Erratum: Role of environmental enrichment on social interaction, anxiety, locomotion, and memory in Wistar rats under chronic methylphenidate intake.

[This corrects the article DOI: 10.3389/fnbeh.2023.1251144.].

IL-10 and Cdc42 modulate astrocyte-mediated microglia activation in methamphetamine-induced neuroinflammation.

Methamphetamine (Meth) use is known to induce complex neuroinflammatory responses, particularly involving astrocytes and microglia. Building upon our previous research, which demonstrated that Meth stimulates astrocytes to release tumor necrosis factor (TNF) and glutamate, leading to microglial activation, this study investigates the role of the anti-inflammatory cytokine interleukin-10 (IL-10) in this process. Our findings reveal that the presence of recombinant IL-10 (rIL-10) counteracts Meth-induced excessive glutamate release in astrocyte cultures, which significantly reduces microglial activation. This reduction is associated with the modulation of astrocytic intracellular calcium (Ca2+) dynamics, particularly by restricting the release of Ca2+ from the endoplasmic reticulum to the cytoplasm. Furthermore, we identify the small Rho GTPase Cdc42 as a crucial intermediary in the astrocyte-to-microglia communication pathway under Meth exposure. By employing a transgenic mouse model that overexpresses IL-10 (pMT-10), we also demonstrate in vivo that IL-10 prevents Meth-induced neuroinflammation. These findings not only enhance our understanding of Meth-related neuroinflammatory mechanisms, but also suggest IL-10 and Cdc42 as putative therapeutic targets for treating Meth-induced neuroinflammation.

Psychostimulants and social behaviors.

Mounting evidence from animal models and human studies indicates that psychostimulants can significantly affect social behaviors. This is not surprising considering that the neural circuits underlying the regulation and expression of social behaviors are highly overlapped with those targeted by psychostimulants, which in most cases have strong rewarding and, consequently, addictive properties. In the present work, we provide an overview regarding the effects of illicit and prescription psychostimulants, such as cocaine, amphetamine-type stimulants, methylphenidate or modafinil, upon social behaviors such as social play, maternal behavior, aggression, pair bonding and social cognition and how psychostimulants in both animals and humans alter them. Finally, we discuss why these effects can vary depending on numerous variables such as the type of drug considered, acute versus long-term use, clinical versus recreational consumption, or the presence or absence of concomitant risk factors.

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

OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

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.

Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters.

Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca2+ mobilization assay wherein voltage-gated Ca2+ channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories.

Self-reported neurostimulant use among university students in Santa Maria, Rio Grande do Sul, Brazil.

University students frequently resort to psychostimulants to enhance their physical and mental performance and manage academic pressures. However, these substances can lead to dependence and other undesired symptoms, and little empirical data are available for relevant stakeholders, raising significant concerns in health care. Therefore, this study aims to characterize neurostimulant use among university students in Rio Grande do Sul, Brazil. We collected from 880 students' data using anonymous self-administration. The questionnaire included consumption patterns of caffeine, nicotine, ecstasy, methamphetamine, "merla" (coca base), methylphenidate, cocaine, crack, and ketamine. Additionally, participants shared information on demographic and socioeconomic factors. Use of at least one neurostimulant was reported by89.2% of the participants. Among nonusers, the most frequently cited reason was "previous information about harmful effects of these drugs." Caffeine, followed by nicotine, ecstasy, and methylphenidate were the most consumed substances, with main reasons being "improving academic performance" and "recreation." Women more often consumed caffeine (72.7%), while other psychostimulants were more consumed by men (42.2%) and individuals of other genders (0.5%). Students who consumed other substances had higher family incomes than that of families of caffeine users. In addition, 60.4% of caffeine users resided with family members, whereas 63.3% of users of other substances did not. Our findings can offer essential data on the reasons and symptoms associated with the use of neurostimulants among university students. This information could aid in raising awareness among students, universities, and health-care agencies about this often-neglected subject.

Suspected geriatric onset of attention-deficit/hyperactivity disorder in a patient with comorbid bipolar disorder.

BACKGROUND: An increasing number of adults over 60 years old are presenting with requests for treatment of attention-deficit/hyperactivity disorder (ADHD). However, the prevalence of ADHD in older adults in geriatrics is unknown. Further, comorbid bipolar disorder and adult ADHD are likely underrecognized with many patients only receiving treatment for one of these conditions. The occurrence of bipolar disorder with geriatric onset ADHD is unknown. CASE PRESENTATION: A 64-year-old Hispanic woman with a psychiatric history of bipolar I disorder (diagnosed in early adulthood) was diagnosed with ADHD suspected of geriatric onset, and able to be successfully managed on concurrent mood stabilizers and psychostimulant medication. CONCLUSIONS: The findings of this case report emphasize the importance of appropriately recognizing and treating comorbid ADHD and bipolar disorder in any age group, including the geriatric population for which this occurrence appears to be very rare. Additionally, this case report demonstrates the safe utilization of psychostimulant medications in a geriatric patient with bipolar disorder without inducing a manic episode or other significant adverse reactions.

Clinical Variables and Peripheral Biomarkers Associated with Substance-Induced Psychotic Disorder: Differences Related to Alcohol, Cannabis, and Psychostimulant Abuse.

Background: The present retrospective observational study aims to identify differences in clinical features and peripheral biomarkers among patients affected by substance-induced psychotic disorder (SIPD) according to the primary substance of abuse. Methods: A sample of 218 patients was divided into three groups according to the type of consumed substance: alcohol, cannabis, and psychostimulants. The three groups were compared using one-way analyses of variance (ANOVAs) for continuous variables and χ2 tests for qualitative variables. After excluding the alcohol-induced psychotic disorder group, the same analyses were repeated. The statistically significant variables from these subsequent analyses were included in a binary logistic regression model to confirm their reliability as predictors of cannabis- or psychostimulant-induced psychotic disorder. Results: Psychotic cannabis abusers were younger (p < 0.01), with illness onset at an earlier age (p < 0.01). Alcohol consumers presented a longer duration of illness (p < 0.01), more frequent previous hospitalizations (p = 0.04) and medical comorbidities (p < 0.01), and higher mean Modified Sad Persons Scale scores (p < 0.01). Finally, psychostimulant abusers had a higher frequency of lifetime history of poly-substance use disorders (p < 0.01). A binary logistic regression analysis revealed that higher mean Brief Psychiatric Rating Scale scores (p < 0.01) and higher sodium (p = 0.012) and hemoglobin (p = 0.040) plasma levels were predictors of cannabis misuse in SIPD patients. Conclusions: Different clinical factors and biochemical parameters con be associated with SIPD according to the main substance of abuse, thus requiring specific management by clinicians.

Psychostimulant drug co-ingestion in non-fatal opioid overdose.

Introduction: In 2019, there were over 16,000 deaths from psychostimulant overdose with 53.5% also involving an opioid. Given the substantial mortality stemming from opioid and psychostimulant co-exposure, evaluation of clinical management in this population is critical but remains understudied. This study aims to characterize and compare clinical management and outcomes in emergency department (ED) overdose patients with analytically confirmed exposure to both opioids and psychostimulants with those exposed to opioids alone. Methods: This was a secondary analysis of a prospective consecutive cohort of ED patients age 18+ with opioid overdose at 9 hospital sites from September 21, 2020 to August 17, 2021. Toxicologic analysis was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Patients were divided into opioid-only (OO) and opioid plus psychostimulants (OS) groups. The primary outcome was total naloxone bolus dose administered. Secondary outcomes included endotracheal intubation, cardiac arrest, troponin elevation, and abnormal presenting vital signs. We employed t-tests, chi-squared analyses and multivariable regression models to compare outcomes between OO and OS groups. Results: Of 378 enrollees with confirmed opioid overdose, 207 (54.8%) had psychostimulants present. OO patients were significantly older (mean 45.2 versus 40.6 years, p < 0.01). OS patients had significantly higher total naloxone requirements (mean total dose 2.79 mg versus 2.12 mg, p = 0.009). There were no significant differences in secondary outcomes. Conclusion: Approximately half of ED patients with confirmed opioid exposures were also positive for psychostimulants. Patients in the OS group required significantly higher naloxone doses, suggesting potential greater overdose severity.

Non-pharmacological treatment of Attention Deficit Disorder with or without Hyperactivity (ADHD). Overview and report of the first international symposium on the non-pharmacological management of ADHD.

Attention Deficit Disorder with or without Hyperactivity (ADHD is a neurodevelopmental disorder which affects the day-to-day functioning of children and adults with this condition. Pharmacological treatment can reduce the symptoms associated with ADHD, but it has some limitations. The objective of this symposium is to determine the effects of non-pharmacological approaches on ADHD symptoms. Results indicate that the following intervention are promising approaches: cognitive behavioral therapy (CBT), mindfulness-based interventions (MBI), yoga, cognitive and metacognitive intervention, neurofeedback and parental training programs. Current research advocates multimodal approaches in conjunction with school or work accommodations integrating innovative technologies.

Third-Generation Antipsychotics and Lurasidone in the Treatment of Substance-Induced Psychoses: A Narrative Review.

This narrative review explores the efficacy and tolerability of third-generation antipsychotics (TGAs)-aripiprazole, cariprazine, brexpiprazole, and lurasidone-for the management of substance-induced psychosis (SIP). SIP is a psychiatric condition triggered by substance misuse or withdrawal, characterized by unique features distinct from those of primary psychotic disorders. These distinctive features include a heightened prevalence of positive symptoms, such as hallucinations and delusions, in addition to a spectrum of mood and cognitive disturbances. This review comprehensively investigates various substances, such as cannabinoids, cocaine, amphetamines, and LSD, which exhibit a greater propensity for inducing psychosis. TGAs exhibit substantial promise in addressing both psychotic symptoms and issues related to substance misuse. This review elucidates the distinctive pharmacological properties of each TGA, their intricate interactions with neurotransmitters, and their potential utility in the treatment of SIP. We advocate for further research to delineate the long-term effects of TGAs in this context and underscore the necessity for adopting an integrated approach that combines pharmacological and psychological interventions. Our findings underscore the intricate and multifaceted nature of treating SIP, highlighting the potential role of TGAs within therapeutic strategies.

The impact of fentanyl on state- and county-level psychostimulant and cocaine overdose death rates by race in Ohio from 2010 to 2020: a time series and spatiotemporal analysis.

BACKGROUND: Over the past decade in the USA, increases in overdose rates of cocaine and psychostimulants with opioids were highest among Black, compared to White, populations. Whether fentanyl has contributed to the rise in cocaine and psychostimulant overdoses in Ohio is unknown. We sought to measure the impact of fentanyl on cocaine and psychostimulant overdose death rates by race in Ohio. METHODS: We conducted time series and spatiotemporal analyses using data from the Ohio Public Health Information Warehouse. Primary outcomes were state- and county-level overdose death rates from 2010 to 2020 for Black and White populations. Measures of interest were overdoses consisting of four drug involvement classes: (1) all cocaine overdoses, (2) cocaine overdoses not involving fentanyl, (3) all psychostimulant overdoses, and (4) psychostimulant overdoses not involving fentanyl. We fit a time series model of log standardized mortality ratios (SMRs) using a Bayesian generalized linear mixed model to estimate posterior median rate ratios (RR). We conducted a spatiotemporal analysis by modeling the SMR for each drug class at the county level to characterize county-level variation over time. RESULTS: In 2020, the greatest overdose rates involved cocaine among Black (24.8 deaths/100,000 people) and psychostimulants among White (10.1 deaths/100,000 people) populations. Annual mortality rate ratios were highest for psychostimulant-involved overdoses among Black (aRR = 1.71; 95% CI (1.43, 2.02)) and White (aRR = 1.60, 95% CI (1.39, 1.80)) populations. For cocaine not involving fentanyl, annual mortality rate ratios were similar among Black (aRR = 1.04; 95% CI (0.96,1.16)) and White (aRR = 1.02; 95% CI (0.87, 1.20)) populations. Within each drug category, change over time was similar for both racial groups. The spatial models highlighted county-level variation for all drug categories. CONCLUSIONS: Without the involvement of fentanyl, cocaine overdoses remained constant while psychostimulant overdoses increased. Tailored harm reduction approaches, such as distribution of fentanyl test strips and the removal of punitive laws that influence decisions to contact emergency services, are the first steps to reduce cocaine overdose rates involving fentanyl among urban populations in Ohio. In parallel, harm reduction policies to address the increase in psychostimulant overdoses are warranted.

Effects of fentanyl and the adulterant levamisole on the rewarding and locomotor effects of methamphetamine in rats.

BACKGROUND: People who use psychostimulant substances can be exposed to unknown adulterants, such as the synthetic opioid fentanyl (FEN) and the anthelmintic cholinergic agent levamisole (LEV). This work explores the rewarding and locomotor effects of methamphetamine (METH) in combination with FEN or LEV. METHODS: We used adult male Wistar rats in the conditioned-place preference (CPP) paradigm (conditioning, extinction, and reinstatement phases) and in the open field test to study effective doses of METH, FEN, or LEV, or ineffective doses of METH+FEN or METH+LEV in combination. RESULTS: METH and LEV, at 1mg/kg METH each, and 30µg/kg FEN produced CPP. Extinction to METH- or LEV-induced CPP occurred after eight saline injections, but it took 8-26 sessions to extinguish FEN-induced CPP. A challenge dose of 0.5mg/kg METH reinstated CPP. The same occurred with 15µg/kg FEN but not with 0.5 or 1mg/kg LEV. Training animals with ineffective doses of METH (0.01mg/kg) combined with either FEN (0.3µg/kg) or LEV (0.01mg/kg) produced CPP. Sub-effective doses of METH or FEN alone did not induce reinstatement after extinction. However, animals challenged with LEV, METH+FEN, or METH+LEV mixtures did it. Combining FEN (3µg/kg) with 0.1mg/kg METH increased locomotor activity. CONCLUSION: Ineffective FEN and LEV doses mixed with METH produce effects larger than would be expected based on the effects of either drug alone. This outcome suggests a supra-additive interaction, which could increase the risk of developing a METH use disorder.

Influence of psychostimulants on bone mineral density and content among children with attention deficit hyperactivity disorder. A systematic review.

There is a controversy over the influence of psychostimulant medications on bone mineral density (BMD) and bone mineral content (BMC) among children with attention-deficit-hyperactivity-disorder (ADHD). The aim of the present systematic review was to assess the influence of psychostimulant medications on BMD and BMC among children with ADHD. A comprehensive search of electronic databases, including PubMed, Scopus, Embase, and Cochrane Library, was conducted to identify relevant studies published up until July 2023. Clinical studies that addressed the focused question "Do psychostimulant medications affect bone mineral density and content in children with ADHD?" were included. Letters to the Editor, studies on animal-models, ex-vivo and in-vitro studies, commentaries and reviews were excluded. The primary outcome measures were changes in BMD and BMC. Study quality was assessed using the risk of bias for non-randomized studies-exposure tool. Five non-randomized clinical studies were included. The number of participants ranged from 18 to 6489 with mean ages ranging from 7.3 to 13.75 years. The study durations ranged between five and seven years. In all studies osseous evaluation was done using dual-energy X-ray absorptiometry. The bone locations examined included total body, lumbar-spine, femur, femoral-neck, femoral body, and pelvis. Two studies reported that psychostimulant medications reduce BMC and BMD. In one study, bone turnover, serum leptin and fat levels were reduced in children using psychostimulant medications but no unusual reduction recorded among controls. In general, 80 % of the studies concluded that psychostimulant medications compromise BMC and BMD. Power analysis was done in one study. One study had a low RoB and the remaining demonstrated some concerns. Given the methodological concerns observed in the included studies, arriving at a definitive conclusion regarding the effects of psychostimulant medications on BMC, BMD, and bone turnover in children with ADHD is challenging. However, it is important to acknowledge that an association between psychostimulant medications and these bone-related parameters cannot be disregarded.

Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward.

BACKGROUND: Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. They function as signaling hubs, enriched with a diverse array of G-protein coupled receptors (GPCRs), including several associated with motivation and drug-related behaviors. However, our understanding of how cilia regulate neuronal function and behavior is still limited. AIMS: The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. METHODS: To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. RESULTS: Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons showed no difference in locomotor sensitization to cocaine compared to wild-type (WT) littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 and 30 mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to WT littermates. CONCLUSIONS: Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell- and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.

Management Strategies for Borderline Personality Disorder and Bipolar Disorder Comorbidities in Adults with ADHD: A Narrative Review.

This narrative review examines two of the common comorbidities of attention-deficit/hyperactivity disorder, bipolar disorder (BD), and borderline personality disorder (BPD), which each share several common features with ADHD that can make assessment and diagnosis challenging. The review highlights some of the key symptomatic differences between adult ADHD and these disorders, allowing for more careful consideration before establishing a formal diagnosis. When the disorders are found to be comorbid, further complications may arise; thus, the review will also help to provide evidence-based treatment recommendations as well as suggestions on how to minimize adverse events. Incorporating evidence from systematic reviews, journal articles, randomized controlled trials, and case reports, this review highlights that the diagnosis of ADHD and some of its common comorbidities is challenging and requires full, in-depth assessment and management. The management strategies of these comorbidities will also be addressed, with emphasis on achieving mood stabilization for BD prior to initiating appropriate ADHD pharmacotherapy. Medications, specifically mood stabilizers, antipsychotics, and antidepressants, are fundamental in treating symptoms seen in BD and some cases of BPD, alongside psychotherapy and lifestyle modifications when appropriate. The review highlights the effectiveness of specific medications, including psychostimulants, atomoxetine, and bupropion, as add-on therapies to mood-stabilizing treatments for addressing ADHD symptoms in patients with these comorbidities. Despite limited research, the review will address various pharmacological and psychotherapeutic approaches for managing comorbid ADHD and BPD, emphasizing the need for further investigations to better understand the unique needs of this patient population.

Aversive agents: Think twice. A case report on disulfiram-induced mania.

We present a case of disulfiram-induced mania in a patient with both alcohol use disorder (AUD) and psychostimulant use disorder (PUD), without a history of psychosis or mania. This acute presentation may be linked to the increased dopamine levels caused by disulfiram metabolism. Our patient developed manic symptoms 10 days after starting disulfiram, prescribed to treat the AUD. It should be noted that the symptoms resolved rapidly after disulfiram cessation during hospitalization. Disulfiram use is an effective treatment for alcohol dependence. However, there are safety concerns associated with it and it requires close monitoring, particularly in patients with a history of mania, psychosis, or psychostimulant use.

Role of environmental enrichment on social interaction, anxiety, locomotion, and memory in Wistar rats under chronic methylphenidate intake.

Introduction: Chronic use of various compounds can have long-lasting effects on animal behavior, and some of these effects can be influenced by the environment. Many environmental enrichment protocols have the potential to induce behavioral changes. Aim: The aim of the present study was to investigate how environmental enrichment can mitigate the effects of chronic methylphenidate consumption on the behavior of Wistar rats. Methods: The animals were housed for 20 days under either an environmental enrichment protocol (which included tubes of different shapes) or standard housing conditions. After seven days, half of the rats received 13 days of oral administration of methylphenidate (2 mg/kg). After seven days, the rats underwent behavioral tests, including the elevated plus maze (anxiety), open field (locomotion), object-in-place recognition test (spatial memory), and a test for social interaction (social behavior). Results: The results showed that the enriched environmental condition reversed the enhanced time in the open arms of the elevated plus maze induced by methylphenidate (F[1,43] = 4.275, p = 0.045). Methylphenidate also enhanced exploratory rearing in the open field (F[1,43] = 4.663, p = 0.036) and the time spent in the open area of the open field (H[3] = 8.786, p = 0.032). The enriched environment mitigated the inhibition of social interaction with peers induced by methylphenidate (H[3] = 16.755, p < 0.001) as well as the preference for single exploratory behavior (H[3] = 9.041, p = 0.029). Discussion: These findings suggest that environmental enrichment can counteract some of the effects of methylphenidate. These results are relevant for the clinical treatment of the long-lasting secondary effects associated with methylphenidate pharmacological treatment.

Striatopallidal cannabinoid type-1 receptors mediate amphetamine-induced sensitization.

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 (CB1) 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 CB1 receptors are not involved in the acute response to amphetamine, the behavioral sensitization and related synaptic changes require the activation of CB1 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.