Biomedical subjects

M D Schechter

Publications and source records attributed to M D Schechter.

At least 37 records · Page 2Linked to original sources

PubMed1995

The discriminative properties of the D1 dopamine agonist dihydrexidine in the rat.

The objective of this study was to train rats to discriminate the interoceptive stimuli produced by a selective dopamine D1 agonist. Fourteen male Sprague-Dawley rats acquired the discrimination of the fully effective, high potency, D1 agonist dihydrexidine (DHX) within 20 sessions using a training dose of 3.0 mg/kg. DHX (0.75-4.5 mg/kg) dose-dependently increased DHX-appropriate responding with an ED50 = 1.44 mg/kg. The selective D1 agonist SKF 38398 (2.0-8.0 mg/kg) dose-responsively generalized with an ED50 = 3.54 mg/kg; significantly less potent than DHX. The selective D1 antagonist SCH 23390 (0.06-0.12 mg/kg) dose-responsively decreased DHX-appropriate discriminative performance. These data would indicate that DHX is a selective D1 agonist that may allow for testing of the selectivity of other putative D1 agonists in this experimental procedure. Administration of non-selective dopaminergically active drugs, including apomorphine, amphetamine and cocaine, were each shown to produce intermediate DHX-appropriate discriminative performance.

Amphetamine↗

PubMed1995

Blockade of cocaine-induced conditioned place preference: relevance to cocaine abuse therapeutics.

Conditioned place preference/aversion testing is a behavioral method believed capable of measuring the affective (positive, neutral or negative) properties of psychoactive drugs. Cocaine injections in rats reliably produces a positive place preference. Drugs that attenuate or block this effect of cocaine have obvious potential for developing treatments to address cocaine addiction as well as to add to the scientific understanding of the mechanism of cocaine's action at the cellular level. To date, six drugs have been reported to block the expression of a cocaine-induced conditioned place preference (CPP) and this review evidences the cocaine-induced CPP blockage by the two potent L-type calcium channel blockers, isradipine and nifedipine, the two serotonin-3 receptor antagonists, MDL72222 and ICS205-930, the delta opioid receptor selective antagonist naltrindole, and lastly, a mixed opioid agonist-antagonist buprenorphine. Additional evidence relating to the blockade of other cocaine behavioral effects by these putative blockers is addressed, where appropriate, from studies employing other procedures such as drug stimulus discrimination, self-administration, electrical brain stimulation and increases in locomotor activity. The significance of these findings is discussed in the context of their relevance to the development of treatment regimens to allow for cessation of cocaine abuse.

Animals↗

PubMed1995

Discriminative stimulus properties of isradipine: effect of other calcium channel blockers.

This study constitutes the first report of a calcium channel blocker used as a drug capable of controlling differential responding in a drug-discrimination paradigm. Male Sprague-Dawley rats were trained to discriminate between intraperitoneally administered 10.0 mg/kg isradipine and its vehicle in a two-lever, food-motivated, operant task. Once trained, rats displayed a dose-related decrease in discriminative responding when tested with lower isradipine doses. An analysis of the dose-response curve indicated an ED50 = 5.71 mg/kg. As all training and dose-response testing occurred at 60 min postadministration, experiments were conducted with varying injection-to-test intervals ranging from 15-240 min. Results indicate that the optimum time for discriminative performance was at the time used in training, and that discrimination returned to nondrug (vehicle) levels 2 h postinjection. Administration of other L-type calcium channel blockers, viz., nifedipine (5-50 mg/kg), diltiazem (10-60 mg/kg), or nicardipine (0.5-3.0 mg/kg), as well as a novel antipsychotic that inhibits dopamine release (10-30 mg/kg of CGS 10746B), did not produce isradipine-like discriminative effects. Thus, there was no generalization from the training dose of 10 mg/kg isradipine to any of these other agents, and the results are discussed in light of the possible specificity of the isradipine discriminative stimulus cue as it is produced in the central nervous system.

Animals↗

PubMed1995

The lethal effects of ethanol and cocaine and their combination in mice: implications for cocaethylene formation.

The HS line of mice was used to determine the LD50 values for cocaine and ethanol, as well as for cocaethylene, the enzymatic product of their coadministration. The LD50 of cocaethylene was found to be significantly lower than that of cocaine, and both were more potent in their lethality than ethanol. When a low-lethality dose of cocaine was administered with a nonlethal dose of ethanol, the result was a significant increase in the prevalence of lethality. Thus, the lethal effects of the dose of cocaine used were increased by the dose of ethanol administered such that the two drugs in combination were equipotent to cocaethylene. The results are discussed in light of the ability of the liver, via transestification, to rapidly form cocaethylene from cocaine in addition to ethanol's ability to decrease the catabolism of cocaine. Thus, the possibility exists that the increased lethality observed is produced by both the production of the more lethal cocaethylene and sustained levels of cocaine.

Animals↗

PubMed1995

Scopolamine-physostigmine combination does not substitute for nicotine.

1. Male Sprague-Dawley rats were trained to discriminate 0.4 mg/kg nicotine subcutaneously administered from its saline vehicle in a food-motivated operant discrimination task. Once trained, the discriminative performance was observed to be dose-responsive with an ED50 = 0.11 mg/kg. 2. The co-administration of 0.1 or 0.2 mg/kg physostigmine with either 0.1, 0.15 or 0.2 mg/kg scopolamine produced intermediate discriminative effects, i.e., neither nicotine- nor saline-like responding. However, the physostigmine-scopolamine combination neither substituted for nor increased the discriminative effects of co-administered nicotine. 3. The theoretical/mechanistic possibility that a combination of a cholinesterase inhibitor to increase available acetylcholine plus a specific anti-muscarinic to allow that increased acetylcholine to stimulate nicotinic receptors was investigated. Results indicate that the combination does not produce nicotine-like discriminative effects and evidence the possibility that nicotine discrimination may involve non-cholinergic mechanisms.

Animals↗

PubMed1995

Premorbid behaviors produced by cocaine, ethanol and cocaethylene in the mouse.

1. The premorbid behaviors produced by the administration of cocaine, ethanol, their combination, as well as a metabolite produced by their co-administration, viz. cocaethylene, were defined, determined and quantified in the HS strain of mice. 2. The LD50 for ethanol was 9.71 g/kg in males and 9.45 g/kg in females, whereas the LD50 values in male and female mice for cocaine were 101.55 and 90.00 mg/kg, respectively. 3. The data indicate that clonic-tonic seizures continued into status epilepticus after cocaine administration and prior to cocaine-induced lethality. In contrast, administration of the cocaine-ethanol metabolite cocaethylene produced status epilepticus without producing clonic-tonic seizures yet still resulted in lethality. 4. Thus, both cocaine and cocaethylene may produce their lethal effects in mice through neuro-regulatory mechanisms mediating protracted seizure induction.

Animals↗

PubMed1994

Conditioned place aversion produced by dopamine release inhibition.

CGS 10746B, a dopamine release inhibitor with properties similar to the atypical antipsychotic clozapine, was assessed as to its behavioral properties using spontaneous locomotor activity and the conditioned place preference test. Rats conditioned with interperitoneally administered doses of 1.25, 2.5, 5.0, 10.0, 20.0 or 30.0 mg/kg CGS 10746B showed a conditioned place aversion, whereas only doses of 5.0 mg/kg or greater suppressed locomotor activity. Results are discussed in terms of dopaminergic mediation of conditioned place preference and spontaneous locomotor activity and methodological concerns involved in employing the conditioned place preference test with drugs that produce opposing affective cues.

Analysis of Variance↗

PubMed1994

Discriminative effects of cocaethylene in rats trained to discriminate cocaine or ethanol.

Two groups of rats were trained to discriminate between the stimulus properties of either intraperitoneally administered 10.0 mg/kg cocaine or 60 mg/kg ethanol and its vehicle in a two-lever operant chamber. Once trained, both groups exhibited a dose-related decrease in discriminative performance when tested with lower doses. A dose of 10 mg/kg cocaine, as well as doses of 10-30 mg/kg cocaethylene, in the ethanol-trained animals produced no greater than 38.9% responding on the ethanol-appropriate lever. Combinations of the approximate ethanol ED50 dose with either 10 mg/kg cocaine or 20 mg/kg cocaethylene did not increase ethanol lever responding. In contrast, in the cocaine-trained animals, administration of cocaethylene produced dose-responsive cocaine-like discrimination with 30 mg/kg producing 88.9% responding on the cocaine-appropriate lever. In addition, 600 mg/kg ethanol co-administered with a (2.5 mg/kg) dose of cocaine that was poorly discriminated produced 85% of responses on the cocaine-appropriate lever. The peak effect of cocaine and cocaethylene were observed to occur in 15-30 min post-administration with cocaine choice behavior decreasing at a faster rate than seen for cocaethylene discrimination. Results are discussed in light of ethanol and cocaine producing a heightened, as well as prolonged, euphoria in humans.

Animals↗

PubMed1994

Isradipine produces neither a conditioned place preference nor aversion.

Isradipine (ISR) has been reported to block cocaine-induced conditioned place preference. Using this procedure, the pairing of this L-type calcium blocker, at doses of 2.5, 5.0 and 10 mg/kg, with a preferred (cue-distinct) environment was investigated. In a separate experiment, ISR injection (10 mg/kg) was paired with the less-preferred environment to determine whether ISR produces a place preference. Testing in the non-drugged state revealed that ISR conditioning failed to affect side preference in both experiments. The neutral affective properties of ISR may be relevant to the development of cocaine use/abuse treatment regimens.

Animals↗

PubMed1994

Conditioned place preference/aversion to fenfluramine in fawn hooded and sprague-Dawley rats.

The Fawn Hooded (FH) rat strain possesses a genetic platelet storage pool deficiency which leads to an impaired capacity for platelets to store and release serotonin. While the relationship between this deficit and possible alterations in brain serotonergic levels or function remains unclear, numerous behavioral studies have indicated that FH rats exhibit differential responses to serotonergic agonists and antagonist relative to other strains. The current study used the conditioned place preference paradigm to examine the ability of fenfluramine to produce a conditioned place preference (CPP) or aversion (CPA) in FH and Sprague-Dawley (SD) rats. Results indicated that fenfluramine failed to produce CPP or CPA in SD rats, but did produce a CPA in FH rats. Results are discussed in terms of the use of conditioned place preference to assess putative differences in serotonergic functioning in FH rats.

Animals↗

PubMed1994

Nicotine place preference using the biased method of conditioning.

1. The objective of the experimentation was to determine whether nicotine (NIC, 0.8 mg/kg subcutaneously administered) would produce a conditioned place preference (CPP) in rats confined for thirty min to their less-preferred side in a three compartment apparatus, or an aversion when another group of rats were confined to their more preferred side. 2. On the non-drugged test day following eight conditioning trials, the rats spent more time in the compartment paired with NIC that was initially less-preferred, whereas animals that were conditioned with NIC in their preferred compartment had no significant change in time spent in that side. 3. Subsequently, locomotor activity was measured during a 30 min test session following the injection of NIC at the dose tested in CPP (0.8 mg/kg). A possible common mechanism on NIC-induced CPP and locomotor stimulation, as they may be regulated by mesolimbic dopamine neurons is discussed.

Animals↗

PubMed1994

Deficits in shock-induced freezing and naltrexone enhancement of freezing in fawn hooded rats.

When a rat is returned to a context associated with mild electric foot shock (1 mA/0.75 s), the environmental cues elicit a species-specific defensive behavior termed freezing. Genetically divergent strains of rats given identical shock conditioning differ in the degree of freezing observed. The acquisition of freezing appears to be mediated, at least in part, by endogenous opioids since the duration that a rat spends freezing is increased by pretreatment prior to training with naltrexone (NTX), an opioid receptor antagonist. The objective of the present studies was to compare the shock-induced freezing and its enhancement with NTX in two unique strains of rats, viz., N/Nih and Fawn Hooded (FH), with that seen in the more commonly employed Sprague-Dawley strain (SPD). Age-matched female rats from these three strains were observed for freezing after shock conditioning. Separate groups of rats from each strain were treated with NTX (7.0 mg/kg) prior to shock. Vehicle (VEH; 0.9% saline)-treated SPD and N/Nih rats were observed freezing for approximately 30% of the testing duration, whereas FH rats froze for only 15% of the test duration. NTX-treated SPD and N/Nih rats displayed an equivalent 130% increase in freezing in comparison to their respective saline controls. Freezing in NTX treated FH rats did not differ from VEH. Collectively, these results suggest that the level of freezing and NTX enhancement of freezing in the N/Nih rat strain are equivalent to SPD. In comparison, FH rats show deficits in freezing and are insensitive to NTX enhancement of freezing.

Animals↗

PubMed1993

Comparison of the behavioral effects of ibogaine from three sources: mediation of discriminative activity.

Ibogaine is an alkaloid employed for its hallucinatory properties in West Central Africa which has been the subject of alleged efficacy as an aid in the interruption and treatment of chemical dependency. The major sources of the Schedule I agent are: Sigma Chemical Co., the National Institute on Drug Abuse and as NDA International Inc.'s Endabuse. The intent of the present study was to, for the first time, train rats to discriminate the interoceptive stimuli produced by (10 mg/kg, intraperitoneally administered) ibogaine. Once trained, these rats were used to investigate the dose-response effects to ibogaine from each of the three suppliers. In addition, stimulus generalization to the dopamine antagonist CGS 10476B, as well as to the serotonergically active compounds fenfluramine, TFMPP (1-(m-trifluoromethylphenyl)piperazine, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), MDMA (3,4-methylenedioxymethamphetamine), quipazine and LSD, was tested. The results indicate that ibogaine is readily discriminable from its vehicle and that ibogaine from each of the three supplies produced statistically similar discrimination with ED50 values ranging from 2.5 to 3.4 mg/kg. In addition, various doses of the novel drugs tested produced, at best, intermediate ibogaine-appropriate responding and, thus, no drug tested can be considered to generalize to ibogaine-like stimuli. Discussion concerns the multiple actions of ibogaine that have been cited in the scientific literature. The similarity in potency of ibogaine from three potential suppliers should allow for pre-clinical work using any of these research samples to be comparable.

Animals↗

PubMed1993

Conditioned place preference produced by the psychostimulant cathinone.

Previous work has indicated that the psychostimulant cathinone produces a location preference in the conditioned place preference task. The present study expanded upon this earlier work by examining the dose-response nature of cathinone-induced conditioned place preference, as well as testing its effect upon spontaneous locomotor activity. At doses ranging from 0.2 to 1.6 mg/kg, cathinone produced a conditioned place preference at all but the lowest dose, and the highest dose but not the lowest dose increased locomotor activity. Results are discussed in terms of dopaminergic mediation of conditioned place preference and the relationship between conditioned place preference and locomotion being subserved by the same neuronal system.

Alkaloids↗

PubMed1993

Differential effects of nicotine but not cathinone on motor activity of P and NP rats.

The locomotor stimulatory effects of nicotine (0.4 and 0.8 mg/kg) and cathinone (0.5 and 1.0 mg/kg) were assessed in alcohol-preferring (P) and -nonpreferring (NP) rats. Whereas P rats demonstrated enhanced (0.8 mg/kg) or no change (0.4 mg/kg) in spontaneous locomotor activity (SMA) to nicotine, NP animals showed no change (0.4 mg/kg) or depression of activity (0.8 mg/kg). However, following cathinone administration both P and NP rats exhibited an increase in SMA. The above results are discussed in light of the genotypic variations between P/NP rats and the potential mediation of differential neurotransmitter effects in the two lines.

Alcohol Drinking↗

PubMed1993

Cocaine discrimination is attenuated by isradipine and CGS 10746B.

The discriminative stimulus properties of cocaine are thought to be mediated by dopaminergic mechanisms that may be modulated by calcium ion influx and/or interact with 5-hydroxytryptamine3 (5-HT3) receptors. To test these possibilities, rats were trained to discriminate between the stimulus properties of 10.0 mg/kg cocaine and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance when tested with lower cocaine doses. An analysis of the dose-response curve indicated an ED50 value of 3.04 mg/kg. Pretreatment with the presynaptic dopamine release-inhibiting agent CGS 10746B (20-40 mg/kg) resulted in a dose-related decrease in cocaine discrimination with the highest dose significantly attenuating cocaine discrimination. Pretreatment with 10-30 mg/kg isradipine, a calcium channel blocker, also resulted in a dose-related decrease in cocaine discriminative performance. In contrast to these positive results, pretreatment with the 5-HT3 receptor antagonist MDL 72222 (3.5-7.0 mg/kg), or the same doses of ibogaine, did not significantly affect cocaine discrimination. The results suggest that cocaine controls differential responding in a discriminative stimulus task by mechanisms that involve presynaptic release of dopamine, which may be regulated by neuronal calcium influx through L-type calcium channels.

Animals↗

PubMed1993

P and NP rats respond differently to the discriminative stimulus effects of nicotine.

Rats selectively bred for ethanol preference, that is, alcohol-preferring (P) and -nonpreferring (NP) rats, were trained to discriminate the interoceptive stimuli produced by IP-administered 1,000 mg/kg ethanol (10% v/v) in a two-lever, food-motivated, operant task. Once criterion performance was attained, dose-response experiments indicated an ED50 value for P rats = 354.1 mg/kg, whereas NP rats generated an ED50 value of 495.1 mg/kg, not significantly different from each other. In contrast to these similar sensitivities to ethanol, administration of doses of nicotine (0.4-1.2 mg/kg, SC) indicated that P rats were significantly more sensitive to the ethanol-like effects of nicotine than were NP rats. The results provide additional evidence for a possible hereditary co-occurrence of alcohol and nicotine sensitivity.

Alcoholism↗

PubMed1993

Place preference for the psychostimulant cathinone is blocked by pretreatment with a dopamine release inhibitor.

1. The objective of Exp. 1 was to determine whether intracerebroventricular (ICV) injection of cathinone CATH (8.0-32 micrograms) would produce a dose-dependent conditioned place preference (CPP) and/or activation in rats. Results indicate that rats conditioned with 16 or 32 micrograms doses of CATH significantly increased the time spent in their less preferred side, whereas rats conditioned with the 8.0 micrograms dose failed to show any shift from baseline preference. The 16 and 32 micrograms doses of CATH also significantly (p < .004) increased activity by more than 65% of baseline. 2. Exp. 2 was designed to determine whether ICV pretreatment with a dopamine release inhibitor CGS 10746B (CGS; 15 micrograms/rat) would block place conditioning produced by CATH. The results demonstrate that CGS pretreatment effectively blocked CATH-induced place conditioning and the CATH-induced elevation of activity.

Alkaloids↗