Chronic Methylphenidate Alters Tonic and Phasic Glutamate Signaling in the Frontal Cortex of a Freely-Moving Rat Model of ADHD.

Glutamate dysfunction has been implicated in a number of substance of abuse studies, including cocaine and methamphetamine. Moreover, in attention-deficit/hyperactivity disorder (ADHD), it has been discovered that when the initiation of stimulant treatment occurs during adolescence, there is an increased risk of developing a substance use disorder later in life. The spontaneously hypertensive rat (SHR) serves as a phenotype for ADHD and studies have found increased cocaine self-administration in adult SHRs when treated with the stimulant methylphenidate (MPH) during adolescence. For this reason, we wanted to examine glutamate signaling in the pre-limbic frontal cortex, a region implicated in ADHD and drug addiction, in the SHR and its progenitor control strain, the Wistar Kyoto (WKY). We chronically implanted glutamate-selective microelectrode arrays (MEAs) into 8-week-old animals and treated with MPH (2 mg/kg, s.c.) for 11 days while measuring tonic and phasic extracellular glutamate concentrations. We observed that intermediate treatment with a clinically relevant dose of MPH increased tonic glutamate levels in the SHR but not the WKY compared to vehicle controls. After chronic treatment, both the SHR and WKY exhibited increased tonic glutamate levels; however, only the SHR was found to have decreased amplitudes of phasic glutamate signaling following chronic MPH administration. The findings from this study suggest that the MPH effects on extracellular glutamate levels in the SHR may potentiate the response for drug abuse later in life. Additionally, these data illuminate a pathway for investigating novel therapies for the treatment of ADHD and suggest that possibly targeting the group II metabotropic glutamate receptors may be a useful therapeutic avenue for adolescents diagnosed with ADHD.

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine.

Opioid antagonists (eg, naltrexone) and positive modulators of γ-aminobutyric acid type A receptors (eg, alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of D-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and "positive" subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone.Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6 to 7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected.Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like "positive" subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10-mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

Methamphetamine self-administration in humans during D-amphetamine maintenance.

Agonist replacement may be a viable treatment approach for managing stimulant use disorders. This study sought to determine the effects of D-amphetamine maintenance on methamphetamine self-administration in stimulant using human participants. We predicted that D-amphetamine maintenance would reduce methamphetamine self-administration. Eight participants completed the protocol, which tested 2 D-amphetamine maintenance conditions in counterbalanced order (0 and 40 mg/d). Participants completed 4 experimental sessions under each maintenance condition in which they first sampled 1 of 4 doses of intranasal methamphetamine (0, 10, 20, or 30 mg). Participants then had the opportunity to respond on a computerized progressive-ratio task to earn portions of the sampled methamphetamine dose. Subject-rated drug effect and physiological measures were completed at regular intervals prior to and after sampling methamphetamine. Methamphetamine was self-administered as an orderly function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects on 12 items of the drug-effects questionnaires, 8 of which were attenuated by D-amphetamine maintenance (eg, increased ratings were attenuated on items such as Any Effect, Like Drug, and Willing to Take Again on the Drug Effect Questionnaire). Methamphetamine produced significant increases in systolic blood pressure, which were attenuated by D-amphetamine maintenance compared to placebo maintenance. Methamphetamine was well tolerated during D-amphetamine maintenance and no adverse events occurred. Although D-amphetamine attenuated some subject-rated effects of methamphetamine, the self-administration results are concordant with those of clinical trials showing that D-amphetamine did not reduce methamphetamine use. Unique pharmacological approaches may be needed for treating amphetamine use disorders.

Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole.

Methamphetamine is thought to produce its behavioral effects by facilitating release of dopamine, serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, whereas results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human drug-discrimination procedures are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, 6 participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (ie, ≥ 80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (eg, increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine.

Methylphenidate increases choice of cigarettes over money.

INTRODUCTION: Stimulants increase cigarette smoking in the naturalistic environment and laboratory. The effects of methylphenidate on a 9-trial, discrete cigarette versus money ($0.25) choice task were tested to elucidate the mechanisms underlying stimulant-induced increases in smoking. METHODS: Eleven participants who reported smoking 10-20 cigarettes/day completed the study. Four doses of methylphenidate (0, 10, 20, and 40 mg) were administered across 5 experimental sessions, with placebo administered twice. One hour following medication administration and at 30-min intervals thereafter, participants chose between smoking a cigarette and receiving US$0.25. The primary behavioral outcome measure was number of cigarette choices. RESULTS: Methylphenidate increased the number of cigarette choices over money. Puffs per session and carbon monoxide levels increased significantly and caloric intake decreased significantly following methylphenidate administration relative to placebo. CONCLUSIONS: The results of this study suggest that methylphenidate increases the relative reinforcing efficacy of cigarette smoking. Stimulant use may thus be an important consideration for individuals attempting to quit smoking.

Reinforcing effects of d-amphetamine: influence of novel ratios on a progressive-ratio schedule.

Progressive-ratio schedules are useful for studying the reinforcing effects of drugs. Earlier human laboratory studies showed that d-amphetamine significantly increased break points relative to placebo. However, the magnitude of the increase was modest, which may be attributable to rather high levels of placebo responding. We used novel response requirements in a modified progressive-ratio procedure and hypothesized that the altered range of response requirements would decrease responding for placebo and increase responding for d-amphetamine. Eight participants completed the study. The participants first sampled oral doses of d-amphetamine (0, 8, 16, and 24 mg). In subsequent sessions, the participants were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure with response requirements ranging from 400 to 1800 mouse clicks. A battery of participant-rated drug-effect questionnaires, a performance measure, and cardiovascular measures were included to more fully characterize the effects of d-amphetamine. Placebo maintained low levels of responding. The intermediate dose of d-amphetamine increased responding significantly above placebo levels. d-Amphetamine produced prototypical subject-rated effects that were an orderly function of dose. These data suggest that the modified response requirements resulted in lower levels of placebo taking and a larger separation between the number of placebo and d-amphetamine capsules earned.

Age disparities in six-month treatment retention for opioid use disorder.

BACKGROUND AND AIMS: Adolescents with opioid use disorder (OUD) are an understudied and vulnerable population. We examined the association between age and six-month treatment retention, and whether any such association was moderated by medication treatment. METHODS: In this retrospective cohort study, we used an insurance database with OUD treatment claims from 2006-2016. We examined 261,356 OUD treatment episodes in three age groups: adolescents (ages 12-17), young adults (18-25) and older adults (26-64). We used logistic regression to estimate prevalence of six-month retention before and after stratification by treatment type (buprenorphine, naltrexone, or psychosocial only). Insurance differences (commercial vs Medicaid) in medication treatment prevalence were also assessed. RESULTS: Adolescents were less likely to be retained compared to adults (17.6 %; 95 % CI 16.5-18.7 % for adolescents; 25.1 %; 95 % CI 24.7-25.4 % for young adults; 33.3 %; 95 % CI 33.0-33.5 % for older adults). This disparity was reduced after adjusting for treatment type. For all ages, buprenorphine was more strongly associated with retention than naltrexone or psychosocial treatment. Adolescents who received buprenorphine were more than four times as likely to be retained in treatment (44.8 %; 95 % CI 40.6-49.0) compared to those who received psychosocial services (9.7 %; 95 % CI 8.8-10.8). Persons with commercial insurance were more likely to receive medication than those with Medicaid (73 % vs 36 %, (χ2 = 38,042.6, p < .001). CONCLUSIONS: Age disparities in six-month treatment retention are strongly related to age disparities in medication treatment. Results point to need for improved implementation of medication treatment for persons with OUD, regardless of age or insurance status.

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

The influence of acute varenicline administration on smoking and eating behavior in humans.

Varenicline (Chantix) is a novel smoking-cessation agent that acts at a number of nicotinic acetylcholine receptors. The aim of this study was to determine the behavioral effects of acute varenicline administration in human subjects. The effects of doses of varenicline (0.5, 1 and 2 mg), methylphenidate (40 mg; positive control) and placebo were assessed in 8 (7 males, 1 female) cigarette smokers. Staggered, double blind dosing was used to examine eating and smoking behavior during the peak effects of varenicline and methylphenidate. Starting at the published time to peak plasma levels of these drugs, subjects were allowed to smoke and eat ad libitum for 4 h. Acute varenicline was devoid of behavioral effects. Methylphenidate produced prototypical stimulant-like effects (e.g., increased smoking behavior; decreased caloric intake). The present results indicate that acute varenicline administration does not alter smoking behavior although the low number of subjects limits the ability to detect small effects. Future research should examine the effects of chronic varenicline on smoking and eating behavior in humans, particularly using operant techniques to determine whether varenicline alters the reinforcing effects of cigarettes and food in humans.

Adderall produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers.

RATIONALE: Adderall is currently used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) and is composed of a novel mixture of approximately 24% L-amphetamine and 76% D-amphetamine salts. There are, however, no investigations of the pharmacological effects of this combination in vivo. OBJECTIVES: The technique of high-speed chronoamperometry using Nafion-coated single carbon-fiber microelectrodes was used to study amphetamine-evoked dopamine (DA) release produced by Adderall, D-amphetamine, or D,L-amphetamine in the striatum of anesthetized male Fischer 344 (F344) rats. The amphetamine solutions were locally applied from micropipettes by pressure ejection. RESULTS: Local applications of Adderall resulted in significantly greater DA release signal amplitudes with prolonged time course of dopamine release and re-uptake as compared to D-amphetamine and D,L-amphetamine. CONCLUSIONS: These data support the hypothesis that the combination of amphetamine enantiomers and salts in Adderall has effects on DA release, which result in increased and prolonged DA release, compared to D- and D,L-amphetamine.

A pharmacological analysis of stimulant-induced increases in smoking.

RATIONALE: Stimulants increase tobacco smoking in healthy adults under controlled laboratory conditions. The mechanisms that mediate stimulant-induced increases in smoking are not known. OBJECTIVE: The purpose of the present experiment was to characterize the pharmacological specificity of stimulant-induced increases in smoking. We tested the effects of methylphenidate and atomoxetine on smoking behavior. Atomoxetine is a norepinephrine transport inhibitor that does not increase dopamine levels in the nucleus accumbens or striatum. If stimulant-induced increases in smoking result from an additive or synergistic effect of these drugs and nicotine on dopamine levels in the nucleus accumbens or striatum, methylphenidate but not atomoxetine should increase smoking. MATERIALS AND METHODS: Doses of methylphenidate (10, 20, and 40 mg) and atomoxetine (20, 40, and 80 mg) were tested once while placebo was tested twice in 12 cigarette smokers. One hour after ingesting drug, participants smoked ad libitum for 4 h. Measures of smoking included total cigarettes, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum, and food intake was calculated. RESULTS: Methylphenidate but not atomoxetine dose-dependently increased the number of cigarettes, puffs, and carbon monoxide levels. Methylphenidate and atomoxetine decreased food intake. CONCLUSIONS: The results of this experiment are consistent with the notion that stimulant-induced increases in smoking may result from an additive or synergistic effect of these drugs and nicotine on dopamine levels in the nucleus accumbens or striatum. Additional research is needed to more fully understand the pharmacological mechanisms that mediate the relationship between stimulant use and smoking.

Dopamine D4 receptor knockout mice exhibit neurochemical changes consistent with decreased dopamine release.

Dopamine D4 receptor (D4R) knockout mice (D4R-/-) provided for unique neurochemical studies designed to understand D4R contributions to dopamine (DA) regulation. In this study, post-mortem brain tissue content of DA did not differ between D4R+/+ and D4R-/- mice in the striatum (Str) or nucleus accumbens core (NAc). However, there was a significant decrease (82%) in the content of 3,4-dihydoxyphenylacetic acid (DOPAC), a major metabolite of DA, in the NAc of D4R-/- mice. Microdialysis studies performed in a region of brain spanning of the dorsal Str and NAc showed lower baseline levels of DA and a significant reduction in KCl-evoked overflow of DA in the D4R-/- mice. Baseline extracellular levels of DOPAC and homovanillic acid were also significantly lower in the D4R-/- mice. In vivo chronoamperometric recordings of KCl-evoked release of DA also showed decreased release of DA in the Str and NAc of the D4R-/- mice. These studies demonstrate a role of D4Rs in presynaptic DA regulation and support the hypothesis that alterations in D4Rs may lead to diminished DA function.

Cerebellar neurotransmission in attention-deficit/hyperactivity disorder: does dopamine neurotransmission occur in the cerebellar vermis?

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis following stimulant administration has also been repeatedly demonstrated. There is no well-characterized dopaminergic pathway that projects to the posterior-inferior cerebellar vermis, although the dopamine transporter (DAT) and tyrosine hydroxylase (TH) have been localized in the posterior-inferior vermis in the non-human primate by immunohistochemistry. We hypothesized that DA neurotransmission may occur in localized "hot spots" in the cerebellar vermis, and if so, that differences in such neurotransmission might be relevant to the pathophysiology of ADHD. To investigate this hypothesis, cerebellar tissue was obtained from rats and non-human primates. Catecholamines were extracted and analyzed using HPLC with coulometric detection. A regional gradient of norepinephrine (NE) and DA was found throughout the cerebellum with NE levels always roughly 10-40-fold higher than DA in both rats and monkeys. In addition, in vivo microdialysis studies were performed in the rat posterior-inferior cerebellar vermis in anesthetized animals. Significant NE overflow was observed over baseline following reverse microdialysis induced release by potassium or d-amphetamine. DA overflow was not observed over baseline for potassium stimulation, but was significant for d-amphetamine stimulation. These studies refute the hypothesis that DA neurotransmission normally occurs in the rat cerebellar vermis, but highlight that vermal DA is released by d-amphetamine. The presence of DAT may therefore allow for enhanced regulation of NE and not regulation of released DA.

A low dose of aripiprazole attenuates the subject-rated effects of d-amphetamine.

Despite increased reports of amphetamine abuse and dependence, a putative pharmacotherapy has yet to be identified. In a previous study from our laboratory, 20 mg aripiprazole, an atypical antipsychotic that has partial agonist activity at D(2) receptors, attenuated many of the behavioral effects of d-amphetamine. Aripiprazole (20 mg) also impaired performance on a computerized version of the DSST when administered alone, indicating that the attenuation observed may have been functional as opposed to receptor mediated. The present experiment was conducted to determine whether a lower dose of aripiprazole (10 mg) could acutely attenuate the discriminative-stimulus, subject-rated, and physiological effects of d-amphetamine (2.5-15 mg) without impairing performance as measured with a computerized version of the DSST. The results of the present experiment indicate that 10 mg aripiprazole attenuated some abuse-related behavioral effects of d-amphetamine and was generally devoid of effects, including significant performance impairment, when administered alone. These findings suggest that 10 mg aripiprazole would be a reasonable starting dose for the treatment of stimulant abuse and dependence. Future research should examine the effects of chronic aripiprazole administration in combination with methamphetamine or cocaine.

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans.

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential.

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans.

BACKGROUND: A medication for treating cocaine use disorder has yet to be approved. Laboratory-based evaluation of candidate medications in animals and humans is a valuable means to demonstrate safety, tolerability and initial efficacy of potential medications. However, animal-to-human translation has been hampered by a lack of coordination. Therefore, we designed homologous cocaine self-administration studies in rhesus monkeys (see companion article) and human subjects in an attempt to develop linked, functionally equivalent procedures for research on candidate medications for cocaine use disorder. METHODS: Eight (N=8) subjects with cocaine use disorder completed 12 experimental sessions in which they responded to receive money ($0.01, $1.00 and $3.00) or intravenous cocaine (0, 3, 10 and 30mg/70kg) under independent, concurrent progressive-ratio schedules. Prior to the completion of 9 choice trials, subjects sampled the cocaine dose available during that session and were informed of the monetary alternative value. RESULTS: The allocation of behavior varied systematically as a function of cocaine dose and money value. Moreover, a similar pattern of cocaine choice was demonstrated in rhesus monkeys and humans across different cocaine doses and magnitudes of the species-specific alternative reinforcers. The subjective and cardiovascular responses to IV cocaine were an orderly function of dose, although heart rate and blood pressure remained within safe limits. CONCLUSIONS: These coordinated studies successfully established drug versus non-drug choice procedures in humans and rhesus monkeys that yielded similar cocaine choice behavior across species. This translational research platform will be used in future research to enhance the efficiency of developing interventions to reduce cocaine use.

Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of D-amphetamine in humans.

The results of animal research suggest that the use of partial agonists at dopamine (DA) D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial agonist activity at D2 receptors. In this experiment, seven human participants with a history of nontherapeutic stimulant use learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (ie > or =80% correct responding on four consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with aripiprazole (0 and 20 mg), were assessed. D-Amphetamine alone functioned as a discriminative stimulus, produced prototypical subject-rated drug effects (eg increased ratings of Active, Alert, Energetic) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion D-amphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of D-amphetamine, as well as some of the subject-rated drug effects. These data are consistent with previous preclinical findings and suggest that DA partial agonists deserve further evaluation as potential pharmacotherapies in the management of stimulant dependence. Future studies should investigate the ability of aripiprazole or related compounds to attenuate the behavioral effects of stimulants associated with a greater degree of dependence, such as methamphetamine or cocaine, in dependent individuals.

Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core.

RATIONALE: Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (D: -amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% L: -amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for D: -amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between D: -amphetamine and L: -amphetamine have not been well characterized. OBJECTIVES: To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes. RESULTS: The presence of L: -amphetamine in the D: ,L: -amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The D: ,L: -amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When L: -amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of D: ,L: -amphetamine. CONCLUSIONS: These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that L: -amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals.

Reinforcing effects of modafinil: influence of dose and behavioral demands following drug administration.

RATIONALE: The reinforcing effects of stimulant drugs are modulated by behavioral demands following drug administration. OBJECTIVE: The objective of this study was to assess the reinforcing effects of modafinil, a drug with purportedly low abuse potential, under different behavioral demands using a modified progressive-ratio procedure. METHODS: The reinforcing effects of oral modafinil (0, 100, 200, and 400 mg) were assessed in six healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session), and the order of performance and relaxation sessions was constant within a dose condition. RESULTS: Modafinil significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Modafinil produced comparable stimulant-like subjective ratings under both the performance and relaxation conditions. CONCLUSION: The findings of the present experiment demonstrate that modafinil can function as a reinforcer and that the reinforcing effects of modafinil are influenced by behavioral demands following drug administration, similar to those of other stimulant drugs.