Biomedical subjects

M D Schechter

Publications and source records attributed to M D Schechter.

At least 91 records · Page 5Linked to original sources

PubMed1989

The antinociceptive effects of 3,4-methylenedioxymethamphetamine (MDMA) in the rat.

The antinociceptive effects of MDMA and morphine were examined in rats using the tail-flick and hot-plate analgesiometric tests. MDMA, in the dose range of 1.5-6.0 mg/kg IP, produced a dose-dependent elevation in hot-plate latency, but did not elevate tail-flick latency. In contrast, morphine (2-8 mg/kg, IP) produced analgesia on both the tail-flick and hot-plate tests in a dose-dependent manner. Neither the opiate antagonist naltrexone nor the adrenoceptor antagonist phentolamine effectively attenuated MDMA-induced analgesia. Conversely, the serotonin antagonist methysergide significantly reversed the analgesic effects of MDMA on the hot-plate test. These findings suggest that the antinociceptive effects of MDMA are serotonergically mediated. Furthermore, the results verify earlier findings describing the test-specific effects of serotonin-induced pain modulation.

3,4-Methylenedioxyamphetamine↗

PubMed1988

Lack of generalization of nisoxetine with amphetamine in the rat.

Rats were trained to discriminate between the stimulus properties of intraperitoneally administered d-amphetamine (0.8 mg/kg) and its vehicle in a two-lever, food-motivated operant task. Once trained, doses of the norepinephrine reuptake inhibiting agent nisoxetine, ranging from 10 to 20 mg/kg, were administered to investigate if the amphetamine-trained rats would generalize to this agent. This did not, however, occur. Thus, it would seem that noradrenergic mechanisms have a negligible role in the production of the amphetamine-induced discriminative stimulus cue in the rat. Previous evidence that indicated a noradrenergic mediation of amphetamine discrimination in the mouse contrasted with the present results in rats and this discrepancy should warrant caution in comparing results of discriminative studies in these two species.

Animals↗

PubMed1988

CGS 10746B is able to attenuate the effects of amphetamine: further evidence for dopaminergic mediation.

Previous results indicate that agents which either decreases synthesis or block postsynaptic dopamine receptors will attenuate the discriminative stimulus produced by d-amphetamine. CGS 10746B has been reported to decrease dopamine release without changing its metabolism or occupying its receptors. In the present study, rats successfully trained to discriminate intraperitoneally administered (0.8 mg/kg) d-amphetamine in a two-lever, food-motivated operant task were observed to be unable to discriminate amphetamine when pretreated with 30 mg/kg CGS 10746B. This antagonism was shown to be dose-responsive and constitutes a third mechanism, i.e., dopamine release inhibition, that evidences the dopaminergic mediation of amphetamine in the discriminative paradigm. When both cathinone (0.8 mg/kg) and cocaine (10.0 mg/kg) were administered to the amphetamine-trained rats they each were recognized as amphetamine and are, thus, considered to generalize to the amphetamine discriminative stimulus. Coadministration of CGS 10746B and cathinone totally antagonized this generalization, whereas pretreatment with CGS 10746B prior to cocaine significantly reduced cocaine's effects. These results implicate dopamine mechanisms in the discriminative stimulus properties of the psychostimulants amphetamine, cathinone and cocaine.

Alkaloids↗

PubMed1988

Use of TFMPP stimulus properties as a model of 5-HT1B receptor activation.

Recent evidence indicates that when 1-(3-trifluoromethylphenyl)piperazine (TFMPP) is used as a training drug in the drug discrimination paradigm it produces a stimulus effect that is site-selective at the 5-HT1B receptor. The present study sought to employ this procedure in order to assess the similarity of novel agents to TFMPP. First, rats were trained to reliably discriminate between the stimulus properties of intraperitoneally administered 1.0 mg/kg TFMPP and its vehicle. Following the acquisition of this discrimination, administration of various doses of TFMPP produced a typical dose-response relationship with an ED50 of 0.27 mg/kg. Rats were subsequently tested with another 5-HT1B specific agonist 1-(3-chlorophenyl)piperazine (mCPP) and a 5-HT releasing agent norfenfluramine and both produced TFMPP-like discriminative responding in a dose-dependent manner. In contrast, the 5-HT2 agonist 4-iodo-1-(2,5-dimethoxyphenyl)-2-aminopropane (DOI) did not generalize from TFMPP. Other drugs, previously trained in other rats and shown to generalize to TFMPP, viz., ethanol, tetrahydro-beta-carboline (THBC) and 3,4-methylenedioxymethamphetamine (MDMA) did not produce TFMPP-like responding. These results provide further evidence for the 5-HT1B receptor acting as the site for the discriminative effects of TFMPP. In addition, the transfer of discrimination between TFMPP and either ethanol, THBC or MDMA appears to be asymmetrical. Reasons for this one-way generalization are suggested.

Animals↗

PubMed1988

Advantages and disadvantages of a rapid method to train drug discrimination.

In an effort to reduce the often extensive period of time needed to train rats to discriminate between a drugged and nondrugged state, a fast training regimen was employed with 1.5 mg/kg 3,4-methylenedioxymethamphetamine (MDMA) used as the training drug in ten rats. This protocol consisted of one to three training sessions per day and it was compared to the more conventional method of once-per-day training in an equal number of rats. Results indicate that the fast-trained rats learned the discrimination in significantly fewer sessions than the slowly-trained rats. However, the subsequent dose-response experiments indicate that when the fast-trained rats are tested with various doses of MDMA, without prior vehicle treatment, their sensitivity to the drug is less than that of the slowly-trained rats. When a vehicle session is presented prior to drug dose-response testing, both groups perform similarly. It appears that the preceding vehicle sessions function as a reference point for the fast-trained rats and, although the more rapid training regimen allows for faster learning, these treatment regimens should be employed with caution when subsequent dose-response tests and generalization tests with other drugs are conducted.

3,4-Methylenedioxyamphetamine↗

PubMed1988

Discriminative stimulus properties of CGS 9896: interactions within the GABA/benzodiazepine receptor complex.

Male rats were trained to discriminate the stimulus effects of CGS 9896 (30.0 mg/kg) from its vehicle. Once trained, discriminative performance was observed to be dose-responsive in the 3.75-30.0 mg/kg range and analysis of the dose-response curve generated an ED50 of 6.44 mg/kg. Generalization testing with chlordiazepoxide and pentobarbital produced CGS 9896-appropriate responding, whereas administration of the GABA agonists SL 75 102 resulted in 75% (intermediate) generalization to the CGS 9896 discriminative stimulus. Although full antagonism of the CGS 9896 cue was obtained following administration of Ro15-1788 and pentylenetetrazole, the inverse agonist DMCM failed to provide complete antagonism. These results suggest that the discriminative properties of CGS 9896 are consistent with its activity as a benzodiazepine receptor agonist.

Animals↗

PubMed1988

Norfenfluramine, the fenfluramine metabolite, provides stimulus control: evidence for serotonergic mediation.

Nine male rats were trained to discriminate 1.4 mg/kg norfenfluramine (NF) from its vehicle using a two-lever, food-motivated, operant discrimination task. Once trained, the rats showed a dose-dependent decrease in responding on the NF-correct lever following decreased doses of NF (ED50 = 0.71 mg/kg). Administration of 2.0 mg/kg fenfluramine (FEN) produced 100% responding on the NF-correct lever and decreasing doses of FEN, likewise, produced a dose-dependent decrease in responding on the NF-correct lever (ED50 = 1.30 mg/kg). Time-course data indicated that NF has a fast onset and a peak effect at 20-60 min after administration. Analysis of the time-course data provided a half-life of approximately 8 hr. In contrast, FEN did not show the rapid onset that was observed with NF. However, NF had a similar peak effect and half-life. These results indicate a pharmacological similarity between NF and FEN. However, the difference in onset of action suggests a possible difference between the parent drug and its metabolite. The serotonergic agonists mCPP, DOI, 5-MeODMT and LSD generalized to 1.4 mg/kg NF, whereas neither TFMPP nor 8-OHDPAT generalized to NF. The dopaminergic agonist AMPH also did not generalize to NF. The implications of these findings are discussed.

Animals↗

PubMed1988

Serotonergic-dopaminergic mediation of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy").

A series of three experiments were conducted to investigate the possible serotonergic and dopaminergic mediation of the discriminative stimulus properties of the "designer" drug MDMA. In Experiment 1, rats trained to discriminate 1.5 mg/kg (+/-)-MDMA from its vehicle at 20 min postadministration were shown to generalize to another drug of abuse, N-ethyl-3,4-methylenedioxyamphetamine (MDE) and to the serotonergically-active agents norfenfluramine and TFMPP. In contrast, testing of various dopaminergically-active agonists did not result in MDMA-like responding. In Experiment 2, dopaminergic and serotonergic antagonist were employed to observe their effect upon MDMA discrimination at 20 min postinjection. The serotonin antagonist pirenperone significantly decreased MDMA discrimination, whereas the dopamine decreasing drugs CGS 10746B and haloperidol had no effect. In Experiment 3, another group of rats were trained to discriminate MDMA at 105 min postadministration to investigate if, at this (later) time, the dopaminergic properties of MDMA may be more salient. Indeed, the dopaminergically-active drugs had a heightened effect upon MDMA at this later time, although the serotonergic component of the MDMA discriminative stimulus was predominant. The results suggest that the effects of MDMA at 20 min postadministration are solely serotonergic in nature. At 105 min postinjection there appears to be the presence of a weak dopaminergic component. This biphasic serotonergic-then-dopaminergic action of MDMA may explain the reported human experience with the drug, as well as the often controversial results in the literature.

3,4-Methylenedioxyamphetamine↗

PubMed1988

The role of dopamine and serotonin receptors in the mediation of the ethanol interoceptive cue.

The drug discrimination paradigm was used to evaluate the contribution of dopamine or serotonin receptors in the mediation of the stimulus properties of ethanol. Briefly, rats were trained to discriminate between ethanol (600 mg/kg, IP) and water vehicle. Dose-response relationships were observed for ethanol and rats were tested with various dopamine and serotonin receptor agonists and antagonists. The specific dopamine receptor agonists SKF 38393 (DA1) and LY 171555 (DA2) failed to produce appreciable ethanol-like stimulus effects. Furthermore, the dopamine receptor antagonists SCH 23390 (DA1) and haloperidol (DA2) did not affect ethanol-appropriate responding when administered in combination with the training dose of ethanol. A number of specific serotonergic receptor ligands were also tested. Quipazine, 5-MeODMT, buspirone, 8-OH-DPAT elicited intermediate ethanol-like stimulus properties in rats. The serotonin receptor blockers pizotifen, pirenperone and (-)propranolol were ineffective in blocking the interoceptive cue produced by 600 mg/kg ethanol. However, TFMPP produced strong ethanol-like discriminative properties and completely substituted for the training dose of ethanol. These results indicate that the stimulus properties of TFMPP are similar to those of a low dose of ethanol.

Animals↗

PubMed1988

Discriminative stimulus control by the anxiogenic beta-carboline FG 7142: generalization to a physiological stressor.

Drug discrimination was employed to investigate the similarities between FG 7142-induced anxiogenesis and the stress produced by exposure to either a novel environment or to footshock. Eight rats were trained to discriminate between the stimulus properties of the beta-carboline FG 7142 (5.0 mg/kg) and its vehicle in a two-lever, food motivated operant task. Once trained, decreasing doses of FG 7142 produced fewer FG 7142-appropriate responses and the dose-response relationship yielded an ED50 of 1.45 mg/kg. Rats were subsequently subjected to two physiological/environmental stressors, footshock and novelty, and then tested in the discriminative paradigm. Exposure to novelty resulted in partial FG 7142-appropriate responding, whereas footshock sessions produced responding predominately on the FG 7142-appropriate lever. This is the first report of stimulus control by FG 7142 and it is likely that the interoceptive cue state produced by this compound is anxiogenic in nature, as reported to occur in man. The anxiogenic nature of the FG 7142 discriminative stimulus is supported by the generalization of FG 7142 to the state produced following stressful environmental manipulation.

Animals↗

PubMed1987

Behavioral suppression following 3,4-methylenenedioxymethamphetamine.

Rotation in rats was employed as an assay of the central dopaminergic activity of 3,4-methylenedioxymethamphetamine (MDMA). This agent was observed to possess predominantly amphetamine-like actions at low doses. However, at higher doses it also appears to stimulate the dopamine receptor directly. Following a third dose of MDMA, a significant decrease in rotation was evident to this drug and to amphetamine, suggesting a neurotoxic or long-term suppressive action of MDMA.

3,4-Methylenedioxyamphetamine↗

PubMed1987

Evidence that the stimulus properties of apomorphine are mediated by both D1 and D2 receptor activation.

Male and female rats were trained to discriminate between the stimulus properties of apomorphine (0.16 mg/kg i.p.) and saline in a two-lever, food-motivated operant procedure. Apomorphine, at doses different than the training dose, produced a similar dose-dependent relationship in both sexes. Consistent with the hypothesis that the behavioral effects of apomorphine are mediated by D2 activation, the apomorphine interoceptive cue generalized to bromocriptine, a drug considered to be a preferential D2 agonist. In addition, the dose-response curve after 5-15 mg/kg bromocriptine administration was parallel to that of apomorphine. Consistent with the biochemical evidence that apomorphine's effects are mediated, to a lesser extent, by D1 activation, the apomorphine cue partially generalized to the selective D1 agonist SKF 38393. Furthermore, the apomorphine cue was not blocked by the selective D1 antagonist SCH 23390. Somewhat surprising was the partial generalization of the apomorphine cue to SCH 23390. However, this is not the first time that the administration of SCH 23390 has resulted in unexpected behavioral responses. Other novel findings include the lack of sex differences in acquisition training to the apomorphine cue and in the generalization tests to the selective agonists. The behavioral results are consistent with previous biochemical evidence that the effects of apomorphine are mediated by both D1 and D2 activation and is further behavioral support that apomorphine's effects are not the result of D2 activation alone, as previously hypothesized.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1987

In vivo electrochemical determination of extracellular dopamine in the caudate of freely-moving rats after a low dose of ethanol.

Low doses of ethanol (i.e. less than 1 g/kg) elicit behavioral stimulation, control discriminative performance and mediate reinforcement in rats. These effects are thought to be mediated through central dopaminergic neuronal systems. In the present study, dopamine and serotonin/uric acid release from caudate was measured by in vivo voltammetry in freely-moving, unanesthetized rats after administration of a low dose of ethanol (600 mg/kg, IP). Within 15 min after a single ethanol administration, extracellular dopamine levels significantly increased in caudate, peaking at 35 min, and returning to baseline by 75 min. In addition, ethanol caused an attenuation of a second voltammetric signal that correlates with extracellular serotonin/uric acid concentrations, and this effect persisted through the course of the experiments. These neurochemical changes may underlie behavioral responses found after low doses of ethanol.

Animals↗

PubMed1987

Tetrahydro-beta-carboline may produce its stimulus effects via 5HT1B receptors.

To further clarify the role of 5-hydroxytryptamine (5HT) in the behavioral effects of tetrahydro-beta-carboline, male rats were trained to discriminate either 20 mg/kg THBC from its vehicle (n = 10) or 2.0 mg/kg fenfluramine from saline (n = 5). THBC was observed to produce fenfluramine-like effects in the fenfluramine-trained rats while fenfluramine produced THBC-like effects in the THBC-discriminating rats. To investigate which of the serotonergic receptors may mediate the THBC-induced discriminative stimulus, various putatively specific 5HT agonists were administered to THBC-trained rats. Results indicate that the 5HT1B receptor agonists TFMPP and m-CPP substitute for THBC in a dose-response manner whereas 5HT1A agonists do not generalize to the THBC-induced discriminative stimulus. These observations support a role for the 5HT1B receptor site in the discriminative stimulus properties of THBC.

Animals↗

PubMed1987

Amfonelic acid: similarity to other dopamine agonists.

Rats were trained to discriminate between the stimulus properties of intraperitoneally administered 0.8 mg/kg amfonelic acid and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower amfonelic acid doses and analysis of the dose-response curve indicated an ED50 of 0.11 mg/kg. Administration of 0.08-0.6 mg/kg d-amphetamine produced a pattern of responding similar to that observed with amfonelic acid, with an ED50 of 0.10 mg/kg and a non-parallel dose-response curve. Likewise, the discriminative stimulus properties of amfonelic acid were shown to generalize to both d,l-cathinone and cocaine but not to apomorphine. The results suggest that amfonelic acid, as well as other non-amphetamine stimulants, acts by a different mechanism of action than does amphetamine and biochemical studies are reviewed to further evidence this observation.

Alkaloids↗

PubMed1987

Behavioral effects of N-ethyl-3,4-methylenedioxyamphetamine (MDE; "EVE").

Eight male rats were trained to discriminate 2.0 mg/kg N-ethyl-3,4-methylenedioxyamphetamine (MDE) from its vehicle using a two-lever, food-motivated operant discrimination task. Once trained, the rats showed a dose-dependent decrease in discriminative accuracy following administration of decreased doses of MDE (ED50 = 0.75 mg/kg). Administration of 1.5 mg/kg 3,4-methylenedioxymethamphetamine (MDMA), a recently restricted Schedule I drug, produced 100% MDE-appropriate responding in the MDE-trained rats and decreased discriminative performance was similarly observed following lower doses of MDMA (ED50 = 0.62 mg/kg). The difference in relative potencies of MDE and MDMA in rats is reminiscent of those seen in human abusers who report effective oral psychotomimetic doses. Time-course data indicated that MDE has a fast onset, 100% drug-correct responding 10 min post-injection, and a peak effect between 10-20 min with declining effect at 60-120 min post-administration. These findings along with those of others show a pharmacological similarity between MDE and MDMA. Implications as to the future scheduling of MDE are discussed.

3,4-Methylenedioxyamphetamine↗

PubMed1987

MDMA as a discriminative stimulus: isomeric comparisons.

Using a two-lever, food-motivated discrimination procedure, eight male rats were trained to discriminate 1.5 mg/kg of racemic 3,4-methylenedioxymethamphetamine (MDMA) from its vehicle, distilled water. Once trained, the rats demonstrated a dose-related decrease in discriminative performance after administration of lower doses of MDMA (ED50 = 0.27 mg/kg). Racemic MDMA-stimulus generalization occurred with both isomers of MDMA with the ED50 of the (+) isomer calculated as 0.50 mg/kg and for the (-) isomer being 1.07. Time-course data indicate that racemic MDMA has a peak effect from 20-60 min post-injection with a declining effect from 120-240 min. This time-course closely resembles that observed by subjective reports in human abusers and, together with previous data, would indicate that the discriminative paradigm would be useful in investigations as to the neurochemical effects of MDMA.

3,4-Methylenedioxyamphetamine↗

PubMed1986

Fenfluramine discrimination in obese and lean Zucker rats: serotonergic mediation of effect.

Genetically obese Zucker rats and their lean littermates were trained to discriminate between the stimulus properties of 2.0 mg/kg fenfluramine and its vehicle in a two-lever, food-motivated operant task. Both groups learned the discrimination at the same rate and all rats showed a dose-related decrease in discriminative performance with lower fenfluramine doses. Analysis of the dose-response curves indicated an ED50 for the obese rats of 0.56 mg/kg and for the lean group of 0.42 mg/kg. Time-course experiments indicted that the obese rats maintain errorless discrimination through 90 min post-injection but discriminate significantly less than the lean rats at 960 min post-administration. These results suggest a similar sensitivity to fenfluramine in obese and lean rats with a difference in the time-course of drug action. Pre-treatment with the specific serotonin receptor antagonist pirenperone significantly attenuated fenfluramine discrimination in lean rats without a similar effect in the obese rats. Possible reasons for this observation are offered.

Animals↗