Discriminative stimulus properties of cocaine and d-amphetamine,and antagonism by haloperidol: A comparative study

This paper presents a comparative study of the discriminative stimulus properties of cocaine and d-amphetamine in the rat. Using a discrete-trial, food-reward, two-lever drug discrimination procedure, one group of rats (n = 7) were trained to discriminate 10 mg/kg cocaine from saline, whereas 1.25 mg/kg d-amphetamine served as a cue to a second group (n = 6). Following training, stimulus generalization gradients were determined for cocaine and d-amphetamine in both groups, and so were the antagonistic effects of haloperidol vs the training drug conditions. The results indicate that the acquisition of discrimination proceeded at a comparable rate in the two groups. In both groups, d-amphetamine was about 5 times more potent than cocaine, and individual threshold doses for the two drugs showed a significant correlation. Haloperidol appeared equally effective in antagonizing 1.25 mg/kg d-amphetamine and 10 mg/kg cocaine. These findings converge to suggest that to a large extent the cueing properties of d-amphetamine and cocaine are similar.     

μ-, δ- and κ-opioid receptor agonists do not alter the discriminative stimulus effects of cocaine or d-amphetamine in rats

Opioid receptor agonists can modulate the activity of dopamine neurons and could therefore, modify the behavioral effects of drugs that act through the dopamine systems, such as d-amphetamine and cocaine. We tested the ability of agonists selective for the μ- (morphine, methadone, buprenorphine, nalbuphine and heroin), δ- (DPDPE and SCH32615), and κ- (U69593 and bremazocine) opioid receptors to alter the discriminative stimulus effects of d-amphetamine and cocaine in rats. Separate groups of male Sprague-Dawley rats were trained to discriminate between 1.0 mg/kg d-amphetamine or 10 mg/kg cocaine from saline. Rats were pretreated with vehicle or an agonist, then dose-response curves for d-amphetamine or cocaine were generated. None of the opioid agonists changed significantly the ED₅₀ values of cocaine and d-amphetamine. As a positive control, we tested for antagonism of these effects by the D1 and D2 dopamine receptor antagonists, SCH23390 and eticlopride, respectively. Both antagonists at least partially attenuated the stimulus effects of both training drugs. Our results suggest that any modulation of dopaminergic neurotransmission by the agonists tested in the present study is not sufficient to affect the stimulus effects of d-amphetamine and cocaine in rats.     

Prolonged Attenuation of the Reinforcing Strength of Cocaine by Chronic d-Amphetamine in Rhesus Monkeys

Chronic treatment with the indirect dopamine agonist d-amphetamine can reduce cocaine use in clinical trials and, in preclinical studies in laboratory animals, attenuates daily cocaine self-administration. The present study extended previous results to conditions designed to reflect a more clinically relevant experience of cocaine exposure and d-amphetamine treatment. Each morning, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement. After determining a dose-response curve for cocaine (0.003–0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule of reinforcement in the evening, cocaine self-administration sessions were suspended and d-amphetamine (0.01–0.056 mg/kg/h, i.v.) was administered continuously for at least 24 days, except during cocaine self-administration sessions, which were conducted using the PR schedule once every 8 days. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was redetermined. Cocaine- and food-maintained responding were also examined after discontinuation of d-amphetamine. Although individual differences in sensitivity were observed, d-amphetamine produced selective, qualitatively similar decreases in the reinforcing strength of cocaine in all monkeys that persisted at least 4 weeks. Moreover, cocaine dose-effect curves were shifted downward and/or to the right. For 2 weeks following discontinuation of d-amphetamine treatment, the reinforcing strength of cocaine varied within and across individuals, however, on the whole no increased sensitivity was apparent. These data provide further support for the use of agonist medications for cocaine abuse, and extend the conditions under which such treatment is successful to those that incorporate clinically relevant patterns of cocaine use and drug treatment.     

Increased sensitivity to d- and l-amphetamine action after midbrain raphe lesions as measured by locomotor activity

This study examined the effects of d- and l-amphetamine on locomotor activity and stereotyped behavior in control rats and rats with lesions in the raphe nuclei (RN) and dorsolateral tegmentum (DLT). Raphe nuclei lesions produced a large (93%) and selective depletion of the telencephalic content of serotonin and an enhancement of both d- and l-amphetamine action on locomotor activity that was characterized by a shift in the dose-effect curve to the left of controls. The ED50 for the locomotor increasing effects of both d- and l-amphetamine was significantly reduced by the RN lesions to approximately one-third of control values. In addition, RN lesions significantly increased the maximum levels of locomotor responding to d- but not l-amphetamine. Finally, rats with RN lesions demonstrated a significantly greater incidence of stereotyped behavior at lower dosages of d- but not l-amphetamine than did controls. Dorsolateral tegmentum lesions that produced a selective but small (54%) decrease in the telencephalic content of norepinephrine had no effect on either d- or l-amphetamine action.     

Neurochemical similarities between d,l-cathinone and d-amphetamine

Cathinone, the principal alkaloid of Khat, was compared to the psychomotor stimulant d-amphetamine on a number of neurochemical measures. Like d-amphetamine, d,l-cathinone released and blocked the uptake of tritiated dopamine (DA) in synaptosomal preparations. In addition, repeated high doses of d,l-cathinone produced long-lasting DA depletions in various rat brain regions and decreased the number of synaptosomal DA uptake sites in a manner similar to that seen after repeated d-amphetamine administration. Importantly, this DA neurotoxic effect of d,l-cathinone, like that of d-amphetamine, is selective since regional brain levels of norepinephrine (NE) or serotonin (5-HT) are not altered on a long-term basis by repeated administration of d,l-cathinone. These findings are discussed with reference to the current practice of Khat leaf chewing by people in north-eastern Africa.     

Food deprivation and stimulant self-administration in rats: differences between cocaine and d-amphetamine

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.     

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

Background:

Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown.

Methods:

This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.

Results:

In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine.

Conclusions:

Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.     

Comparative effects of d-amphetamine,l-amphetamine and methylphenidate on mood in man

The comparative effects of d-amphetamine, l-amphetamine, and methylphenidate were assessed in 16 normal subjects, using a double-blind, crossover placebo-controlled design. Within the dose range tested, the efficacy ratio of d-amphetamine: l-amphetamine was about 2:1, and graphic presentation of dose response scores indicated a relatively small difference in potency between the amphetamine isomers. Methylphenidate was intermediate in efficacy between d-amphetamine and l-amphetamine. The efficacy ratios for d-amphetamine: l-amphetamine on increasing euphoric mood in man were similar to the previously reported ratios of these two isomers in inducing or exacerbating psychosis in humans. These findings do not support the suggestion, made by Snyder and others, that the differential effects of d-amphetamine vs. l-amphetamine on a specific type of behavior in man could be utilized to infer the predominance of noradrenergic vs. dopaminergic mediation of amphetamine's effects on this behavior.This research was begun when both authors were associated with the Illinois State Psychiatric Institute     

A comparison of drug-seeking behavior maintained by d-amphetamine, l-deprenyl (selegiline), and d-deprenyl under a second-order schedule in squirrel monkeys

l-Deprenyl (selegiline) is used in the treatment of Parkinson’s disease and has been proposed as an aid for cigarette smoking cessation and a treatment for psychostimulant abuse. l-Deprenyl is metabolized in the body to l-methamphetamine and l-amphetamine, suggesting that it may have abuse potential. The current study assessed whether l-deprenyl or its isomer would maintain drug-seeking behavior on a second-order schedule and whether l-deprenyl would alter drug-seeking behavior maintained by d-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash, and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of d-amphetamine (0.56 mg/kg), administered over a 2-min period at the end of the session. When responding was stable, saline or different i.v. doses of d-amphetamine (0.3–1.0 mg/kg), l-deprenyl (0.1–10.0 mg/kg), and d-deprenyl (0.1–3.0 mg/kg) were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg l-deprenyl intramuscularly 30 min prior to d-amphetamine baseline sessions. d-Amphetamine maintained high rates of drug-seeking behavior on the second-order schedule. d-Deprenyl maintained high rates of drug-seeking behavior similar to d-amphetamine. l-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with l-deprenyl failed to alter drug-seeking behavior maintained by d-amphetamine. These results indicate that d-deprenyl, but not l-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behaviors are actively maintained by d-amphetamine, l-deprenyl, at doses that specifically inhibit type B monoamine oxidase, may not be effective as a treatment.     

Acute neuroactive drug exposures alter locomotor activity in larval zebrafish

As part of the development of a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae by assessing the acute effects of prototypic drugs that act on the central nervous system. Initially, we chose ethanol, d-amphetamine, and cocaine, which are known, in mammals, to increase locomotion at low doses and decrease locomotion at higher doses. Wild-type larvae were individually maintained in 96-well microtiter plates at 26 °C, under a 14:10 h light:dark cycle, with lights on at 0830 h. At 6 days post-fertilization, ethanol (1–4% v/v), d-amphetamine sulfate (0.1–20.0 µM) or cocaine hydrochloride (0.2–50.0 µM) were administered to the larvae by immersion. Beginning 20 min into the exposure, locomotion was assessed for each animal for 70 min using 10-minute, alternating light (visible light) and dark (infrared light) periods. Low concentrations of ethanol and d-amphetamine increased activity, while higher concentrations of all three drugs decreased activity. Because ethanol effects occurred predominately during the light periods, whereas the d-amphetamine and cocaine effects occurred during the dark periods, alternating lighting conditions proved to be advantageous. These results indicate that zebrafish larvae are sensitive to neuroactive drugs, and their locomotor response is similar to that of mammals.     

Dissociating effects of cocaine and <Emphasis Type="Italic">d</Emphasis>-amphetamine on dopamine and serotonin in the perirhinal,entorhinal, and prefrontal cortex of freely moving rats

Rationale Neuroimaging studies with humans showed widespread activation of the cortex in response to psychostimulant drugs. However, the neurochemical nature of these brain activities is not characterized. Objective The aim of the present study was to investigate the effects of cocaine and d-amphetamine on dopamine (DA) and serotonin (5-HT) in cortical areas of the hippocampal network in comparison to the prefrontal cortex (PFC). Materials and methods We conducted in vivo microdialysis experiments in behaving rats measuring DA and 5-HT in the perirhinal cortex (PRC), entorhinal cortex (EC), and PFC, after application of cocaine (0, 5, 10, 20 mg/kg; i.p.) or d-amphetamine (0, 0.5, 1.0, 2.5 mg/kg; i.p.). Results Cocaine and d-amphetamine dose-dependently increased DA and 5-HT levels in the PRC, EC, and PFC. A predominant DA response to d-amphetamine was only found in the PFC, but not in the PRC and EC. Cocaine increased DA and 5-HT to an equal extent in the PFC and PRC but induced a predominant 5-HT response in the EC. When comparing the neurochemical responses between the drugs at an equal level of behavioral activation, cocaine was more potent than d-amphetamine in increasing 5-HT in the PFC, while no differences were found in the PRC or EC or in the DA responses in all three cortical areas. Conclusions We conclude that cocaine and d-amphetamine increase DA and 5-HT levels in PRC and EC largely to the same extent as in the PFC.     

Effects of stimulants,anorectics, and related drugs on schedule-controlled behavior

The effects of nine drugs were studied in rats responding under either fixed-ratio 30 (FR-30) or fixed-interval 2-min (FI-2) schedules of food presentation. All the drugs decreased average rates of responding under both schedules in a dose-related manner, with apomorphine and clonidine being the most potent and caffeine the least potent.d-Amphetamine was about three times more potent thanl-amphetamine in decreasing responding under the FR schedule, while the two isomers were equipotent in reducing the average response rates under the FI schedule. A 10 mg/kg dose of fenfluramine decreased responding for two to three days after administration, but this treatment did not produce long-lasting changes in control performance or in the effects of the serotonergic drugs quizapine andd-paramethoxyamphetamine. The effects of the drugs on the local rates of responding during the FI may be divided into three categories: (1) those drugs that increased low rates of responding and decreased high rates of responding (rate-dependent effects) at dosages that did not markedly decrease the average response rates (d-amphetamine, methylphenidate, and cocaine); (2) those that produced rate-dependent effects only at dosages that markedly reduced average response rates (fenfluramine, quipazine, and clonidine); and (3) those that did not produce clear rate-dependent effects at any dose tested (l-amphetamine, apomorphine, and caffeine). These behavioral results are discussed in relation to their known biochemical effects on brain catecholamine and serotonin systems.     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

A comparison of the kinetics of d- and l-amphetamine in the brain of isolated and aggregated rats

The kinetics of d- and l-amphetamine were investigated in isolated and aggregated male rats. The i.p. injection of 15 mg/kg of d- or l-¹⁴C-amphetamine was followed by the determination of drug concentrations in the cerebral cortex, hypothalamus, medulla oblongata-pons, cerebellum, striatum, hippocampus, and the whole brain after solvent extraction.In isolated rats, the disappearance curves of the labelled amphetamines were monoexponential. The half-lives of d- and l-amphetamine in whole brain were 1.2±0.1 and 1.3±0.1 h, respectively. In whole brains of aggregated rats the disappearance curves were biexponential (half-lives: d-amphetamine, 0.9±0.1 and 2.3±0.2 h; l-amphetamine, 0.7±0.1 and 2.3±0.1 h).For the brain areas of isolated rats, the elimination curves of amphetamines were monoexponential and the half-lives of d- and l-amphetamine were almost identical. In aggregated rats certain differences were observed. d-Amphetamine was eliminated from the striatum and hippocampus as a biexponential function, and l-amphetamine elimination was biphasic only in the striatum. In other brain regions both d- and l-amphetamine were eliminated as a monoexponential function. The half-lives of d-amphetamine in different brain areas were, however, shorter than those of the l-isomer.The observed differences between d- and l-amphetamine kinetics in brain areas of isolated and aggregated rats may explain certain aspects of the pharmacological activities of these drugs.     

Effect of d- and l-amphetamine on rat plasma prolactin levels

Although d- and l-amphetamine had no effect on plasma prolactin levels in untreated male rats, both d- and l-amphetamine reversed the increase in plasma prolactin levels produced by reserpine and 5-hydroxytryptophan (5-HTP). Only d-amphetamine significantly reversed the effect of alpha-methylparatyrosine (AMPT) on plasma prolactin levels. This reversal is probably due to a direct or indirect dopamine agonist effect of amphetamine, rather than to an effect on norepinephrine. This conclusion is based on the finding that apomorphine, a direct-acting dopamine agonist, reversed the reserpine-induced increase in prolactin secretion, while clonidine, a direct-acting alpha-adrenergic agonist, potentiated the reserpine-induced stimulation of prolactin secretion. The effect of d-amphetamine on the increase in plasma prolactin levels produced by reserpine, 5-HTP, or AMPT was always greater than that of the l-isomer, suggesting that the d-isomer has a more profound effect on dopaminerelease or neuronal reuptake, or both, than l-amphetamine. Chronic administration of d-amphetamine prior to reserpine did not inhibit the ability of d-amphetamine to reverse the reserpine-induced increase in plasma prolactin. Chronic administration of AMPT did not enhance the ability of d-amphetamine to reverse the AMPT-induced increase in plasma prolactin.     

In vivo monoamine oxidase inhibition by d-amphetamine

In vitro, d- and l-amphetamine (AMPH) are reversible monoamine oxidase (MAO) type A inhibitors, the d-form being approximately five times more potent. Experiments were conducted in rats to determine whether MAO inhibition occurs in vivo. d-AMPH was more effective than l-AMPH at decreasing striatal 3,4-dihydroxyphenylacetic acid (DOPAC). However, assays of striatal MAO activity following administration of AMPH in vivo failed to show MAO inhibition. In other experiments, rats were treated with d-AMPH (zero time) followed by phcnelzine (1 hr), an irreversible MAO inhibitor, and were killed at 25 hr. MAO activity was determined in vitro for the striatum and the rest of the brain using serotonin (MAO-A) and phenylethylaminc (MAO-B) as substrates. d-AMPH provided significant protection against MAO-A inhibition by phenelzine, whereas l-AMPH and cocaine (used instead of AMPH) were without effect. d-AMPH failed to protect against MAO-B inhibition by phenelzine. Thus, d-AMPH appears to inhibit reversibly MAO type A in vivo. However, using the same ‘protection protocol’, d-AMPH failed to oppose phenelzine-induced lowering of striatal DOPAC. Experiments were undertaken to determine whether the protective effect of d-AMPH on MAO type A would influence striatal dopamine depletion by RO4-1284, a rapidly acting reserpine-like agent. RO4-1284-induced depletion of dopamine was inhibited by phenelzine. Prior treatment with d-AMPH reduced significantly the protective effect of phenelzine, suggesting reversible, intraneuronal MAO inhibition by d-AMPH in vivo. The possible neuronal mechanisms for these events are discussed.     

Discriminative stimulus and reinforcing effects of <Emphasis Type="Italic">p</Emphasis>-fluoro-<Emphasis Type="SmallCaps">l</Emphasis>-deprenyl in monkeys

Rationale para-Fluoro-l-deprenyl (Fludepryl), a halogenated derivative of l-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. Objectives p-Fluoro-l-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. Methods One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. Results Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-l-deprenyl. l-Deprenyl and the metabolites of p-fluoro-l-deprenyl, p-fluoro-l-amphetamine, and p-fluoro-l-methylamphetamine were more potent, producing full generalization at doses of 1.0–3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-l-deprenyl up to 1.0 mg/kg. However, p-fluoro-l-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-l-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or d-amphetamine. Conclusions p-Fluoro-l-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, l-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.     

Effects of chronic<Emphasis Type="Italic"> d</Emphasis>-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys

Rationale. d-Amphetamine is a candidate agonist medication for the treatment of cocaine dependence, and evaluation of d-amphetamine effects on abuse-related effects of cocaine in preclinical assays is warranted. Objective. This study was designed to assess the effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys. The effects of schedule manipulations on cocaine and food-maintained responding were also examined for comparison with d-amphetamine effects. Methods. Key-press responding under a progressive-ratio schedule resulted in the delivery of cocaine (0.032 mg/kg per injection) or 1 g food pellets. The effect of manipulating cocaine dose (saline, 0.001–0.1 mg/kg per injection) or the number of food pellets delivered (0, 1 and 4 pellets) was determined. Subsequently, three schedule parameters were manipulated: (1) starting ratio value, (2) increments of the ratio progression, and (3) duration of post-reinforcer time-outs when the ratio value was constant. Finally, the effects of 10-day treatment with d-amphetamine (0.01–0.1 mg/kg per hour) were examined. Results. Break points increased as a function of cocaine dose or the number of food pellets, and similar break points were maintained by delivery of 0.032 mg/kg per injection cocaine and 1 food pellet. Manipulation of schedule parameters produced similar effects on responding maintained by cocaine (0.032 mg/kg per injection) or food (1 pellet). In contrast, d-amphetamine produced a dose-dependent decrease in cocaine-maintained responding and had less consistent effects on food-maintained responding. Conclusions. These results are consistent with the hypothesis that chronic treatment with d-amphetamine decreases cocaine self-administration in rhesus monkeys, possibly by attenuating the reinforcing effects of cocaine. Electronic Publication     

Studies on electroencephalogram (EEG) in rats suggest that moderate doses of cocaine ord-amphetamine activate D1 rather than D2 receptors

The effects of cocaine andd-amphetamine, two psychomotor stimulant drugs with pronounced addictive properties, on the electroencephalogram (EEG) of rats were studied by telemetric recordings from the skull in non-anesthetized, freely moving rats. The electrocorticogram (ECoG) was recorded. Both cocaine (10 mg/kg IP) andd-amphetamine (0.4 mg/kg IP) produced a desynchronization, characterized by a general lowering in power in all of the frequency bands. These effects of both drugs were mimicked by the selective agonist at D₁ receptors SK&F 38393 (3 mg/kg SC) and were reversed by the antagonist at D₁ receptors SCH 23390 (0.2 mg/kg IP) but not influenced by haloperidol (0.1 mg/kg IP) in a dose which is likely to block D₂ rather than D₁ receptors. These doses of cocaine ord-amphetamine did not produce stereotyped behaviour and slight, if any, increases in locomotor activity only. Large doses of cocaine (30 mg/kg IP) ord-amphetamine (4 mg/kg IP) produced stereotyped behaviour and alterations in EEG which are, based on previous own studies, characteristic for additional stimulation of D₂ receptors. This was manifest in a selective increase in power of the alpha-1 band. A similar effect was also produced by the agonist both at D₁ and D₂ receptors, apomorphine (0.5 mg/kg SC). These results suggest that moderate, but probably rewarding doses of cocaine ord-amphetamine mainly activate D₁ dopamine receptors. This activation might be relevant for the rewarding properties of these drugs.     

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.