Search

Abstract Designer drugs are synthetically formulated to mimic the psychostimulatory effects of an original controlled/illegal drug of abuse. Designer drugs have similar chemical structure or functional analog as compared to existing controlled psychostimulatory drugs. There is a substantial rise in the production and use of designer drugs globally. Piperazine designer drugs were synthesized as an alternative to MDMA and have shown to induce numerous toxic effects leading to huge health, safety, law enforcement & monetary problems, and lethality. Currently, there are very few studies on the dopaminergic neurotoxicity of 1-(3-trifluoromethylphenyl) piperazine (3-TFMPP) and its derivatives (structural congeners). N27 rat dopaminergic neurons are valid cells to investigate the neurotoxic effects and establish the neurotoxic mechanisms of various substances. In the current study, we studied the time and dose-dependent neurotoxicity mechanisms of dopaminergic neurotoxicity of 3-TFMPP (parent compound) and its derivatives (2-TFMPP, 4-TFMPP). TFMPP derivatives-induced significant neurotoxicity (induced dopaminergic neuronal death. TFMPP derivatives-induced oxidative stress, mitochondrial dysfunction, apoptosis and decreased tyrosine hydroxylase expression. If the use of designer drugs are not strictly regulated and restricted around the world, this can lead to numerous central and peripheral disorders leading to a liability to the current and future society. [ABSTRACT FROM AUTHOR]

Abstract: The availability of new psychoactive substances (NPS) on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM), and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization, and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic, and mass spectrometric platforms. Pharmacological studies were conducted to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to 3,4‐methylenedioxymethamphetamine (MDMA). The combination of test purchases, analytical characterization, targeted organic synthesis, and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace. [ABSTRACT FROM AUTHOR]

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

Rationale: The synthetic cathinone α-pyrrolidinopentiophenone (α-PVP) has been associated with bizarre public behavior in users. Association of such behavior with extended binges of drug use motivates additional investigation, particularly since a prior study found that half of male rats experience a binge of exceptionally high intake, followed by sustained lower levels of self-administration during the acquisition of intravenous self-administration (IVSA) of a related drug, 3,4-methylenedioxypyrovalerone.Objectives: The binge-like acquisition pattern is novel for rat IVSA; thus, the present study sought to determine if this effect generalizes to IVSA of α-PVP in female rats.Methods: Female Wistar rats were trained in IVSA of α-PVP (0.05 mg/kg/inf) in experimental chambers containing an activity wheel. Groups were trained with the wheels fixed (No-Wheel group), fixed for the initial 5 days of acquisition or free to move throughout acquisition (Wheel group). The groups were next subjected to a wheel access switch and then all animals to dose-substitution (0.0125-0.3 mg/kg/inf) with the wheels alternately fixed and free to move.Results: Approximately half of the rats initiated their IVSA pattern with a binge day of exceptionally high levels of drug intake, independent of wheel access condition. Wheel activity was much lower in the No-Wheel group in the wheel switch post-acquisition. Dose-effect curves were similar for wheel access training groups, for binge/no binge phenotypic subgroups and were not altered with wheel access during the dose-substitution.Conclusion: This confirms the high reinforcer effectiveness of α-PVP in female rats and the accompanying devaluation of wheel activity as a naturalistic reward. [ABSTRACT FROM AUTHOR]

Drug addiction is a chronic brain disease characterised by a compulsion to seek drugs, a loss of control with respect to drug consumption and negative emotional states, including increased anxiety and irritability during withdrawal. Central vasopressin (AVP) and its receptors are involved in controlling social behaviour, anxiety and reward, all of which are altered by drugs of abuse. Hypothalamic AVP neurones influence the stress response by modulating the hypothalamic‐pituitary‐adrenal (HPA) axis. The extrahypothalamic AVP system, however, is commonly associated with social recognition, motivational and anxiety responses. The specific relationship between AVP and drugs of abuse has been rarely reviewed. Here, we provide an overview of the interaction between the brain AVP system and psychostimulants and alcohol. We focus on the effects of alcohol and psychostimulants on AVP regulation of the HPA axis, their effect on the brain AVP system and their behavioural implications, the influence of the AVP system on addictive behaviours, and the organisational effects of AVP on the brain and consequently on behaviour. In addition, we highlight clinical studies on the relationship between the AVP system and drug addiction. Finally, we discuss the data aiming to address areas that need further research with respect to supporting clinical trials and preventing drug‐related disorders. [ABSTRACT FROM AUTHOR]

Desde el año 2014 disponemos en nuestro arsenal terapéutico del dimesilato de lisdexanfetamina (LDX); que es el primer psicoestimulante de larga duración con tecnología de profármaco, aprobado para su uso en España en niños en los que ha habido una inadecuada respuesta al tratamiento con metilfenidato, a partir de los 6 años de vida. Con el advenimiento de la Guanfancina en 2016, hemos asistido a una ampliación considerable del abanico de opciones terapéuticas farmacológicas disponibles a nuestro alcance, posibilitando de esta manera un control más efectivo de los síntomas nucleares del TDAH. Objetivos: El principal objetivo de este trabajo se centra en la descripción y caracterización de una población de niños y adolescentes con diagnóstico de TDAH, en los que se realizó ensayo terapéutico con LDX. En base a los resultados obtenidos y a la revisión de la bibliografía, se presentan los diferentes "escenarios" en los cuales el uso de LDX ha demostrado ser de especial utilidad en el manejo de niños y adolescentes con TDAH. Material y Métodos: Se llevó a cabo un estudio longitudinal y descriptivo, en el cual se revisaron por un lado las diferentes respuestas obtenidas con LDX en función de las características clínicas de la población objeto de análisis (niños y adolescentes de entre 6 y 18 años con diagnóstico de TDAH, previamente expuestos a diferentes pautas de MFD y/o ATX), así como el perfil de tolerabilidad y de efectos secundarios presentados. Resultados: Se incluyeron en el trabajo 200 pacientes (n=200), de los cuales 140 fueron varones y 60 niñas (relación varón/niñas 2.3), con un rango de edades comprendido entre los 6 y los 18 años, y una media de edad de 15 años. De los 200 pacientes incluidos, 178 (89%) presentaron una respuesta buena o muy buena, mientras que los 22 restantes (11%) tuvieron una inadecuada respuesta y/o una tasa de efectos secundarios que motivaron la suspensión del tratamiento con LDX. Los que mejor respondieron al cambio a LDX fueron aquellos individuos en los que existía una respuesta previa parcial a diferentes pautas farmacológicas, en los que necesitaban múltiples tomas de MFD para obtener una mejor cobertura a lo largo del día, o en los que existían efectos indeseables sobre el "carácter" (especialmente en adolescentes sin otras comorbilidades asociadas). El 89% de los pacientes presentaron efectos secundarios de intensidad leve-moderada (en la línea de los ya descriptos con los psicoestimulantes), con tendencia a mejorar o desaparecer con el paso del tiempo. No se evidenciaron efectos secundarios graves en la serie analizada. Conclusiones: Existe un perfil clínico de pacientes con diagnóstico de TDAH en los cuales el uso de LDX parece mostrar un alto perfil de eficacia, con una adecuada tolerabilidad a corto, mediano y largo plazo; y una aceptable tasa de efectos secundarios. Introduction: Attention deficit hyperactivity disorder (ADHD) is one of the most frequent neurodevelopmental disorders, with an estimated worldwide prevalence of approximately 5% [1,2]. Until a few years ago, the pharmacological options in Spain for the treatment of ADHD were basically confined to methylphenidate in its different presentations (MFD), and to Atomoxetine (ATX). Since 2014 we have in our therapeutic arsenal the lisdexanfetamine dimesylate (LDX); which is the first long-term psychostimulant with prodrug technology, approved for use in Spain in children in whom there has been an inadequate response to treatment with methylphenidate, from 6 years of age. With the advent of guanfancine in 2016, we have witnessed a considerable expansion of the range of pharmacological therapeutic options available to us, thus enabling a more effective control of the core symptoms of ADHD. Objectives: The main objective of this work focuses on the description and characterization of a population of children and adolescents diagnosed with ADHD, in which a LDX therapeutic trial was conducted. Based on the results obtained and the review of the literature, the different "scenarios" are presented in which the use of LDX has proved to be especially useful in the management of children and adolescents with ADHD. Material and Methods: A longitudinal and descriptive study was carried out, in which the different responses obtained with LDX were reviewed on the one hand according to the clinical characteristics of the population under analysis (children and adolescents between 6 and 18 years old). with a diagnosis of ADHD, previously exposed to different MFD and / or ATX guidelines), as well as the tolerability profile and side effects presented. Results: 200 patients were included in the study (n = 200), of which 140 were males and 60 girls (relation between males / girls 2.3), with a range of ages between 6 and 18 years, and an average of age of 15 years. Of the 200 patients included, 178 (89%) had a good or very good response, while the remaining 22 (11%) had an inadequate response and / or a rate of side effects that led to the suspension of treatment with LDX. Those who responded best to the change to LDX were those individuals in whom there was a partial prior response to different pharmacological guidelines, in which they needed multiple doses of MFD to obtain better coverage throughout the day, or in which there were undesirable effects. about "character" (especially in adolescents without other associated comorbidities). 89% of the patients presented side effects of mildmoderate intensity (in line with those already described with psychostimulants), with a tendency to improve or disappear with the passage of time. There were no serious side effects in the series analyzed. Conclusions: There is a clinical profile of patients diagnosed with ADHD in whom the use of LDX seems to show a high efficacy profile, with adequate tolerability in the short, medium and long term; and an acceptable rate of side effects. [ABSTRACT FROM AUTHOR]

Rationale: Delay-discounting procedures involving choice between small immediate rewards and large delayed rewards are used to study impulsivity in rodents. Improving existing procedures may provide new insights into the neurobiological mechanisms underlying decision-making processes.Objectives: To develop a novel delay-discounting procedure that adjusts the delay value within individual sessions based on the rat’s most recent choices.Methods: Compared to previously developed procedure, we required a more consistent demonstration of preference, five consecutive choices of the large or small reward, a criterion that is more likely to reflect deliberate choice by the animal, as opposed to two consecutive choices. In addition, delays were changed in steps of 5 s (rather than 1 s), because 5-s increments should be more easily discriminated and may produce a more distinct effect on choice. We characterized the procedure behaviorally by manipulating the duration of the session and the consecutive choice criterion, and we investigated the stability of the behavior upon interruption of training. We also characterized the procedure pharmacologically by investigating the effects of dopaminergic compounds.Results: Our procedures allowed obtaining two complementary measures of delay discounting: (1) the percentage of choices of the delay option and (2) the mean adjusting delay, an index of the delay that animals choose more frequently. We found that our procedure rapidly establishes a baseline of choice behavior that remains stable over time and is highly sensitive to manipulations of the dopaminergic system.Conclusions: This procedure may provide a useful tool for investigating the neurobiology of inter-temporal choice and decision-making. [ABSTRACT FROM AUTHOR]

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

Background: Methamphetamine use has been posited to be a risk factor for the development of Parkinson's disease (PD) and parkinsonism. The clinical implications of a potential association between methamphetamine use and PD are considered.Methods: A review of methamphetamine and PD and parkinsonism was conducted, including evidence from animal models, clinical and population studies.Results: There is biological plausibility to a link between methamphetamine use and PD. Though clinical and epidemiological evidence in this area is scant, a number of studies suggest that methamphetamine is associated with a moderately increased risk of PD and parkinsonism, and may also lead to premature onset of PD. The long lag time between exposure to methamphetamine and onset of PD, the potential for recovery from neurotoxic effects, and tobacco smoking each may attenuate the association. Individual and drug use characteristics that may modulate a user's risk remain poorly understood.Conclusions: The use of methamphetamine may be an initiating event in the development of PD and parkinsonism, in addition to other risk factors that a given individual may hold. Clinicians should be vigilant to signs of prodromal and emerging PD among methamphetamine users. In individuals with premature onset illness, information on current or prior exposure to methamphetamine should be sought. [ABSTRACT FROM AUTHOR]

Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (re-creating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p < 0.0001). The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p < 0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left PFC and caudate, and bilaterally in the cerebellum (all p values<0.01), suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes. [ABSTRACT FROM AUTHOR]

Trace-amine associated receptor 1 (TAAR1) is the best-characterized member of the family of TAARs. TAAR1 is broadly expressed in the brain, especially within the monoaminergic systems. Evidence from electrophysiological and neurochemical studies evaluating the effects of genetic and pharmacological interventions on TAAR1 revealed that TAAR1 modulates transmission of monoamines, especially dopamine. TAAR1 agonists dampened drugs of abuse-induced dopamine accumulation. In general, TAAR1 agonists specifically inhibited the rewarding and reinforcing effects of drugs of abuse and drug-abuse related behaviors. Details of the mechanism of TAAR1 remain elusive; however, it is thought to be regulated by its interactions with D2 receptors. In addition, the alternative cellular mechanism such as an interaction between TAAR1 and D3 may also participate in the action of TAAR1 agonists. Further studies are required to investigate the role of TAAR1 in other drugs of abuse-related behaviors and the underlying neural mechanisms. Collectively, TAAR1 negatively modulates dopaminergic systems and dopamine-related behaviors and TAAR1 agonists are promising pharmacotherapy to treat drug addiction and relapse. [ABSTRACT FROM AUTHOR]

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenylethylamine derivative, structurally similar to mescaline. It is a serotonin 5-hydroxytryptamine-2A (5-HT2A), 5-hydroxytryptamine-2B (5-HT2B), and 5-hydroxytryptamine-2C (5-HT2C) receptor partial agonist used recreationally as a new psychoactive substance. It has been reported that 2C-B induces mild psychedelic effects, although its acute pharmacological effects and pharmacokinetics have not yet been fully studied in humans. An observational study was conducted to assess the acute subjective and physiological effects, as well as pharmacokinetics of 2C-B. Sixteen healthy, experienced drug users self-administered an oral dose of 2C-B (10, 15, or 20 mg). Vital signs (blood pressure and heart rate) were measured at baseline 1, 2, 3, 4, and 6 hours (h). Each participant completed subjective effects using three rating scales: the visual analog scale (VAS), the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2-3 and 6 h after self-administration (maximum effects along 6 h), and the Hallucinogenic Rating Scale (maximum effects along 6 h). Oral fluid (saliva) was collected to assess 2C-B and cortisol concentrations during 24 h. Acute administration of 2C-B increased blood pressure and heart rate. Scores of scales related to euphoria increased (high, liking, and stimulated), and changes in perceptions (distances, colors, shapes, and lights) and different body feelings/surrounding were produced. Mild hallucinating effects were described in five subjects. Maximum concentrations of 2C-B and cortisol were reached at 1 and 3 h after self-administration, respectively. Oral 2C-B at recreational doses induces a constellation of psychedelic/psychostimulant-like effects similar to those associated with serotonin-acting drugs. [ABSTRACT FROM AUTHOR]

Background: In order to better understand the recent rise in nonprescribed use of psychostimulants on college campuses, motives, outcomes, and acceptability of nonprescribed psychostimulants have been evaluated. Despite knowledge that students use nonprescribed medical stimulants for improved academic performance and recreational use, gender differences in these motives have not been examined, despite the fact that the social construction of gender may well affect motives for use.Objectives: The goal of the present study was to examine gender differences in motives, outcomes, and acceptability of nonprescribed psychostimulant use.Methods: 2716 undergraduates (1448 male) between the ages of 17 and 57 years (M= 19.43 years,SD= 1.7 years) completed an online survey examining subjective motives of nonprescribed psychostimulant use, as well as behaviors after use and moral views of nonprescribed use.Results: Consistent with hypotheses and known gender differences in social motivation, results suggested that while females are more likely to use nonprescribed psychostimulants for reasons related to schoolwork, males are typically more likely to use psychostimulants for reasons related to partying and socializing. Additional gender differences were that males are more likely to take part in other risky behaviors after use of psychostimulants, as well as view nonprescribed use as more moral and less physically dangerous than females.Conclusions/Importance: This work suggests that there are striking gender differences in motivation and outcomes of use of nonprescribed psychostimulants, which may have implications for personalized approaches for prevention of nonprescribed psychostimulant use on campuses based on gender. [ABSTRACT FROM PUBLISHER]

Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction‐relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug‐addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction‐relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction. [ABSTRACT FROM AUTHOR]

Commonalities in addictive behavior, such as craving, stimuli-driven drug seeking, and a high propensity for relapse following abstinence, have pushed for a unified theory of addiction that encompasses most abused substances. This unitary theory has recently been challenged – citing distinctions in structural neural plasticity, biochemical signaling, and neural circuitry to argue that addiction to opioids and psychostimulants is behaviorally and neurobiologically distinct. Recent more selective examination of drug-induced plasticity has highlighted that these two drug classes promote an overall reward circuitry signaling overlap through modifying excitatory synapses in the nucleus accumbens – a key constituent of the reward system. We discuss adaptations in presynaptic/postsynaptic and extrasynaptic glutamate signaling produced by opioids and psychostimulants, and their relevance to circuit remodeling and addiction-related behavior – arguing that these core neural adaptations are important targets for developing pharmacotherapies to treat addiction to multiple drugs. [ABSTRACT FROM AUTHOR]

Trace amines (TAs), endogenous amino acid metabolites that are structurally similar to the biogenic amines, are endogenous ligands for trace amine-associated receptor 1 (TAAR1), a GPCR that modulates dopaminergic, serotonergic, and glutamatergic activity. Selective TAAR1 full and partial agonists exhibit similar pro-cognitive, antidepressant- and antipsychotic-like properties in rodents and non-human primates, suggesting TAAR1 as a novel target for the treatment of neurological and psychiatric disorders. We previously reported that TAAR1 partial agonists are wake-promoting in rats and mice, and that TAAR1 knockout (KO) and overexpressing mice exhibit altered sleep-wake and EEG spectral composition. Here, we report that locomotor and EEG spectral responses to the psychostimulants modafinil and caffeine are attenuated in TAAR1 KO mice. TAAR1 KO mice and WT littermates were instrumented for EEG and EMG recording and implanted with telemetry transmitters for monitoring locomotor activity (LMA) and core body temperature (Tb). Following recovery, mice were administered modafinil (25, 50, 100 mg/kg), caffeine (2.5, 10, 20 mg/kg) or vehicle p.o. at ZT6 in balanced order. In WT mice, both modafinil and caffeine dose-dependently increased LMA for up to 6 h following dosing, whereas only the highest dose of each drug increased LMA in KO mice, and did so for less time after dosing. This effect was particularly pronounced following caffeine, such that total LMA response was significantly attenuated in KO mice compared to WT at all doses of caffeine and did not differ from Vehicle treatment. Tb increased comparably in both genotypes in a dosedependent manner. TAAR1 deletion was associated with reduced wake consolidation following both drugs, but total time in wakefulness did not differ between KO and WT mice. Furthermore, gamma band EEG activity following both modafinil and caffeine treatment was attenuated in TAAR1 KO compared to WT mice. Our results show that TAAR1 is a critical component of the behavioral and cortical arousal associated with two widely used psychostimulants with very different mechanisms of action. Together with our previous findings, these data suggest that TAAR1 is a previously unrecognized component of an endogenous wake-modulating system. [ABSTRACT FROM AUTHOR]

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

Humans often administer psychostimulants in party or music festival settings characterized by warm ambient temperatures, which may impact drug effects; however, preclinical studies rarely investigate drug effects at multiple ambient temperatures. Work with 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) suggests that the presence of a 3,4-methylenedioxy ring moiety may influence ambient temperature-dependent effects. Locomotor activity and conditioned place preference dose-response curves were generated at 20±2 °C for two amphetamine analogues (MDMA and methamphetamine [METH]) and two cathinone analogues (MDPV and α-pyrrolidinopentiophenone [αPVP]) in mice. Effects were then redetermined at 29±2 °C for each drug and assay. All four drugs elicited dose-dependent locomotor stimulation at the cool ambient temperature. At the warm ambient temperature, MDMA and MDPV produced sensitization to stereotypy, whereas METH and αPVP produced sensitization to locomotor activity. Regarding place conditioning, the warm ambient environment potentiated place preference elicited by doses of METH and αPVP that were sub-threshold in the cool ambient environment, but attenuated the effects of analogous doses of MDMA and MDPV. These studies suggest that warmer ambient temperatures may potentiate typical stimulant effects for the drugs lacking the 3,4-methylenedioxy ring, but may potentiate the behaviorally toxic/adverse effects for the drugs containing a 3,4-methylenedioxy ring. Thus, preclinical abuse liability studies conducted at standard laboratory temperatures may not fully capture the effects of psychostimulants and highlight the need to model the environments in which drugs are typically used by humans. • At a warm ambient temperature, MDMA and MDPV produced increases in stereotypy. • At a warm ambient temperature, METH and αPVP produced increased locomotor activity. • A warmer environment increased time spent in a chamber paired with METH or αPVP. • A warmer environment decreased time spent in a chamber paired with MDMA and MDPV. [ABSTRACT FROM AUTHOR]

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

Immediate early genes (IEGs) were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN) subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior.

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

Semen exosomes (SE) from HIV-uninfected (HIV−) individuals potently inhibit HIV infection in vitro. However, morphological changes in target cells in response to SE have not been characterized or have the effect of HIV infection or the use of illicit substances, specifically psychostimulants, on the function of SE been elucidated. The objective of this study was to evaluate the effect of HIV infection, psychostimulant use, and both together on SE-mediated regulation of monocyte function. SE were isolated from semen of HIV− and HIV-infected (HIV+) antiretroviral therapy (ART)-naive participants who reported either using or not using psychostimulants. The SE samples were thus designated as HIV−Drug−, HIV−Drug+, HIV+Drug−, and HIV+Drug+. U937 monocytes were treated with different SEs and analyzed for changes in transcriptome, morphometrics, actin reorganization, adhesion, and chemotaxis. HIV infection and/or use of psychostimulants had minimal effects on the physical characteristics of SE. However, different SEs had diverse effects on the messenger RNA signature of monocytes and rapidly induced monocyte adhesion and spreading. SE from HIV infected or psychostimulants users but not HIV−Drug− SE, stimulated actin reorganization, leading to the formation of filopodia-like structures and membrane ruffles containing F-actin and vinculin that in some cases were colocalized. All SE stimulated monocyte chemotaxis to HIV secretome and activated the secretion of matrix metalloproteinases, a phenotype exacerbated by HIV infection and psychostimulant use. SE-directed regulation of cellular morphometrics and chemotaxis depended on the donor clinical status because HIV infection and psychostimulant use altered SE function. Although our inclusion criteria specified the use of cocaine, humans are poly-drug and alcohol users and our study participants used psychostimulants, marijuana, opiates, and alcohol. Thus, it is possible that the effects observed in this study may be due to one of these other substances or due to an interaction between different substances.

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

Amphetamine (AMPH)-mediated norepinephrine transporter (NET) downregulation requires NET-T258/S259 trafficking motif. The present study utilizes cell permeable NET-T258/S259 motif interfering peptide, which blocks AMPH-induced NET downregulation, to explore the role of this form of NET regulation in AMPH-mediated behaviors. In rats receiving intra-accumbal microinjections of TAT-conjugated peptides encompassing NET-T258/S259 motif, acute systemic AMPH failed to inhibit NE transport in the TAT-NET-T258/S259 wild-type (WT) peptide injected hemisphere but not in the vehicle or scrambled peptide injected hemisphere. Acute AMPH-induced hyperactivity was significantly reduced in rats receiving intra-accumbal TAT-NET-T258/S259 WT peptide compared to those receiving intra-accumbal vehicle or TAT-NET-T258A/S259A mutant peptide or corresponding TAT-conjugated scrambled peptide. Basal locomotor activity was not altered by peptide infusions alone. Similarly AMPH-induced locomotor sensitization was significantly reduced in rats receiving intra-accumbal TAT-NET-T258/S259 WT peptide prior to AMPH challenge and not in rats receiving the mutant or scrambled peptide. In conditioned place preference (CPP) paradigm, a single bilateral intra-accumbal microinjection of TAT-NET-T258/S259 WT peptide prior to CPP testing significantly reduced AMPH-induced CPP expression. Likewise, a single bilateral intra-accumbal microinjection of TAT-NET-T258/S259 WT peptide prior to drug-challenge significantly attenuated AMPH-primed CPP reinstatement. On the other hand, bilateral intra-accumbal microinjection of scrambled peptide did not affect AMPH-induced CPP expression or reinstatement. These data demonstrate a role for T258/S259-dependent NET regulation in AMPH-induced hyperactivity and sensitization as well as AMPH-induced CPP expression and reinstatement. [ABSTRACT FROM AUTHOR]

Long-term effects of psychostimulants such as methylphenidate on ADHD patients have been proved to be difficult to capture in cross-sectional studies comparing medicated and non-medicated samples and in longitudinal studies with children, with age-related maturational processes possibly confounding independent effects of medication. However, chronic psychostimulant administration at therapeutic doses has been proven to yield profound neuroadaptive changes in rodent models. Here, we present for the first time the effect of psychostimulant treatment on brain volumes in a sample of medication-naïve adult ADHD patients. We investigated grey matter volume changes in a sample of 41 medication-naïve adult ADHD patients before and after three years of psychostimulant treatment (N = 25) or no treatment (N = 16) compared to healthy adults (N = 25). We found a significant group x time interaction effect on left putamen grey matter volumes, with a decrease in left putamen volumes in the non-medicated group compared to both the medicated group and controls, and no differences between the medicated group and controls. Our results suggest a normalizing effect of psychostimulant treatment on the left putamen volume loss detected in non-medicated ADHD patients. [ABSTRACT FROM AUTHOR]

Objective: The Treatment of Severe Childhood Aggression (TOSCA) project examined augmentation of stimulant treatment and parent training (PT) with risperidone for severe physical aggression. This article summarizes the clinical implications; reanalyzes the data to examine the utility of 4 criteria for deciding to augment; and presents a treatment algorithm.Method: The newly analyzed 4 criteria for augmenting after 3 weeks of stimulant and PT treatment consisted of not meeting a Clinical Global Impressions-Improvement (CGI-I) score of 1 and a normal score (≤15) on the Nisonger Child Behavior Rating Form Disruptive-Total (D-Total); a CGI-I score of 1 or 2 plus 25% improvement in D-Total score; a D-Total score no higher than 15; and a CGI-Severity score of 3 (mild) or better. Effect sizes were calculated. Prior TOSCA publications were reviewed for clinically relevant findings.Results: All 4 criteria resulted in medium or better effect sizes (d = 0.59-0.72) when comparing risperidone with placebo. Providing risperidone to children who did not reach a CGI-I score of 1 plus a D-Total score no higher than 15 resulted in the greatest benefit. In addition, a review of clinically relevant data suggests that stimulant plus PT shows further improvement after 3 weeks even without augmentation.Conclusion: For those children who did not attain a CGI-I score of 1 and a D-total score no higher than 15, adding risperidone maximized the number of children benefitting from treatment and the average amount of benefit. Unless clinical circumstances dictate otherwise, practitioners should delay an antipsychotic drug for at least 1 month after the optimal stimulant dose is achieved and PT has commenced. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov; NCT00796302. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Insomnia is diagnosed when there is dissatisfaction with sleep quantity or quality. It has a prevalence in the general population ranging from 31 to 56%. Insomnia has previously been associated with adult attention-deficit/hyperactivity disorder (ADHD). In this review, we address three topics: (1) the cross-sectional relationship between ADHD and insomnia in adulthood, (2) the longitudinal relationship between ADHD and insomnia, and (3) insomnia as a side effect of pharmacological treatments for adult ADHD.Recent Findings: Three cross-sectional, clinical, and population studies report a prevalence of insomnia in ADHD adults ranging from 43 to 80%. Longitudinal evidence for a link between childhood-onset ADHD and insomnia at later age is mixed, with one study confirming and another study not supporting such a longitudinal association. In randomized, placebo-controlled trials, insomnia is reported significantly more often in the treatment arm than in the placebo arm. In varying percentages of trial participants, insomnia is a treatment-emergent adverse effect in triple-bead mixed amphetamine salts (40-45%), dasotraline (35-45%), lisdexamfetamine (10-19%), and extended-release methylphenidate (11%). Ten to seventeen percent of subjects in placebo-controlled trials of atomoxetine report insomnia, possibly related to poor metabolizer status. The mechanisms explaining the relationship between ADHD and sleep problems are incompletely understood, but both genetic and non-shared environmental influences may be involved. Adults with ADHD should be assessed for insomnia, which is frequently comorbid, and both conditions should be treated. [ABSTRACT FROM AUTHOR]

Background Although it is well established that methylphenidate (MPH) enhances sustained attention, the neural mechanisms underpinning this improvement remain unclear. We examined how MPH influenced known electrophysiological precursors of lapsing attention over different time scales. Methods We measured the impact of MPH, compared with placebo, on behavioral and electrocortical markers while healthy adults ( n = 40) performed a continuous monitoring paradigm designed to elicit attentional lapses. Results MPH led to increased rates of target detection, and electrophysiological analyses were conducted to identify the mechanisms underlying these improvements. Lapses of attention were reliably preceded by progressive increases in alpha activity that emerged over periods of several seconds. MPH led to an overall suppression of alpha activity across the entire task but also diminished the frequency of these maladaptive pretarget increases through a reduction of alpha variability. A drug-related linear increase in the amplitude of the frontal P3 event-related component was also observed in the pretarget timeframe (3 or 4 seconds). Furthermore, during immediate target processing, there was a significant increase in the parietal P3 amplitude with MPH, indicative of enhanced perceptual evidence accumulation underpinning target detection. MPH-related enhancements occurred without significant changes to early visual processing (visual P1 and 25-Hz steady-state visual evoked potential). Conclusions MPH serves to reduce maladaptive electrophysiological precursors of lapsing attention by acting selectively on top-down endogenous mechanisms that support sustained attention and target detection with no significant effect on bottom-up sensory excitability. These findings offer candidate markers to monitor the therapeutic efficacy of psychostimulants or to predict therapeutic responses. [ABSTRACT FROM AUTHOR]

The DSM5-based dimensional diagnostic approach defines substance use disorders on a continuum from recreational drug use to habitual and ultimately addicted behavior. Biomarkers that are indicative of recreational drug use and addicted behavior are lacking. We performed a translational [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study in the multi-dimensional 0/3crit model of cocaine addiction. Addict-like (3crit) and non-addict-like (0crit) rats, which shared identical life conditions and levels of cocaine self-administration, were acquired for FDG-PET under baseline conditions and following cocaine and yohimbine challenges. Compared to cocainenaïve control rats, 0crit animals showed higher glucose uptake in the caudate putamen (CPu) and medial prefrontal cortex (mPFC) respect to naïve controls. 3crit animals did not show this adaptive higher glucose utilization, but had lower uptake in several cortical areas. Both cocaine and yohimbine challenges affected glucose uptake in control rats in several brain sites, but not in 0crit and 3crit rats, indicating that impaired glucose mobilization in response to these challenges is not specifically associated with addictive behavior. Compared to 0crit, 3crit rats showed higher reinstatement responses, which were negatively associated with glucose uptake in the ventral tegmental area. Data indicate that cocaine non-addict- and addict-like phenotypes are associated with several potential biomarkers. Specifically, we propose that increased glucose uptake in the CPu and mPFC is a function of controlled drug use, whereas a loss of striatal and prefrontal metabolic activity and reduced uptake in cortical areas are indicative of addictive behavior. [ABSTRACT FROM AUTHOR]

Cancer-related fatigue is a symptom of cancer where most patients or the general practitioners tend to misinterpret due to the insufficient understanding or knowledge of cancer-related fatigue (CRF). This paper will provide a better perspective for the patients and the health professionals on how to manage and handle CRF for both mild and severe fatigue patients. Articles were selected from the searches of PubMed database that had the terms "randomized controlled trials," "cancer," "fatigue," "pharmacologic treatment," and "nonpharmacologic treatment" using both Mesh terms and keywords. The authors have reviewed the current hypothesis and evidence of the detailed etiology of the CRF present in the literature for healthier management, directives, and strategies to improve the treatment of cancer-related fatigue. An algorithm has been blueprinted on screening, and management, of the CRF, and various kinds of effective treatments and assessment tools have been briefly studied and explained. Although many strategies seemed promising, the quality of randomized controlled trials is generally quite low in studies, making it difficult to draw conclusions about the effectiveness of each self-care strategies. Therefore, future studies require better design and reporting of methodological issues to ensure evidence-based self-care recommendations for people receiving cancer treatment. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood, which shows diagnostic persistence and morbidity into adulthood. Psychostimulants are generally first-line pharmacotherapy for ADHD, but some patients do not achieve symptomatic remission, especially those who have Oppositional Defiant Disorder (ODD) comorbidity. In those cases, there is growing evidence that a combination of psychostimulants and nonscheduled medications to manage ADHD, may be useful. The alpha-2 adrenergic agonist guanfacine extended release (GXR), a non-stimulant treatment, has recently been approved by the European Medicines Agency (EMA) as new therapeutic option for ADHD. In Spain it has been available from the end of January 2017. The aim of this study is to test the efficacy and tolerability of a combined therapy of psychostimulant (lisdexamfetamine) and GXR in a patient with ADHD and ODD. [ABSTRACT FROM AUTHOR]

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