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The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.

A series of experiments was conducted to assess the sensitivity of the acoustic startle response to chronic morphine administration and naloxone-precipitated withdrawal. Rats were implanted with two subcutaneous pellets containing either 75 mg each of morphine or containing only placebo. In experiment 1, withdrawal induced by 0.05-0.2 mg/kg naloxone dose-dependently decreased the magnitude of the startle response. Physical dependence was confirmed by a naloxone-induced acute weight loss seen in morphine-implanted rats, but naloxone had no effect on startle or body weight in non-dependent animals. In experiment 2, a modified procedure with fewer trials per session and fewer test days was employed. Naloxone (0.2 mg/kg) given 4-5 days after implantation induced large startle-response decreases in morphine-dependent rats while having no effect in placebo-implanted rats. Post-naloxone saline tests revealed no significant differences in startle between morphine and placebo groups. Startle scores were significantly higher in morphine-implanted rats than in placebo rats during a saline test given 3 days following pellet implantation. In a separate group of animals, however, acute IP injections of morphine from 0.3-10 mg/kg had no significant effect on startle amplitude. The effect of repeated pairings of withdrawal with the startle environment was assessed in experiment 3. Morphine-dependent rats startled significantly less if naloxone injections were given before the startle session than if they were administered 4 h later. Conditioned withdrawal effects, expressed during a final test session when all rats received saline, were observed for the body-weight measure but not for the startle response.(ABSTRACT TRUNCATED AT 250 WORDS)

Two novel phenyltropane analogs of cocaine, 3 beta-(4-chlorophenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-31) and 3 beta-(4-methylphenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-32), were evaluated for cocaine-like discriminative stimulus effects in rats. Two groups of rats were trained to discriminate 10 mg/kg cocaine from saline using a standard 2-lever discrimination procedure with correct-lever responding reinforced under a fixed-ratio 20 schedule of food reinforcement. One group of rats was used to evaluate RTI-COC-31 and the unsubstituted-3 beta-phenyltropane reference compound WIN 35,065-2 in substitution tests. Another group of rats was used to evaluate RTI-COC-32. For purposes of comparison, a cocaine dose-effect curve was also determined in each group. Both RTI-COC-31 and RTI-COC-32, as well as WIN 35,065-2, substituted completely for cocaine. RTI-COC-31 was 26.8-fold and RTI-COC-32 was 6-fold more potent than cocaine for producing cocaine-lever responding. The potent cocaine-like effects of the RTI analogs in vivo correspond with their high affinities for a cocaine recognition site on the dopamine transporter, providing further evidence that this site may mediate behavioral effects of cocaine relevant to its abuse.

Prepulse inhibition of acoustic or tactile startle (PPI), a form of sensorimotor gating, occurs when a weak prestimulus precedes a startling stimulus and inhibits the startle response. Studies of PPI have revealed that schizophrenic patients exhibit a deficit in this form of sensorimotor gating. In rats, PPI is blocked by dopamine agonists such as apomorphine or quinpirole, effects that are antagonized by haloperidol. Phencyclidine (PCP) has been suggested as a possible model psychotogen and produces a deficit in PPI that is similar to what is observed in schizophrenic patients. Dizocilpine is an anticonvulsant drug that, like PCP, is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA)-induced excitations in brain and also disrupts PPI. In the present study, PPI of acoustic and tactile startle was measured in male Sprague-Dawley rats after injections of 5.0 mg/kg PCP with or without pretreatment with 0.02 or 0.1 mg/kg haloperidol, or with 0.5 mg/kg dizocilpine with or without pretreatment with 0.1 mg/kg haloperidol. The 0.1 mg/kg dose of haloperidol blocks the effects of apomorphine or quinpirole on PPI in rats. Startle was elicited by noise bursts at 105 or 120 dB or by air-puffs (tactile) and was inhibited by 75 or 85 dB prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals. Both NMDA antagonists significantly reduced the amount of PPI induced by the 75 dB prestimulus, independently of the level of startle responses elicited by the startle stimuli. Haloperidol did not block the disruption of PPI induced by either PCP or dizocilpine. In addition, PCP was unable to block PPI when the 85 rather than the 75 dB prepulse was used to inhibit either acoustic or tactile startle. These results confirm that putative NMDA antagonists inhibit sensorimotor gating in rats and suggest that these effects are not mediated by the activation of central dopamine systems.

Pre-pulse inhibition of the acoustic startle response is a model of reflex modification which is thought to reflect sensorimotor gating mechanisms and is sensitive to disruption by non-competitive N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine. The effects of two competitive antagonists, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) (3-30 mg/kg) and cis-4-phosphonomethyl-2-piperidine-carboxylate (CGS 19755) (1-10 mg/kg), the non-competitive NMDA antagonist dizocilpine (0.5 mg/kg), and NMDA itself (1-30 mg/kg) were studied in the pre-pulse inhibition model. Rats were exposed to sessions in which 122 dB[A] startle-eliciting stimuli were presented either alone or preceded by weak 80 dB[A] prepulses with durations of 3, 10 and 30 ms, which under control conditions reduced the magnitude of the startle response. Neither NPC 12626 nor CGS 19755 produced disruption of pre-pulse inhibition as normally observed with phencyclidine-like drugs. NMDA also did not affect pre-pulse inhibition. As in previous experiments, dizocilpine produced a significant disruption of pre-pulse inhibition at all pre-pulse durations. These data suggest that actions at the phencyclidine binding site, and not the NMDA site, are responsible for the disruption of pre-pulse inhibition by phencyclidine-like drugs, and support reports of differences in the behavioral effects of competitive and noncompetitive NMDA antagonists. The effects of phencyclidine-like drugs on pre-pulse inhibition may represent a useful pharmacological model of schizophrenia-like cognitive deficits.

The discriminative stimulus effects of phencyclidine (PCP), pentobarbital and the competitive N-methyl-D-aspartate antagonist 3-([+/-]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) were examined in rats trained to discriminate PCP from saline under a 2-lever, food-maintained operant schedule. Dose-response curves were obtained for all three drugs at a PCP training dose of 1.25 mg/kg; subsequently, rats were retrained to discriminate either 0.56 or 3.0 mg/kg PCP. The dose-response to PCP was not substantially changed by raising or lowering the training dose. However, doses of pentobarbital and CPP produced augmented levels of substitution when the training dose was lowered and decreased substitution when it was raised. The changes in PCP training dose were, therefore, effective in either diminishing or amplifying the pharmacological specificity of the PCP stimulus. Under conditions where specificity was high (high training dose), neither pentobarbital (0.1-17 mg/kg) nor CPP (1-17 mg/kg) produced appreciable PCP-like stimulus effects, supporting evidence that competitive NMDA antagonists may be no more PCP-like than are barbiturates. These data provide additional evidence for differences in the behavioral effects of noncompetitive and competitive NMDA antagonists.

Effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) and competitive antagonists 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) were studied in 6 squirrel monkeys trained under a multiple schedule of unpunished and punished lever pressing. PCP (0.03-0.3 mg/kg, IM) failed to produce increases in punished responding, even at doses that produced extreme response-rate decreases in nonpunishment components. Similarly, CPP (1-17 mg/kg) and NPC 12626 (3-30 mg/kg) did not produce increases in punished responding at any dose tested. Repeated administration of NPC 12626 (17 mg/kg) for 4 consecutive days did not result in increased rates of punished responding. The benzodiazepine anxiolytic midazolam (0.3 mg/kg) and, to a lesser extent, the barbiturate pentobarbital (5.6 mg/kg), produced increases in punished responding in the same subjects at doses that did not markedly affect unpunished responding. Coadministration of PCP (0.03 mg/kg) with doses of midazolam ranging from 0.03-3 mg/kg did not produce changes in the midazolam dose-response curve for either unpunished or punished responding. These results fail to support findings in rats that NMDA antagonists produce antipunishment effects similar to those of benzodiazepine anxiolytics.

Prepulse inhibition of the acoustic startle response is a form of reflex modification known to be sensitive to drugs and to subtle procedural manipulations. The present study examined the importance of prepulse length and prepulse-pulse interval in the expression of prepulse inhibition and its modification by the noncompetitive N-methyl-D-aspartate antagonist, ketamine. In contrast to a previous report, ketamine disrupted prepulse inhibition at doses of 5.6 and 10 mg/kg when its short time course was taken into consideration. In a second experiment, the amount of prepulse inhibition was found to be directly related to prepulse length, with prepulse inhibition produced by shorter prepulse durations slightly more sensitive to disruption by ketamine. A third experiment examined prepulse-pulse time intervals (30-2000 ms). While prepulse inhibition produced by prepulses occurring 60-500 ms before the startle stimulus was disrupted by 10 mg/kg of ketamine, prepulses preceding the startle stimulus by only 30 ms produced either no effect or slight prepulse facilitation under control conditions, and significant prepulse facilitation when ketamine was administered. A fourth experiment examined the time course of prestimulus modification by continuous lead stimuli, ranging in onset from 15 to 75 ms before the startle stimulus. Prepulse facilitation, when observed, tended to occur in earlier portions of the session and was enhanced by ketamine. These results suggest that prestimulus modification of the startle reflex has important parametric and experiential determinants that may influence the effects of drugs. Some of these temporal determinants may have relevance to sensorimotor function in schizophrenia.

The reinforcing effects of (+/-)-cis-2-Amino-4-methyl-5-phenyl-2-oxazoline (4-methylaminorex) were determined in two models of intravenous drug self-administration in primates. In baboons, lever pressing was maintained under a fixed-ratio (FR) 80- or 160-schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections per day. Vehicle or 4-methylaminorex doses were substituted for cocaine for a period of 15 or more days. One of the two 4-methylaminorex doses evaluated (0.32 mg/kg per injection) maintained self-administration behavior above vehicle control levels in all four animals. This dose of 4-methylaminorex maintained cyclic patterns of self-injection behavior across days and produced signs of psychomotor stimulant toxicity. In rhesus monkeys, 4-methylaminorex (0.0003-0.1 mg/kg per injection) was made available to animals trained to self-administer cocaine (0.01 or 0.033 mg/kg per injection) under an FR 10 schedule of reinforcement during daily 1-h sessions. Each of the three monkeys self-administered at least two doses of 4-methylaminorex at rates exceeding those maintained by vehicle injections. Taken together with reports of recreational abuse of 4-methylaminorex, the present results indicate that this drug has a potential for abuse similar to that of other psychomotor stimulants.

Studies of prepulse inhibition and habituation of startle responses elicited by intense stimuli provide some unusual opportunities for cross-species explorations of attentional deficits characteristic of schizophrenic patients. Schizophrenic patients exhibit deficits in both the prepulse inhibition of startle and the habituation of startle. The behavioral plasticity of startle responses and the comparability of the test paradigms used in rats and humans greatly facilitates the development of animal models of specifiable behavioral abnormalities in schizophrenic patients. This review describes two such examples of parallel animal and human models, one involving sensorimotor gating and the other examining behavioral habituation. Evidence is presented supporting the involvement of mesolimbic dopaminergic systems in the modulation of prepulse inhibition or sensorimotor gating and the importance of central serotonergic systems in the habituation of startle.

Prepulse inhibition of acoustic startle is deficient in schizophrenic patients and in animals injected with either direct or indirect dopamine (DA) agonists. The present experiments confirmed the hypothesis that the dopaminergic blockade of prepulse inhibition is attributable to the activation of D2 DA receptors. After systemic administrations of the D1 agonist SK&F 38393, the D2 agonist quinpirole, or a combination of the two, rats were tested for prepulse inhibition of the startle response by presenting acoustic stimuli or acoustic stimuli preceded by weak prepulses that inhibit startle. Although the D1 agonist SK&F 38393 had no effect on prepulse inhibition [0.3 to 30.0 mg/kg (1.03 to 102.82 mumols/kg)], the D agonist, quinpirole, blocked prepulse inhibition at doses of 0.3 mg/kg (1.17 mumols/kg) and 0.9 mg/kg (3.51 mumols/kg). Lower doses of quinpirole, 0.03 mg/kg (0.12 mumols/kg) and 0.1 mg/kg (0.39 mumols/kg), were ineffective. When an ineffective dose of quinpirole (0.1 mg/kg) was coadministered with 10.0 mg/kg SKF 38393, prepulse inhibition was reduced relative to saline controls. This reduction of prepulse inhibition is consistent with the synergistic effect of D1 and D2 DA receptor stimulation noted in studies of dopaminergic influences on stereotyped behavior in rats. These findings confirm that a disruption of sensorimotor gating results from D2 dopaminergic stimulation in the rat and extend the applicability of this animal model for the similar behavioral deficits exhibited by schizophrenic patients.

Separate experiments conducted in two different laboratories assessed the importance of the prepulse intensity in the ability of apomorphine to reduce prepulse inhibition of acoustic startle responses. Rats were presented with noise bursts alone or noise bursts 100 ms after presentation of prepulse stimuli ranging from 70 to 85 or 90 dB. Throughout testing, the background noise was maintained at 65 dB. In both laboratories, apomorphine markedly decreased the absolute magnitude of prepulse inhibition when the prepulse stimuli were no more than 10 dB above the background. With more intense prepulse stimuli, apomorphine had no significant effect on prepulse inhibition. Hence, apomorphine does not interfere with the inhibitory process which actually mediates prepulse inhibition, but appears to affect the detectability of the prepulse.

A potentiated whole-body startle response was produced in rats by pairing intense acoustic stimuli with a light (conditional stimulus) formerly presented contiguously with electric shock. Administration of the selective serotonin (5-HT) 1A ligand 8-hydroxy-2-(di-n-propylamino)tetralin (0.125 and 0.5 mg/kg) blocked the potentiation of startle induced by the conditional stimulus. 1-[3-Chlorophenyl]piperazine, a non-anxiolytic 5-HT1B/1C agonist, did not block potentiated startle, even at a dose (1.0 mg/kg) that induced significant overall decreases in startle amplitude. The non-benzodiazepine anxiolytics buspirone (1.25-5.0 mg/kg), gepirone (3.0-10.0 mg/kg) and the related 5-HT1A ligand ipsapirone (1.0-10.0 mg/kg) blocked potentiated startle, though effects of the non-selective serotonin antagonist methysergide (0.3-10.0 mg/kg) fell short of significance. These data support a role for the 5-HT1A binding site in the anti-anxiety effects of buspirone and related compounds over a range of behavioral procedures.

Under several behavioral procedures, such as punished responding and drug discrimination, the effects of the atypical anxiolytic buspirone are similar to those of its analogue gepirone, and to those of the 5-HT1A receptor agonist 8-OH-DPAT. Similarities in the effects of these compounds occur despite the fact that buspirone produces strong dopaminergic actions, whereas both gepirone and 8-OH-DPAT effects mainly appear to be serotonergically mediated. When keypeck responding of pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixed ratio schedule of food presentation, responding under both the fixed-interval and fixed-ratio schedules was decreased over a range of buspirone doses (0.3-5.6 mg/kg). As has been reported with many antipsychotic compounds, performance under the fixed-interval schedule was more sensitive to the rate-decreasing effects of buspirone. In contrast, both gepirone (0.03-3.0 mg/kg) and 8-OH-DPAT (0.03-1.0 mg/kg) increased responding under the two schedules. Differences in the effects of buspirone from the other compounds in this study, compared to the similar effects of these drugs obtained using other procedures, emphasize the importance of the specific behavior as a determinant of drug action. The multiple fixed-interval, fixed-ratio schedule may be useful for delineating the relative balance of dopaminergic and serotonergic effects produced by drugs that are less apparent using other behavioral procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125-4.0 mg/kg) and d-amphetamine (0.5-4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.

The effects of MK-212 (6-chloro-2[1-piperazinyl]pyrazine), a centrally-active 5-hydroxytryptamine (5-HT; serotonin) agonist, were studied alone and in combination with the 5-HT antagonists, methysergide (0.01-0.1 mg/kg), metergoline (0.01-1.0 mg/kg) and ketanserin (0.01-3.0 mg/kg). Pigeons were maintained under a procedure where key pecks were reinforced under a multiple fixed-interval (FI) fixed-ratio (FR) schedule of food presentation. In the fixed-interval component, the first response after 3 min had elapsed, produced food, while in the fixed-ratio component, the thirtieth response was reinforced. The drug MK-212 (0.1-3.0 mg/kg) produced dose-related decreases in response rates under both components of the schedule. In smaller doses of MK-212 (0.3 and 1.0 mg/kg), the decrease in the response rate was greater in the fixed-interval component than in the fixed-ratio component. Small doses of methysergide (0.03 mg/kg) and metergoline (0.1 mg/kg), which had little effect when given alone, partially blocked the effects of MK-212 (1.7 and 3.0 mg/kg) in decreasing rate. Larger doses of these compounds, which sometimes increased the response rate when given alone, resulted in a more complete restoration of response rates when administered with MK-212. Ketanserin, a selective 5-HT2 antagonist, reversed the effects of MK-212 in some cases, but the patterning of responses remained disturbed.(ABSTRACT TRUNCATED AT 250 WORDS)

Prepulse inhibition of the startle response occurs when a weak prestimulus precedes a startling stimulus and decreases the resulting reflex response. Prepulse inhibition provides a measure of sensorimotor gating that is readily assessed in humans and animals. As in event-related-potential models of sensory gating, prepulse inhibition is decreased in schizophrenic patients. In the present study, prepulse inhibition was measured in rats following injections of the N-methyl-D-aspartate (NMDA) antagonists phencyclidine, ketamine, and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine (MK-801). Startle was elicited by two different noise intensities or by air-puffs (tactile) and was inhibited by weak acoustic prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals, startle being increased by phencyclidine and MK-801. Both phencyclidine (3.0 to 10.0 mg/kg) and MK-801 (0.3 to 1.0 mg/kg) significantly reduced the amount of acoustic prepulse inhibition whereas ketamine did not. These results demonstrate that putative noncompetitive NMDA antagonists disrupt sensorimotor gating in rats and suggest that their effects may provide a model of the deficits in sensory gating exhibited by schizophrenic patients.

Electroencephalographic activity and behaviors were recorded in unrestrained adult rats during their first meal and intermeal interval following 17 hrs of food deprivation. Cholecystokinin (CCK-8), in doses of 5, 10, 20, 40, and 80 IDU/kg injected intraperitoneally 10 min after feeding began, suppressed ingestion, elicited and prolonged rest behavior, synchronous wave sleep, and desynchronous wave sleep in a dose-related manner. The 80 IDU/kg dose elicited EEG and behavioral patterns indistinguishable from those of the postprandial control rats. The results suggest that cholecystokinin elicits satiety for food in rats, not illness. The results also suggest that EEG measures can be used to quantify the postprandial state of satiety.

The effects of the benzodiazepine receptor antagonist, Ro 15-1788, were examined on analgesia induced by morphine after central (intracerebroventricular, i.c.v., or intrathecal, i.t.) and systemic administration. Analgesia was assessed in squirrel monkeys trained to respond under an electric shock titration procedure and in mice using the radiant heat tail-flick test. Central and systemic administration of morphine produced antinociceptive effects that were antagonized by 0.1 mg/kg of naloxone in both species. Ro 15-1788 antagonized the effects of morphine after central (i.c.v. or i.t.) administration but did not alter the effects of morphine given by the systemic route. This novel interaction suggests that Ro 15-1788 may be useful in pharmacologically separating neural substrates subserving opiate analgesia.

Food intake was monitored in three female and one male adult rabbits following the administration of three drugs known to result in feeding increases in other species. The drugs, diazepam (1.0 mg/kg), cyproheptadine (0.03 mg/kg) and chlorpromazine (1.0 mg/kg) all produced large increases in food intake; of these, only the effect of diazepam, a benzodiazepine, was reversed by doses of the benzodiazepine antagonists Ro 15-1788 (0.3 mg/kg) and Ethyl beta-carboxylate (beta-CCE) (1.0 mg/kg) which, when given alone, did not affect feeding. The results support evidence suggesting that Ro 15-1788 and beta-CCE are specific antagonists of the benzodiazepine receptor and of their effects on a wide range of behaviors.

N-Ethyl-3,4-methylenedioxyamphetamine (MDEA) is a derivative of methylenedioxyamphetamine (MDA), a substituted amphetamine with demonstrated abuse liability. MDA, MDEA and a third substituted amphetamine, methylenedioxymethamphetamine (MDMA), all produce a destructive action on central serotonin neurons and appear to induce some similar behavioral effects. The present study investigated the effects of racemic MDEA and its stereoisomers on prepulse inhibition of the acoustic startle response, a behavioral model of sensorimotor gating that is sensitive to psychostimulant drugs. Rats were subjected to 122 dB[A] acoustic noises, some of which were preceded by a weak 80 dB[A] prepulse noise. In vehicle-injected control rats, the prepulse induced a significant decrease in startle amplitude when compared to trials in which startle stimuli were not preceded by prepulses. Administration of racemic MDEA (0.3-10.0 mg/kg) and (+) MDEA (0.1-3.0 mg/kg) induced a significant attenuation in prepulse inhibition, while (-) MDEA (0.3-10.0 mg/kg) did not. Racemic MDMA (0.3-10.0 mg/kg) produced similar though not significant effects. These results confirm a stimulant-like behavioral effect of MDEA despite its relatively modest effects on dopamine markers, and support findings that the (+) stereoisomers of substituted amphetamines are more potent than tha (-) stereoisomers in producing psychostimulant-like biochemical and behavioral effects.