S(+)- and R(-)N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) as discriminative stimuli: effect of cocaine

Racemic N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (methylenedioxymethamphetamine, MDMA), a central stimulant and empathogenic agent, and cocaine are drugs of abuse that function as training drugs in drug discrimination studies. In tests of stimulus generalization (substitution), asymmetric generalization occurs between the two agents: a (+/-)MDMA stimulus generalized to cocaine, but a cocaine stimulus did not generalize to (+/-)MDMA. A possible explanation may be found, at least in part, in the stimulus effects of the optical isomers of MDMA. In the present study, groups of male Sprague-Dawley rats were trained to discriminate either S(+)MDMA (training dose=1.5 mg/kg, i.p.; n=10; ED50=0.6 mg/kg) or R(-)MDMA (training dose=1.75 mg/kg, i.p.; n=7; ED50=0.4 mg/kg) from saline vehicle using a VI-15s schedule of reinforcement. Tests of stimulus generalization with cocaine were conducted in each of the two groups. Cocaine only partially substituted for the S(+)MDMA stimulus (maximum=39% drug-appropriate responding), and various doses of cocaine did not enhance the percent drug-appropriate responding produced by a low dose (0.5 mg/kg) of S(+)MDMA. In contrast, the R(-)MDMA stimulus generalized completely to cocaine (ED50=1.3 mg/kg). Taken together with an earlier report that a (+/-)MDMA stimulus generalizes to cocaine, it would seem that the stimulus actions of cocaine might share greater similarity with R(-)MDMA than with S(+)MDMA.     

Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA)

The discriminative stimulus effects of the stereoisomers of 3,4-methylenedioxymethamphetamine (MDMA) were studied in rats trained to discriminate 1.25mg/kg of (+)-MDMA or 3.5mg/kg of (-)-MDMA from saline, in a two lever, water-reinforced, drug discrimination situation. The isomers of MDMA and 3,4-methylenedioxyamphetamine (MDA) substituted completely for both training drugs. The stimulants amphetamine and cocaine did not substitute for either MDMA isomer. The hallucinogens (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-lysergic acid diethylamide (LSD), and mescaline failed to substitute completely for (+)-MDMA. Similarly, DOM and mescaline did not substitute for (-)-MDMA; however, LSD did substitute for this isomer at a dose of 0.06mg/kg but not at higher doses. Substitution tests with 5-HT-releasing agents revealed that fenfluramine substituted partially for (+)-MDMA and completely for (-)-MDMA, while p-chloroamphetamine substituted completely for both isomers of MDMA. When given in combination with (+)-or (-)-MDMA, neither the 5-HT(2) antagonist pirenpirone nor the less selective 5-HT antagonist metergoline consistently blocked drug-appropriate responding. These results indicate that the stereoisomers of MDMA and MDA have similar discriminative stimulus properties. More importantly, the present findings suggest that 5-HT release may be important for the discriminative stimulus effects of (+)-and (-)-MDMA. Actions at 5-HT(2) receptors, however, do not appear to be critical.     

Analysis of D2 and D3 receptor-selective ligands in rats trained to discriminate cocaine from saline.

This study examined the role of dopamine D3 receptors in the stimulus generalization produced by 7-OH-DPAT and PD 128907 in rats trained to discriminate cocaine from saline. Twelve male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-choice operant procedure using a FR20 schedule of water reinforcement. Stimulus generalization tests were administered with the D3-preferring agonists (+/-)-7-OH-DPAT (0.01-0.3 mg/kg), (+)-7-OH-DPAT (0.01-0.3 mg/kg), and PD 128907 (0.01-0.3 mg/kg), and the selective D2 agonist PNU-39156 (0.01-0.3 mg/kg). Complete generalization to cocaine was observed with (+/-)-7-OH-DPAT at doses that markedly suppressed response rate. Only partial stimulus generalization was observed with (+)-7-OH-DPAT and PD 128907 when these compounds were administered intraperitoneally, although subcutaneous injections of these compounds produced complete substitution. Response rate was also significantly reduced by these compounds. The selective D2 agonist, PNU-91356 also fully substituted for the cocaine cue and suppressed response rate in a dose-dependent manner. To ascertain the importance of D3 receptor actions in the stimulus generalization produced by (+/-)-7-OH-DPAT (0.1 mg/kg) and PD-128907 (0.3 mg/kg), the fairly selective D3 antagonist, PNU-99194A (2.5-20 mg/kg) was also tested in combination with these compounds. Although PNU-99194A partially attenuated the stimulus generalization produced by (+/-)-7-OH-DPAT, it failed to block PD-128907 substitution for cocaine. These results indicate at least some involvement of D3 receptors in the stimulus effects of (+/-)-7-OH-DPAT, although further investigations are clearly warranted. The present results also suggest that the cue properties of cocaine may be dissociated from the locomotor activating effects of this drug, because D3/D2 receptor agonists suppress locomotor activity but produce stimulus generalization to cocaine.     

Central stimulants as discriminative stimuli. Asymmetric generalization between (-)ephedrine and S(+)methamphetamine

Central stimulants readily serve as training stimuli in drug discrimination studies and typically substitute for one another in tests of stimulus generalization regardless of which is used as training drug. We have previously found that, although substitution occurs between (+)amphetamine and (-)ephedrine, substitution did not occur upon administration of S(+)methamphetamine to (-)ephedrine-trained animals. In the present investigation, rats were trained to discriminate S(+)methamphetamine (1 mg/kg) from saline vehicle and tests of stimulus generalization were performed with several stimulants, including (-)ephedrine. The S(+)methamphetamine stimulus (ED(50)=0.06 mg/kg) generalized to R(-)methamphetamine (ED(50)=1.61 mg/kg), S(+)amphetamine (ED(50)=0.28 mg/kg), S(-)methcathinone (ED(50)=0.21 mg/kg), methylphenidate (ED(50)=0.28 mg/kg), cocaine (ED(50)=3.68 mg/kg) and (-)ephedrine (ED(50)=13.1 mg/kg). Hence, stimulus generalization between S(+)methamphetamine and (-)ephedrine is apparently asymmetrical. In a companion study, R(-)methamphetamine was administered to rats trained to discriminate (-)ephedrine (4 mg/kg); substitution occurred and R(-)methamphetamine (ED(50)=0.92 mg/kg) was found to be nearly equipotent with (-)ephedrine (ED(50)=0.8 mg/kg). Although the exact basis for the observed results are unclear, they are discussed in terms of the different effects of (-)ephedrine and the methamphetamine optical isomers on neurotransmitter release and reuptake.     

The effect of MDMA ("Ecstasy") and its optical isomers on schedule-controlled responding in mice

Eleven mice were trained to respond under an FR 20 schedule of reinforcement and, after learning the schedule, were administered doses of saline and the following phenylisopropylamines: (+/-)-MDMA, S(+)-MDMA, R(-)-MDMA and (+)-amphetamine. Each of the phenylisopropylamines decreased rates of operant responding in a dose-dependent manner. S(+)-MDMA (ED50 = 3.1 mg/kg) was nearly equipotent with racemic MDMA and four times more potent than R(-)-MDMA (ED50 = 4.1 and 11.6 mg/kg, respectively), but less potent than (+)-amphetamine (ED50 = 0.74 mg/kg). The present study constitutes the first enantiomeric behavioral-potency comparison for the optical isomers of MDMA.     

Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in rats

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) increases locomotor activity when administered to rats. Although the published pharmacology of MDMA has focused almost exclusively on the roles of serotonin and dopamine, in vitro studies indicate that MDMA induces serotonin and norepinephrine release with equal potency. The present experiments tested the hypothesis that blockade of alpha(1)-adrenoceptors with systemic or local administration of the antagonist prazosin would attenuate the locomotor response to systemic administration of (+/-)-MDMA. Pretreatment with systemic prazosin (0.5 mg/kg) or microinjections into either the prefrontal cortex or ventral tegmental area completely blocked the locomotor stimulant effects of 5 mg/kg (+/-)-MDMA, assessed using a computerized Behavioral Pattern Monitor. Prazosin was more potent in blocking the locomotor stimulant effects of (+/-)-MDMA than a 2 mg/kg dose of (+)-amphetamine that produced a similar locomotor activity increase. These results indicate that activation of alpha(1)-adrenoceptors in both the prefrontal cortex and ventral tegmental areas modulates the locomotor response to MDMA.     

Role of the serotonin 5-HT<Subscript>2A</Subscript> receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine

Rationale Contradictory evidence exists regarding the role of the 5-HT_2A receptor (5-HT_2AR) in hyperactivity and hyperthermia elicited by the substituted amphetamine (+)-3,4-methylenedioxymethamphetamine.Objectives The present studies examined the ability of the selective 5-HT_2AR antagonist M100907 to block hyperactivity and hyperthermia produced across the (+)-MDMA dose-effect curve.Methods Male rats were pretreated with M100907 (0, 0.25, 0.5, 1, and 2 mg/kg) followed by treatment with (+)-MDMA (0–12 mg/kg); activity was recorded for 90 min followed by determination of rectal temperature. Additionally, we investigated the ability of M100907 (0 and 0.5 mg/kg) to reverse hyperthermia elicited by (+)-MDMA (12 mg/kg).Results The first study demonstrated that M100907 attenuated hyperactivity in the periphery of the monitor and eliminated rearing induced by (+)-MDMA (3 mg/kg) with no effect on basal activity. In two subsequent studies, (+)-MDMA (0–12 mg/kg) dose-dependently increased peripheral activity and rearing and produced hyperthermia. Pretreatment with M100907 decreased peripheral activity evoked by (+)-MDMA, right-shifted the dose-effect curve for rearing, and blocked (+)-MDMA-induced hyperthermia, while having no effect when administered alone. A final study demonstrated the ability of M100907 (0.5 mg/kg) to reverse hyperthermia produced by (+)-MDMA (12 mg/kg).Conclusions These results suggest that the 5-HT_2AR contributes to the generation of peripheral hyperactivity and rearing and, especially, the hyperthermia evoked by (+)-MDMA and that 5-HT_2AR antagonists should be further investigated as treatments for the psychological and hyperthermic effects of (±)-MDMA.     

Chlorphentermine may produce dual stimulus effects: a preliminary investigation

1. Rats were trained to discriminate injections of either (+)-amphetamine (0.75 mg/kg) or (+/-)-fenfluramine (1.5 mg/kg) from saline in a two-lever drug discrimination task. 2. After stable discrimination performances were attained in each group, stimulus generalization studies were conducted with amphetamine, fenfluramine, and chlorphentermine. 3. Stimulus generalization (substitution) did not occur between amphetamine and fenfluramine when either drug was used as the training stimulus. 4. In contrast, both the amphetamine stimulus and the fenfluramine stimulus generalized completely to chlorphentermine. 5. Taken together, the results suggest that chlorphentermine may be capable of producing dual stimulus effects in animals.     

MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice

Racemic MDMA (0.3-30 mg/kg), S(+)-MDMA (0.3-30 mg/kg), R(-)-MDMA (0.3-50 mg/kg) and saline vehicle (10 ml/kg) were comprehensively evaluated in fully automated and computer-integrated activity chambers, which were designed for mice, and provided a detailed analysis of the frequency, location, and/or duration of 18 different activities. The results indicated that MDMA and its isomers produced stimulation of motor actions, with S(+)-MDMA and (+/-)-MDMA usually being more potent than R(-)-MDMA in measures such as movement (time, distance, velocity), margin distance, rotation (clockwise and counterclockwise), and retraced activities. Interestingly, racemic MDMA appeared to exert a greater than expected potency and/or an enhanced effect on measures such as movement episodes, center actions (entries and distance), clockwise rotations, and jumps; actions that might be explained by additive or synergistic (i.e. potentiation) effects of the stereoisomers. In other measures, the enantiomers displayed different effects: S(+)-MDMA produced a preference to induce counterclockwise (versus clockwise) rotations, and each isomer exerted a different profile of effect on vertical activities and jumps. Furthermore, each isomer of MDMA appeared to attenuate the effect of its opposite enantiomer on some behaviors; antagonism effects that were surmised from a lack of expected activities by racemic MDMA. S(+)-MDMA (but not R(-)-MDMA), for example, produced an increase in vertical entries (rearing) and a preference to increase counterclockwise (versus clockwise) rotations; (+/-)-MDMA also should have induced such effects but did not. Apparently, R(-)-MDMA, when combined with S(+)-MDMA to form (+/-)-MDMA, prevented the appearance of those increases (from control) in activities. Similarly, R(-)-MDMA (but not S(+)-MDMA) produced increases in episodes (i.e. jumps) and vertical distance that racemic MDMA also should have, but were not, exhibited. Evidently, the presence of S(+)-MDMA in the racemic mixture inhibited the appearance of those increases (from control) in behavior. Taken together, the various and complex effects of MDMA and its stereoisomers are noted and a strategy is suggested for future studies that stresses the importance of steric effects and interplay, probable interaction(s) with various neurotransmitters, and interaction(s) with the particular behavioral or biological event (or action) being measured.     

Effects of dopamine D1- or D2-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA

Rationale Both dopamine (DA) and serotonin (5-HT) release are evoked by (+)-MDMA; however, little is known of the contribution of DA D₁- and D₂-like receptors (D₁R and D₂R, respectively) in the behavioral effects of (+)-MDMA.Objectives To test the hypothesis that a D₁R or D₂R antagonist would attenuate the hypermotive or discriminative stimulus effects of (+)-MDMA.Methods Male Sprague-Dawley rats (n=164) were pretreated with the D₁R antagonist SCH 23390 (3.125–50 g/kg, SC) or the D₂R antagonist eticlopride (12.5–50 g/kg, SC) prior to treatment with (+)-MDMA (3 mg/kg, SC) and locomotor activity was recorded using photobeam monitors. Twelve additional rats trained to discriminate (+)-MDMA (1 mg/kg, IP) from saline in a two-lever water-reinforced FR20 task were administered SCH 23390 (6.25 g/kg, IP) or eticlopride (12.5 g/kg, IP) prior to (+)-MDMA (0.375–1.0 mg/kg, IP). Rats were then placed in the drug discrimination chambers and the percent (+)-MDMA appropriate responding and response rate were measured.Results Both SCH 23390 and eticlopride blocked (+)-MDMA-evoked hyperactivity in a dose-related manner; the highest doses of the antagonists also effectively suppressed basal locomotor activity. In rats trained to discriminate (+)-MDMA from saline, SCH 23390 (6.25 g/kg), but not eticlopride (12.5 g/kg), blocked the stimulus effects of (+)-MDMA without altering response rate.Conclusion These data indicate that DA released indirectly by (+)-MDMA administration results in stimulation of D₁R and D₂R to enhance locomotor activity. Furthermore, the D₁R appears to play a more prominent role than the D₂R in the discriminative stimulus properties of (+)-MDMA.     

Rolipram as a discriminative stimuli: transfer to phosphodiesterase inhibitors

Rats were trained to discriminate (+/-)-rolipram (0.32 mg/kg, i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (FR 10). (+/-)-Rolipram served as a drug discriminative stimulus, and its discrimination was readily established with a mean of 42 training sessions to achieve criterion performance (at least 80% correct response in the consecutive generalization tests with both saline and (+/-)-rolipram). Thereafter, this stimulus was stably maintained. The (-)-isomer of rolipram was generalized at about one-third of the training dose of the (+/-)-compound, but the (+)-isomer was generalized only at 10 times the dose of the (+/-)-compound. This finding suggests that the (-)-compound is more extensively involved as a stimulus than either (+/-)-rolipram or the (+)-isomer. Ro20-1724, caffeine and theophylline, which are phosphodiesterase inhibitors, were generalized to (+/-)-rolipram. This result strongly suggests that phosphodiesterase inhibition may be an important factor involved in (+/-)-rolipram discrimination.     

An examination of isomeric phenylpropanolamines in (-)ephedrine-trained rats

A total of eight isomeric phenylpropanolamines are possible when the terminal amine is either an N-monomethylamine or a primary amine: (-)ephedrine, (+)ephedrine, (+)pseudoephedrine, (-)pseudoephedrine, (-)norephedrine, (+)norephedrine, (+)cathine, and (-)cathine. Few previous studies have examined the individual optical isomers of these phenylpropanolamines and, with the exception of one report on locomotor effects, no comparative behavioral data have been published on this series of agents. Using rats trained to discriminate 4 mg/kg of (-)ephedrine (i.p.) from saline vehicle using standard operant conditioning with a VI 15-s schedule of reinforcement, all eight agents were examined in tests of stimulus generalization. The (-)ephedrine stimulus (ED50 = 0.90 mg/kg) generalized to (+)ephedrine (ED50 = 2.64 mg/kg), (+)pseudoephedrine (ED50 = 6.58 mg/kg), (-)norephedrine (ED50 = 1.86 mg/kg), (+)norephedrine (ED50 = 5.75 mg/kg), and (+)cathine (ED50 = 4.87 mg/kg). The (-)ephedrine stimulus failed to generalize to either (-)pseudoephedrine or (-)cathine; the latter agents produced a maximum of 29 and 31% (-)ephedrine-appropriate responding, respectively. Thus, (a) six of the eight phenylpropanolamines produced ephedrine-like stimulus effects, (b) (-)ephedrine was the most potent of the examined agents, and (c) where stimulus generalization occurred, ED50 values spanned less than a tenfold range.     

alpha-Ethyltryptamine (alpha-ET) as a discriminative stimulus in rats

alpha-Ethyltryptamine (etryptamine, alpha-ET) is a drug of abuse that first appeared on the clandestine market in the mid-1980s. Its pharmacological actions are poorly understood. In this investigation, it is reported for the first time that alpha-ET serves as a training drug in drug discrimination studies. Male Sprague-Dawley rats were trained to discriminate (30-min pretreatment time) 2.5 mg/kg of alpha-ET (ED(50)=1.3 mg/kg) from saline vehicle using a standard two-lever operant paradigm and a VI-15s schedule of reinforcement for appetitive reward. Once established, the alpha-ET stimulus was shown to have an onset to action of 30 min and a duration of effect of at least 4 h. In tests of stimulus generalization (substitution), the alpha-ET stimulus generalized to S(-)alpha-ET (ED(50)=1.6 mg/kg) and R(+)alpha-ET (ED(50)=1.3 mg/kg). Tests of stimulus generalization were also conducted with prototypical phenylisopropylamines: (+)amphetamine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), and N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). The alpha-ET stimulus generalized to DOM (ED(50)=0.4 mg/kg) and PMMA (ED(50)=0.7 mg/kg), but only partially generalized (ca. 40% maximal drug-appropriate responding) to (+)amphetamine. The results suggest that alpha-ET produces a complex stimulus.     

The 5-HT3 receptor partial agonist MD-354 (meta-chlorophenylguanidine) enhances the discriminative stimulus actions of (+)amphetamine in rats

The effect of the 5-HT3 receptor partial agonist MD-354 (meta-chlorophenylguanidine) was examined on the discriminative stimulus produced by (+)amphetamine. Using male Sprague-Dawley rats trained to discriminate 1.0 mg/kg (i.p.) of (+)amphetamine from saline vehicle (VI 15-s schedule of reinforcement) in a two-lever operant procedure for appetitive reward, tests of stimulus generalization (substitution) and antagonism showed that MD-354 neither substituted for, nor antagonized, the amphetamine stimulus at the doses evaluated. Administration of (+)amphetamine doses in combination with a fixed (i.e., 1.0 mg/kg) dose of MD-354 shifted the (+)amphetamine dose-response curve to the left such that, following 0.3 mg/kg of (+)amphetamine, stimulus generalization occurred. Furthermore, MD-354 doses of 0.1, 0.3 and 1.0 mg/kg, but not doses of 0.01, 0.5, 1.5 or 3.0 mg/kg (i.p.), administered in combination with the ED(50) dose (0.33 mg/kg) of (+)amphetamine resulted in stimulus generalization (i.e., >80% drug-appropriate responding). It is concluded that even though MD-354 lacks amphetamine-like central stimulant actions of its own it can modulate the discriminative stimulus effects of (+)amphetamine in rats.     

Modulation of a (+)amphetamine discriminative stimulus in rats by 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OH DPAT)

It is well established that the discriminative stimulus (DS) effect of amphetamine involves a dopaminergic and/or noradrenergic mechanism. These catecholamines can be modulated by the 5-HT(1A) serotonin receptor agonist 8-hydroxy-2-(N,N-di-n-propylamino)tetralin (8-OH DPAT). The present study was conducted to determine whether 8-OH DPAT could influence the DS effects of (+)amphetamine. Administration of 8-OH DPAT doses to Sprague-Dawley rats trained to discriminate 1 mg/kg of (+)amphetamine (ED(50)=0.33 mg/kg) using a two-lever operant paradigm (VI-15 s schedule of reinforcement for appetitive reward) failed to result in stimulus generalization when administered alone, and failed to antagonize the stimulus effect when administered in combination with the training dose of (+)amphetamine. However, administration of 8-OH DPAT doses that produced saline-like responding (i.e., 0.01-0.1 mg/kg; <20% amphetamine-appropriate responding) in combination with the ED(50) dose of (+)amphetamine resulted in the animals' making a progressively greater number of responses on the drug-appropriate lever such that a combination of 0.1 mg/kg of 8-OH DPAT plus (+)amphetamine (0.33 mg/kg) elicited 91% (+)amphetamine-appropriate responding. In a separate study, administration of (+)amphetamine doses in combination with fixed doses of 8-OH DPAT (either 0.01 or 0.1 mg/kg) resulted in an apparent leftward shift of the dose-response curve. The results indicate that (+)amphetamine can be more effective as a discriminative stimulus in the presence of 8-OH DPAT than in its absence.     

Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine.

Using a standard two-lever operant procedure with rats trained to discriminate 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus antagonism and stimulus generalization were performed to better understand the stimulus properties of this agent. The agents examined for ability to antagonize the TFMPP stimulus were prazosin, quipazine, zacopride, buspirone, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), 1-(2-methoxyphenol)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), haloperidol, and 1-(2-pyrimidinyl)piperazine (1-PP); only buspirone attenuated the response to TF-MPP. In separate experiments, the lowest nondisrupting dose of buspirone (1.2 mg/kg) caused a rightward shift of the TFMPP dose-response curve (TFMPP alone, ED50 = 0.19 mg/kg; TFMPP + buspirone, ED50 = 0.43 mg/kg). In addition, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93, 129), 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrolo[1,2-a]quinox ali ne (CGS 12066B), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 3-chlorophenylbiguanide (mCPBG), NAN-190, nisoxetine, zacopride, 1-PP, (+)-N-allylnormetazocine ((+)-NANM), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) were analyzed in tests of stimulus generalization. The TFMPP stimulus generalized only to CGS 12066B (ED50 = 4.2 mg/kg) and (+)-NANM (ED50 = 8.8 mg/kg). Tests with DOI and MDMA resulted in partial generalization. Up to doses that disrupted behavior, all other agents had little effect on TFMPP-appropriate responding. The results of these and other published studies suggest roles for 5-hydroxytryptamine 1B (5-HT1B), 5-HT1C, and, possibly, sigma-receptors in the mediation of the TFMPP stimulus and indicate a lack of involvement of 5-HT1A, 5-HT2, dopaminergic, and adrenergic mechanisms in this behavior.     

Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs)

Polychlorinated biphenyls (PCBs) are environmental neurotoxicants known to affect the brain dopaminergic (DA) system. This project investigated whether developmental exposure to PCBs would alter the discriminative stimulus effects of psychostimulant drugs known to act on the DA system. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day of an environmentally relevant PCB mixture from four weeks prior to breeding through weaning of their litters on PND 21. When they reached adulthood one male and female/litter were trained to discriminate cocaine (10.0 mg/kg, IP) from saline by repeatedly pairing cocaine injections with reinforcement on one operant response lever, and saline injections with reinforcement on the other lever. After response training, generalization tests to four lower doses of cocaine (7.5, 5.0, 2.5, and 1.25 mg/kg, IP) and to amphetamine (1.0, 0.5, 0.25, and 0.125 mg/kg, IP) were given two days/week, with additional training dose days in-between. Percent responding of the PCB-exposed rats on the cocaine-paired lever was significantly higher than that of controls for the highest generalization dose of cocaine, and lower than that of controls for the highest dose of amphetamine. Response rate and percent responding on the cocaine lever did not differ among the exposure groups on the days when the training dose of cocaine was given, suggesting that the generalization test results were not due to pre-existing differences in discrimination ability or rate of responding. These findings suggest that developmental PCB exposure can alter the interoceptive cues of psychostimulants.     

Stimulus effects of N-monoethyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDE) and N-hydroxy-1-(3,4-methylenedioxyphenyl)-2-aminopropane (N-OH MDA) in rats trained to discriminate MDMA from saline

Tests of stimulus generalization were conducted using rats trained to discriminate 1.5 mg/kg of N-monomethyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane HCl (MDMA) from saline in order to determine if two structurally related analogs (MDE and N-OH MDA) would produce similar stimulus effects. The MDMA-stimulus (MDMA, ED50 value = 0.76 mg/kg) generalized both to MDE (ED50 value = 0.73 mg/kg) and N-OH MDA (ED50 value = 0.47 mg/kg). Administration of (+)amphetamine resulted in partial generalization (maximum of 49% MDMA-appropriate responding) in the MDMA-trained animals. Taken together with our previous studies showing that MDMA substitutes for the phenylisopropylamine stimulant (+)amphetamine, but that neither MDE nor N-OH MDA substitute for (+)amphetamine or for the phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), the present results [i.e., MDMA-stimulus generalization to MDE, N-OH MDA, but not to (+)amphetamine] suggest that 1) MDMA produces effects other than those that may be considered amphetamine-like, and 2) MDE and N-OH MDA are MDMA-like agents with even less of an amphetamine-like component of action than MDMA itself.     

Effect of 1-(3,4-methylenedioxyphenyl)-2-aminopropane and its optical isomers in PMMA-trained rats

1-(3,4-Methylenedioxyphenyl)-2-aminopropane (MDA) is a drug of abuse that is known to produce stimulus effects similar to those of the stimulant phenylalkylamine (+)amphetamine and the hallucinogenic phenylalkylamine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). Earlier, a working model was described to account for the stimulus effects produced by phenylalkylamines. Such agents can produce one or more of three distinct effects: an amphetamine effect, a DOM effect and a third effect that is typified by the agent N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). Because MDA is known to produce two of the three effects, in the present investigation, we sought to determine if racemic MDA or either of its optical isomers could produce a PMMA-like effect in animals. Administration of S(+)MDA, R(-)MDA and (+/-)MDA to rats trained to discriminate 1.25 mg/kg of PMMA from saline vehicle under a VI 15-s schedule of reinforcement resulted in substitution in each case. (+/-)MDA and S(+)MDA were nearly equipotent and several fold more potent than R(-)MDA. The results are not only consistent with the proposed model but also identify (+/-)MDA as the first phenylalkylamine shown to produce all three types of stimulus effects (i.e., amphetamine-like, DOM-like and PMMA-like) in rats.     

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement

RATIONALE: The reinforcing effects of MDMA and its enantiomers have not been extensively characterized in laboratory animals. OBJECTIVES: To investigate whether MDMA and its stereoisomers would be self-administered intravenously by rhesus monkeys ( Macaca mulatta), and to assess the effects of serotonin(2) receptor antagonists on MDMA-maintained responding. METHODS: Four adult male rhesus monkeys were maintained on a fixed ratio 10, time-out 60-s schedule for 0.01 mg/kg cocaine or saline injections. Racemic MDMA and its stereoisomers, and racemic methamphetamine were periodically substituted for cocaine or saline. In subsequent antagonist experiments, five adult rhesus monkeys (three male, two female) were maintained on a multiple dose fixed ratio 30, time-out 45-s schedule for cocaine or saline injections. Racemic MDMA and its enantiomers were periodically substituted for cocaine or saline, with or without a pre-session injection of the serotonin(2) receptor antagonists ketanserin or MDL100907. RESULTS: In the initial self-administration experiments, MDMA and its stereoisomers generated "inverted U"-shaped self-administration curves across the dose range tested. Racemic MDMA doses between 0.01 and 0.1 mg/kg per injection, S(+)-MDMA doses between 0.003 and 0.1 mg/kg per injection, and R(-)-MDMA doses between 0.01 and 0.1 mg/kg per injection engendered more responding than saline; however, no dose of any form of MDMA maintained as much behavior as cocaine or methamphetamine. In subsequent antagonist experiments, pretreatments with 0.1 or 0.3 mg/kg ketanserin or MDL100907 attenuated responding for S(+)-MDMA, and completely abolished responding for R(-)-MDMA, but did not affect cocaine-maintained behavior. CONCLUSIONS: MDMA and its stereoisomers serve as reinforcers in rhesus monkeys. We suggest that stimulation of 5-HT(2A) receptors is integral to the reinforcing effects of MDMA.