preconditioned cue, an effect that was reversed in the cocaine-VK4-116 group, which demonstrating responding to the preconditioned cue at levels comparable to controls. These preclinical findings demonstrate that highly selective dopamine D3R antagonists, particularly VK4-116, can reverse the long-term negative behavioral consequences of cocaine use.

Inflammatory based psychotic symptoms: when psychosis means encephalitis

AbstractSchizophrenia, as one of the most common disorders from the psychotic spectrum is most commonly detected in the phase of first psychosis and may pose a diagnostic challenge, as commonly comprise a heterogeneous group of schizophrenias, with distinct clinical presentations. If it detected in its prodromal phase without clearly developed psychotic symptoms, the diagnosis is even more unreliable, as the transition to full blown psychosis in the next two years happens in 15-40% of more, depending probably on a variety of cumulative environmental risk factors (including childhood trauma, the use of high-potency cannabis, urbanicity, season of birth). Moreover, the first episode psychosis may underlie for example the first manic episode, brief intermittent psychotic symptoms in persons with borderline personality disorders, acute reaction to trauma, the use of cannabis and psychostimulants and different organics causes, such as endocrinologic disorders and autoimmune encephalitis. Therefore, in everyday clinical practice, the diagnosis of first episode psychosis always requires an assessment of possible causes of psychosis, and also factors that may influence prognosis and treatment. Usual assessment include detailed anamnestic and heteroanamnestic data, physical examination, standard blood laboratory findings, drugs in urine/ blood, EEG and CT/MR scan. The absence of typical risk factors for schizophrenia, as well as the absence of premorbid symptoms and developmental course typical for schizophrenia, abrupt course of psychotic symptoms, symptoms such as disorientation, catatonia, speech disturbances, alteration of consciousness, neurologic signs, autonomic dysfunction and laboratory aberrations may be especially indicative for organic cause and possibly encephalitis and require further confirmation with the analysis of cerebrospinal liquor with antineuronal antibodies.Disclosure of InterestNone Declared

Non-medical Use of Prescription Psychostimulants and Academic Performance in Medical Students

Objective: It is well-known that healthy medical students use psychostimulants to improve their cognitive functions and reduce their need for sleep. The main motivation behind this cognitive enhancement is to increase academic performance. However, the literature is not clear enough to support this situation.
 Methods: This cross-sectional study was conducted with an online survey and 585 students participated. The grade point average number was used to assess the student' academic performance. Additionally, the scale based on self-evaluations was used to assess levels of pharmaceutical knowledge, study performance, academic success, academic anxiety, and study performance.
 Results: Out of 585 healthy students, 40 (7.3%) admitted to using psychostimulants to enhance their academic performance. However, there was no significant difference in grade point average scores and perceived academic success levels between users and non-users. Nonetheless, most of the users reported that they benefited from taking psychostimulant drugs. Risk factors for non-medical use of prescription psychostimulants included high levels of pharmacology knowledge, smoking, and poor academic performance.
 Conclusion: Although non-medical use of prescription psychostimulants did not appear to affect academic performance significantly, most students reported positive subjective experiences, which could have a motivational effect. Therefore, it is crucial to investigate the benefits and side effects of psychostimulants in healthy young individuals in more detail and to provide them with up-to-date information on this issue.

Analysis of SLC6A4 (5 ‑HTTLPR) gene polymorphism depending on clinical features and efficacy of therapeutic and rehabilitation measures in patients with psychostimulant addiction

The annual increase in the number of patients with psychostimulant addiction and the low duration of remissions as a result of treatment of such disorders prompt researchers to search for new approaches to therapy. It seems relevant to search for and introduce into practice new clinical and genetic markers that increase the effectiveness of psychostimulant addiction therapy within the framework of a personalized approach. The purpose of the study is to determine the impact of a number of clinical characteristics and SLC6A4 (5‑HTTLPR) gene polymorphism on the efficacy of treatment and rehabilitation program in patients with psychostimulant addiction. Materials and methods. The study included 325 patients diagnosed with «mental and behavioral disorders due to use of psychostimulants» (F14.2, F15.2, F19.2 according to ICD-10); men and women aged 18 to 50 years, ethnically Russian, signed informed consent to participate in the study. Methods: clinical-psychopathological, anamnestic, molecular-genetic, psychometric (Montgomery — Åsberg Depression Rating Scale (MADRS)), and statistical methods. Results. All patients were divided into groups depending on the psychoactive substances used and comorbid psychiatric pathology. It was found that SSRI monotherapy (Escitalopram) for the relief of affective disorders in the post-withdrawal period was most effective in the patients who used only psychostimulants (p<0.005). Combined psychopharmacotherapy was more efficient in other groups (p<0.001). The patients with SS and SL genotypes of the SLC6A4 (5‑HTTLPR) gene tolerated Escitalopram monotherapy worse; a statistical difference was achieved for the patients with LL and SL/SS genotypes of group 2 (p<0.036). There were more patients who passed the rehabilitation program and with the longest remissions among those with the SL and SS genotypes of the SLC6A4 (5‑HTTLPR) gene in all groups. Conclusion. After analyzing the results, the conclusions about the association between a number of clinical and genetic characteristics of patients with psychostimulant addiction and the effectiveness of treatment and rehabilitation measures were drawn.

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats.

Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10mg/kg; i.p.) or its structural analog SH 3-24 (1, 3mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.

Drug poisoning deaths by occupation and drug type, Massachusetts 2010-2019.

To investigate variation in drug poisoning mortality rates by drug type and occupation in Massachusetts. Death certificates for deaths by drug poisonings occurring between 2010 and 2019 in Massachusetts were coded based on the decedent's occupation. Mortality rates and rate ratios (with all other occupations as the reference group) were calculated based on the occupation of the workers according to drug type. Poisson regression was used to determine significantly elevated mortality rates and trends in drug poisoning deaths by occupation and drug type. The rate of drug poisoning deaths increased from 2010 to 2016 after which they plateaued. With respect to specific substances, fentanyl- and cocaine-related deaths increased throughout the surveillance period. For drug poisoning deaths overall, workers in construction trades (3,017); food preparation and serving (1,116); transportation and material moving (1,062) occupations had the highest number of drug poisoning deaths. When adjusting for age, sex, race/ethnicity, and educational attainment, workers in 7 occupations had significantly elevated mortality rate ratios for drug poisonings overall: farming, fishing, and forestry (3.42, P < 0.001); construction trades (2.58, P < 0.001); health care support (1.61, P < 0.001); community and social service (1.60, P < 0.001); food preparation and serving related (1.54, P < 0.001); personal care and service (1.37, P < 0.001); and arts, design, entertainment, sports, and media (1.21, P = 0.010). In many cases, workers in these same occupations had elevated mortality rate ratios for poisonings from specific substances. Health care practitioners and technical occupation workers only had elevated rates for methadone-related poisonings (1.73, P = 0.010). These findings highlight that workers in certain occupations have an elevated risk for drug poisonings and that the patterns differ with respect to the drug type. These findings can be useful for providing services to workers in high-risk occupations and in identifying occupational factors that may be related to the risk of drug poisoning death. While previous research has begun to uncover work-related factors that may contribute to opioid use, further work is needed to identify occupational factors that may contribute to psychostimulant and benzodiazepine use.

Attention-deficit hyperactivity disorder and psychostimulant use in patients seeking dental care-Associations with common orofacial pain complaints.

Dental medicine should expand its scope to properly assess medical and psychosocial factors that might have an impact on patients' oral health. Based on previous literature and clinical experience, attention-deficit/hyperactivity disorder and psychostimulant medications might represent factors associated with orofacial pain symptoms. The aim of the study was to assess whether common orofacial pain complaints such as jaw pain, jaw clicking, teeth clenching and headaches are more prevalent in dental patients who have an ADHD diagnosis and/or use psychostimulant medications. Orofacial pain symptoms prevalence was compared among four groups from a sample of new patients seeking dental care at Tufts University School of Dental Medicine (n = 11 699) based on ADHD diagnosis and psychostimulants intake: G1: no ADHD, no stimulants; G2: yes ADHD, yes stimulants; G3: yes ADHD, no stimulants; G4: no ADHD, yes stimulants. In multivariable logistic regression models adjusting for age, gender, tobacco use, and alcohol consumption, significant differences were found for clenching (p < .0001), jaw pain (p < .0001), and headache (p < .0001). Compared to G1, two groups (G2 and G4) exhibited significantly higher odds of clenching and headaches, whereas only G2 exhibited significantly higher odds of jaw pain. In comparison with patients without ADHD and not taking psychostimulants medications, dental patients using psychostimulants with and without ADHD diagnosis report headaches and teeth clenching more frequently, while jaw pain is reported more frequently only by those taking psychostimulants with an ADHD diagnosis. Further research is necessary to assess the nature of these associations and their clinical relevance.

Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity.

Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered "atypical" dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-à-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1'-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.

Cholesterol modulation of interactions between psychostimulants and dopamine transporters.

The dopamine transporter (DAT) is a key site of action for cocaine and amphetamines. Dysfunctional DAT is associated with aberrant synaptic dopamine transmission and enhanced drug-seeking and taking behavior. Studies in cultured cells and ex vivo suggest that DAT function is sensitive to membrane cholesterol content. Although it is largely unknown whether psychostimulants alter cholesterol metabolism in the brain, emerging evidence indicates that peripheral cholesterol metabolism is altered in patients with psychostimulant use disorder and circulating cholesterol levels are associated with vulnerability to relapse. Cholesterol interacts with sphingolipids forming lipid raft microdomains on the membrane. These cholesterol-rich lipid raft microdomains serve to recruit and assemble other lipids and proteins to initiate signal transduction. There are two spatially and functionally distinct populations of the DAT segregated by cholesterol-rich lipid raft microdomains and cholesterol-scarce non-raft microdomains on the plasma membrane. These two DAT populations are differentially regulated by DAT blockers (e.g. cocaine), substrates (e.g. amphetamine), and protein kinase C providing distinct cholesterol-dependent modulation of dopamine uptake and efflux. In this chapter, we summarize the impact of depletion and addition of membrane cholesterol on DAT conformational changes between the outward-facing and the inward-facing states, lipid raft-associated DAT localization, basal and induced DAT internalization, and DAT function. In particular, we focus on how the interactions of the DAT with cocaine and amphetamine are influenced by membrane cholesterol. Lastly, we discuss the therapeutic potential of cholesterol-modifying drugs as a new avenue to normalize DAT function and dopamine transmission in patients with psychostimulant use disorder.

Effect of lateral septum vasopressin administration on reward system neurochemistry and amphetamine-induced addictive-like behaviors in female rats.

Introduction: The chronic use of psychostimulants increases the risk of addiction and, there is no specific pharmacologic treatment for psychostimulant addiction. The vasopressin (AVP) system is a possible pharmacological target in drug addiction. Previous results obtained in our laboratory showed that amphetamine (AMPH) treatment decreases lateral septum (LS) AVP levels in male rats, and AVP microinjection in LS decreases addictive-like behavior. The aim of the present work was to investigate the effect of AMPH treatment on LS AVP levels and the effect of LS AVP administration on the expression of AMPH-conditioned place preference (CPP) in female rats. The secondary objectives were to study the effect of LS AVP administration on LS GABA and glutamate release in male and female rats and on nucleus accumbens (NAc) dopamine (DA) release in female rats. Methods: Female rats were conditioned with AMPH (1.5mg/kg i.p.) or saline for 4days. Results: Conditioning with AMPH did not change LS AVP content in females. However, AVP microinjection into the LS decreased the expression of conditioned place preference (CPP) to AMPH. Glutamate and GABA extracellular levels in the LS induced by AVP were studied in males and females. NAc GABA and DA extracellular levels induced by LS AVP microinjection in female rats were measured by microdialysis. In males, AVP perfusion produced a significant increase in LS GABA extracellular levels; however, a decrease in GABA extracellular levels was observed in females. Both in males and females, LS AVP perfusion did not produce changes in LS glutamate extracellular levels. Microinjection of AVP into the LS did not change GABA or DA extracellular levels in the NAc of females. Discussion: Therefore, AVP administration into the LS produces different LS-NAc neurochemical responses in females than males but decreases CPP to AMPH in both sexes. The behavioral response in males is due to a decrease in NAc DA levels, but in females, it could be due to a preventive increase in NAc DA levels. It is reasonable to postulate that, in females, the decrease in conditioning produced by AVP microinjection is influenced by other factors inherent to sex, and an effect on anxiety cannot be discarded.