Biomedical subjects

M D Schechter

Publications and source records attributed to M D Schechter.

At least 73 records · Page 4Linked to original sources

PubMed1991

Effect of MDMA neurotoxicity upon its conditioned place preference and discrimination.

Experiments were conducted to investigate the functional consequences of a neurotoxic regimen of MDMA administration upon two behaviors, conditioned place preference and drug discrimination. Rats were trained to discriminate 1.5 mg/kg MDMA from its vehicle and their discriminative performance was shown to be dose-responsive. Subsequently, MDMA was observed to produce a conditioned place preference as three conditioning sessions with 1.5 mg/kg MDMA paired with the nonpreferred chamber increased the time the rats spent in the chamber paired with MDMA. Administration of a proportedly neurotoxic dose (20 mg/kg subcutaneous) of MDMA, twice-a-day for four days, did not affect this conditioned place preference when it was redetermined at a time of maximal neurochemical compromise. In contrast, sensitivity to 1.0 mg/kg MDMA in the drug discrimination task was shown to be significantly decreased after the neurotoxic regimen. Results are discussed in light of MDMA effects upon both central serotonergic and dopaminergic neurons.

3,4-Methylenedioxyamphetamine↗

PubMed1991

Lack of neuroleptic-like activity of l-fenfluramine.

Rats were trained to differentiate between the dopaminergically mediated discriminative stimuli produced by intraperitoneal administration of 4.8 mg/kg cathine and its vehicle. Once trained, three doses of l-fenfluramine (1.0, 2.0 and 2.5 mg/kg) were administered to determine if this agent would produce cathine-appropriate discriminative performance. All doses of l-fenfluramine were observed to produce vehicle-like responding. The 2.0 mg/kg dose of l-fenfluramine as well as 3.0 mg/kg chlorpromazine were administered in separate experiments prior to either cathine or vehicle. Chlorpromazine attenuated cathine-lever responding after cathine administration but did not affect vehicle responding. In contrast, l-fenfluramine had no effect upon cathine discrimination. The results indicate that l-fenfluramine shares neither agonist nor antagonist activity in the dopamine-mediated discriminative performance produced by cathine.

Animals↗

PubMed1991

Conditioned place aversion following the central administration of a novel dopamine release inhibitor CGS 10746B.

Numerous drugs of abuse that elevate brain extracellular dopamine concentrations by either increasing the firing rate of dopaminergic neurons or producing dopamine release have been shown to reliably condition a preference for place. If dopamine release is a necessary component for conditioned place preference (CPP), one reciprocal hypothesis may be that inhibition of dopamine release will result in conditioned place aversion (CPA). This hypothesis has been tested pharmacologically by employing CGS 10746B (CGS), a novel neuroleptic known to inhibit the release of dopamine via presynaptic mechanisms. In previous work the peripheral administration of CGS (1.25-20 mg/kg) produced place aversion at doses above 5 mg/kg. However, the contribution of peripheral mechanisms in the production of CGS-induced CPA is unknown. To test whether central administration of CGS would also result in CPA, rats were fitted with chronic intraventricular cannula. Groups of rats subsequently received four conditioning trials with one of four intraventricular (ICV) doses of CGS (1-30 micrograms) when confined to their preferred side of a place conditioning apparatus. Vehicle was similarly administered on four interspersed days prior to confining these same rats to their nonpreferred side of the apparatus. At the conclusion of these eight conditioning trials, the rats were tested, on separate days, in a nondrugged and a CGS-drugged state. The highest dose of CGS (30 micrograms) produced a CPA as evidenced by rats spending less time in the environment initially found to be preferred. Locomotor activity was also measured over a 30-min period with and without ICV injection of CGS (1-30 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Effect of learned behavior upon conditioned place preference to cathinone.

The purpose of this study was to examine whether first training rats to discriminate the stimulus cues produced by an indirect dopamine agonist, cathinone, would influence a subsequent test of preference. The conditioned place preference (CPP) paradigm was used to evaluate the reinforcing effects of l-cathinone in four differently treated groups of rats. Half of the animals were trained to discriminate the interoceptive cues produced by 0.8 mg/kg cathinone in a two-lever, food-motivated operant task. The other animals were equally divided between two groups, one receiving saline and noncontingent reinforcements on the same schedule as those trained to discriminate cathinone; the other group, the "yoked-control" rats, received the same cathinone and saline regimen of administration as the discrimination-trained animals. Results of CPP testing indicate that cathinone produced a statistically significant conditioned place preference only in the group trained to discriminate cathinone and not in the saline or yoked control groups. Furthermore, when half of the cathinone discrimination-trained rats were pretreated with the dopamine release inhibitor CGS 10746B, the conditioned place preference to cathinone was attenuated. The results would indicate that pairing cathinone with a nonpreferred environment tended to make the rat spend more time in that environment and the amount of time spent in the cathinone-associated environment can be increased by prior discrimination training and decreased by diminished dopamine function in the brain.

Alkaloids↗

PubMed1991

Inverse agonist properties of the FG 7142 discriminative stimulus.

A two-lever, food-motivated discrimination was established between the benzodiazepine receptor partial inverse agonist FG 7142 (5.0 mg/kg) and its vehicle. The FG 7142 discriminative stimulus was pharmacologically characterized by testing trained rats with a variety of benzodiazepine receptor ligands. Administration of the inverse agonist DMCM (0.15-0.30 mg/kg) dose-dependently mimicked the FG 7142 stimulus. In contrast, the benzodiazepine receptor agonist chlordiazepoxide, partial agonist ZK 91 296, mixed agonist/antagonist CGS 9896 and antagonist RO 15-1788 blocked the FG 7142 cue. These results indicate that the FG 7142 discriminative stimulus is based on its inverse agonist activity. The generalization of FG 7142 to the anxiogenic/convulsant compound pentylenetetrazole (PTZ), but not to the anorectic agent norfenfluramine, indicates that the anxiogenic properties of FG 7142, rather than its anorectic actions, may underlie the FG 7142 discriminative stimulus.

Animals↗

PubMed1991

Effect of repeated administrations upon cathinone discrimination and conditioned place preference.

1. Eight male rats were trained to discriminate the interoceptive cues produced by 0.8 mg/kg l-cathinone in a two-lever, food-motivated operant task and they were, subsequently, tested for preference to cathinone in a conditioned place preference (CPP)-test. 2. Once trained, the rats were placed on a 10 day regimen of twice-a-day non-contingent administrations of saline followed by a similar regimen of multiple injections of 0.8 mg/kg cathinone. 3. After each series of non-contingent administrations, the rats' ability to discriminate (0.2-0.8 mg/kg) cathinone, as well as their preference for it, was determined. 4. Results indicate that tolerance tends to develop to the effect of cathinone in its ability to control discriminative behavior as indicated by deficits in discriminative performance and a two-fold shift of the dose-response curve to the right. 5. In contrast, preference for cathinone, in the CPP-tests, was not significantly affected by the multiple cathinone administration regimen. 6. The possibility that tolerance to some behavioral effects may occur in habitual users of the cathinone-containing Khat shrub is discussed.

Alkaloids↗

PubMed1991

Effect of serotonin depletion by p-chlorophenylalanine upon discriminative behaviours.

1. Para-chlorophenylalanine (p-CPA), a competitive inhibitor of the serotonin (5-HT) synthesis enzyme tryptophan hydroxylase, was administered to rats at a dosage (100 mg/kg daily for 3 days) that depletes 5-HT. 2. Different groups of these rats were previously trained to discriminate the interoceptive stimuli produced by amphetamine, cathinone, 3,4-methylenedioxymethamphetamine (MDMA), N-ethyl-3,4-methylenedioxyamphetamine (MDE), fenfluramine or yohimbine, and the effect of p-CPA pretreatment upon their discriminative performance was compared with the effect of saline (control) pretreatment. 3. p-CPA was shown to have no effect upon the dopaminergically-mediated stimuli produced by the stimulants amphetamine and cathinone or upon yohimbine performance. 4. p-CPA significantly decreased discriminative performance with the serotonergic releasing drugs MDMA, MDE and fenfluramine. This decrease in discriminative performance returned to pre-p-CPA (criterion) levels at a time (9-12 days) when 5-HT has been reported to replete to normal brain concentrations. 5. It is concluded that p-CPA pretreatment lowers brain 5-HT and, in turn, significantly decreases the ability of rats to discriminate centrally active drugs whose interoceptive cueing stimuli are mediated by 5-HT neurons.

Animals↗

PubMed1990

Increased drug sensitivity in the drug discrimination procedure afforded by drug versus drug training.

Rats were trained to discriminate norfenfluramine (NF) 1.4 mg/kg from its vehicle or amphetamine (AMPH) 0.8 mg/kg or pentobarbital (PB) 6.0 mg/kg in order to determine the role that drug combination training plays in the rate of learning and sensitivity to lower drug doses. The results suggest that drug versus drug training can increase the rate of drug discrimination learning for some drugs that are learned slowly when trained in a drug versus vehicle training procedure, whereas drug versus drug training does not increase the rate of learning for other drugs that are learned rapidly. Drug versus drug training does, however, appear to increase the level of stimulus control of the training drug for all drugs examined in this study.

Amphetamine↗

PubMed1990

Rats become acutely tolerant to cathine after amphetamine or cathinone administration.

The drug discrimination paradigm was used to evaluate in rats the ability of the discriminate response to either 0.8 mg/kg d-amphetamine or 0.8 mg/kg l-cathinone to generalize to 2.4-6.0 mg/kg of the active cathinone metabolite d-norpseudoephedrine, also known as cathine. When tested 24 h after vehicle administration, cathine generalized in a dose-related fashion in rats (n = 6) trained with cathinone (ED50 = 3.03 mg/kg) and in rats (n = 8) trained with amphetamine (ED50 = 2.93 mg/kg). In contrast, when cathine was tested 24 h after the administration of either amphetamine or cathinone, it produced significantly decreased discriminative performance. The possibility that this acute tolerance may have been produced by release, and subsequent depletion, of brain dopamine was tested by pretreating rats with the dopamine release inhibitor CGS 10746B. When CGS 10746B was administered prior to cathinone it significantly decreased cathinone discrimination. In addition, acute tolerance to cathine at 24 h after vehicle-cathinone co-administration was reversed when cathine was tested 24 h after CGS 10746B-cathinone co-administration. The results suggest that cathinone-produced discriminative stimulus, as well as the acute tolerance to cathine, may be dopaminergically mediated.

Alkaloids↗

PubMed1990

Comparison of anorectic drugs in rats trained to discriminate between satiation and deprivation.

Eight male rats were trained to discriminate between the internal states produced by food deprivation of 3 hours (satiation) and that produced by food deprivation of 27 hours duration (deprivation). One lever, in a two-lever operant chamber, had to be pressed to receive reinforcement in the satiation state, whereas pressing the other lever was required when the rat was in the deprivation state. Once the rats were trained, increasing the number of hours of food deprivation, from 1 to 48 hours, resulted in more deprivation-appropriate lever responses in the two-lever operant task. Administration of doses of fenfluramine (0.5-1.5 mg.kg), its active metabolite norfenfluramine (0.25-1.0 mg/kg) or d-amphetamine (0.5-1.5 mg/kg) produced a dose-responsive decrease in deprivation-appropriate responses when each drug/dose was injected (i.p.) 15 min prior to deprivation (27 hours) testing. Norfenfluramine was 1.5 times more potent than fenfluramine which was 1.5 times more potent than amphetamine.

Amphetamine↗

PubMed1990

Effects of cathinone and amphetamine on the neurochemistry of dopamine in vivo.

The effects of (-)cathinone, the primary psychoactive alkaloid of the Khat plant, were compared to those of (+)amphetamine in the anterior caudate-putamen and the nucleus accumbens. In vivo microdialysis was used to measure extracellular levels of dopamine and metabolites in both regions of the brain simultaneously, after intraperitoneal administration of 0.8, 1.6 or 3.2 mg/kg of either drug (doses expressed as the salts). Both drugs increased levels of dopamine but decreased levels of metabolites in a dose-dependent manner. However, the relative magnitude of these effects depended upon the specific drug, the dose and area of the brain examined. At the largest dose used, amphetamine had a relatively greater effect than cathinone on dopamine in both caudate and accumbens. However, among smaller doses, this difference was only observed in the nucleus accumbens after administration of 1.6 mg/kg. The results also demonstrated a differential regional effect of both drugs at 3.2 mg/kg, in that both had a greater effect on dopamine in the caudate, as opposed to the accumbens. These findings demonstrate a functional heterogeneity of the striatum of the rat, that may be relevant to the understanding of both normal brain function and the neural responses to psychoactive drugs.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Dopaminergic nature of acute cathine tolerance.

Cathine is a psychoactive constituent in the leaves of the Khat shrub which are habitually ingested for their stimulatory effects in many parts of the world. Rats were trained to discriminate the stimulus effect of intraperitoneally administered 4.8 mg/kg d-cathine and, once trained, administration of another Khat constituent, cathinone, was shown to produce cathine-like effects. This generalization to cathinone was dose-responsive when testing occurred 24 hr after vehicle administration, whereas prior administration of cathine resulted in a diminished discriminative response to subsequent cathinone administration possibly as a result of the development of acute tolerance. CGS 10746B, a compound that blocks presynaptic release of dopamine, significantly decreased rats' ability to discriminate cathine when it was administered 25 min prior to cathine testing and it reversed the acute tolerance observed when cathine was tested 24 hr after cathine administration. These results indicate that a previously reported acute tolerance effect to cathine after cathinone administration in cathinone-trained rats appears to be symmetrical in that there is acute tolerance to cathinone after cathine in these cathine-trained rats. The results with CGS 10746B would suggest that both the cathine-induced discriminative cue and cathine's ability to produce acute tolerance are mediated by presynaptic dopamine release.

Alkaloids↗

PubMed1990

Temporal differences in behavioral effect of fenfluramine and norfenfluramine.

Ten male rats were trained to discriminate the anorectic drug d,l-fenfluramine (2.0 mg/kg intraperitoneally administered) from its vehicle using a food-reinforced (fixed-ratio 10 schedule) two-lever operant task. Once learned, the fenfluramine stimulus was dose-dependent (ED50 = 0.8 mg/kg) and stereoselective with the d-isomer (ED50 = 0.6 mg/kg) approximate twice as potent as the l-isomer (ED50 = 1.2 mg/kg). Time-course data indicate that the fenfluramine metabolite norfenfluramine produces a significantly faster onset and longer duration of action than does the parent compound. The results suggest that both stereoisomers of fenfluramine have discriminative stimulus properties and that the fenfluramine metabolite, norfenfluramine, contributes to the discriminative stimulus properties of the parent drug.

Animals↗

PubMed1990

Discriminative stimulus properties of (+)cathine, an alkaloid of the khat plant.

The effects of the psychostimulant (+)cathine (norpseudoephedrine) were examined in a two-choice, food-motivated, drug-discrimination paradigm. Rats were able to discriminate cathine from vehicle and this effect was dose- and time-dependent. Prior administration of cathine resulted in a diminished response (tolerance) to subsequent cathine and this effect developed and dissipated rapidly. Thus, different dose-response curves were generated depending upon whether cathine or vehicle was administered the day before testing. The development of tolerance also shortened cathine's time course of action and enhanced the ability of haloperidol to antagonize the cathine cue. These results suggest caution in interpreting effects produced by intermittent drug injection schedules.

Alkaloids↗

PubMed1990

Functional consequences of fenfluramine neurotoxicity.

Male Sprague-Dawley rats were trained to discriminate the anorectic drug d,l-fenfluramine (2.0 mg/kg intraperitoneally administered) from its vehicle using a food-motivated (fixed-ratio 10 schedule) two-lever operant task. Once trained, doses of 0.5, 1.0 and 1.5 mg/kg fenfluramine tested 20 min after IP administration produced dose-responsive discrimination performance. Subsequently, noncontingent twice-a-day administrations of 1 ml/kg saline were made for 4 days and the dose-effect relationship redetermined on the 13th to 15th day after initiation of the chronic saline regimen. Results of these dose-response experiments indicated that there was no significant effect upon fenfluramine discrimination after multiple saline injections or after 10 days without training. Following four days of retraining, 6.25 mg/kg fenfluramine twice-a-day for four days was followed 10 days later by another dose-response determination. This purportedly neurotoxic regimen of fenfluramine significantly increased the rats' ability to discriminate fenfluramine. These results suggest the possibility that chronic release of serotonin or selective damage to serotonin-containing neurons produced by fenfluramine may lead to postsynaptic supersensitivity as manifested by the functionally increased discriminative performance observed.

Animals↗

PubMed1989

Stability of the stimulus properties of drugs over time.

Three separate groups of rats were trained to discriminate the stimulus effects of either 600 mg/kg ethanol (n = 5), 0.8 mg/kg d-amphetamine (n = 8) or 1.0 mg/kg 1-(3-trifluoromethylphenyl)piperazine (TFMPP; n = 10). Once criterion performance was attained, each group was tested with various doses of the drug used in their training, thus allowing for calculations of dose-response curves and ED50 values. A second dose-response relationship was established at a later time, averaging over a year later, and this result was compared to the initial curve. In none of the three groups was there substantial change in the sensitivity of the rats to different doses of the drug used in training as indicated by similar ED50 values. These results suggest that the drug discrimination procedure is stable over a period of continuous training and testing.

Animals↗

PubMed1989

Temporal parameters of cathinone, amphetamine and cocaine.

Rats were trained to discriminate intraperitoneally administered 0.8 mg/kg 1-cathinone from its vehicle in a two-lever operant procedure. The normal injection-to-session interval was fifteen minutes. When tested in session at 2-180 min postadministration, cathinone discrimination was seen to have a rapid onset (5 minutes) and offset (60 minutes). When the same rats were tested with either 0.8 mg/kg d-amphetamine or 10.0 mg/kg cocaine at the same postinjection time periods, the peak discriminative generalization to each of these other psychostimulants was observed to be later, i.e., an onset of action at 15-30 minutes with a slightly longer duration of action. The results indicate that cathinone exerts discriminative response control within five minutes of intraperitoneal injection and that it has a shorter duration than amphetamine and cocaine.

Alkaloids↗

PubMed1989

Potentiation of cathinone by caffeine and nikethamide.

The drug discrimination paradigm was employed to evaluate the effect of coadministration of both caffeine and nikethamide upon the discrimination of a low dose of cathinone. In rats trained to discriminate between 0.8 mg/kg l-cathinone and its vehicle in a two-lever food-motivated operant task, 0.2 mg/kg cathinone produced 29.2% of responses on the cathinone-appropriate lever. This lever was chosen in 0 and 50% of trials with 25 mg/kg nikethamide and 20 mg/kg caffeine, respectively. Coadministration of caffeine, nikethamide, or caffeine plus nikethamide with low-dose cathinone produced strong cathinone-like discriminative performance. This potentiattion of cathinone by caffeine and nikethamide is reflective of noncontrolled drugs of abuse containing similar combinations especially for that of antiadipositum X-112, a drug containing all three agents and widely abused in Europe.

Alkaloids↗