Biomedical subjects

M D Schechter

Publications and source records attributed to M D Schechter.

At least 19 recordsLinked to original sources

PubMed1995

Genetic selection for nicotine activity in mice correlates with conditioned place preference.

Genetically heterogenous stock (HS) mice are being used to develop lines which have differential locomotor response to subcutaneously administered (0.75 mg/kg) nicotine. These groups of nicotine-depressed, nicotine-activated or randomly bred control mice were tested as to conditioned place preference using the same dose of nicotine employed to determine their locomotor performance in activity tests. Results indicate that the nicotine-activated mice showed a significantly greater preference to nicotine when compared to the nicotine-depressed mice; this effect was seen in the first generation and continued in the more recently tested third generation. Evidence is offered to support the hypothesis that it is the stimulatory effects of drugs (of abuse) that can be directly correlatable with the strength of their reinforcing effect upon behavior.

Analysis of Variance↗

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

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

Dopaminergic mediation of the stimulant generalization of nicotine.

1. Experiments were conducted to investigate if the psychostimulant cathinone, like d-amphetamine, would produce generalization of the discriminative stimulus effects of nicotine. 2. Rats were trained to discriminate either 0.8 mg/kg cathinone from its vehicle or 0.8 mg/kg nicotine from its vehicle and, subsequently, administered various doses of the other compound. 3. Results of Exp 1 indicate that animals trained to discriminate cathinone only partially generalize to the effects of 0.8-1.6 mg/kg nicotine. In contrast, animals trained to discriminate nicotine dose-responsively generalize to cathinone doses ranging from 0.1-1.2 mg/kg. 4. Exp 2 served to investigate the effects of the dopamine release inhibiting drug CGS 10746B upon the observed cathinone generalization in nicotine-trained rats. Pretreatment with this compound at doses of 20 and 30 mg/kg significantly attenuated cathinone generalization in these animals. 5. The results are discussed in light of the growing evidence that nicotinic receptors reside upon mesolimbic dopamine neurons and the possibility that the consequent increase in extracellular dopamine may produce the discriminative stimuli, as well as the reinforcing properties, of nicotine.

Alkaloids↗

PubMed1992

Differences in response to the aversive properties and activity effects of low dose ethanol in LAS and HAS selectively bred rats.

Rats selectively bred for high alcohol sleep times (HAS) and those that are less affected (LAS) by hypnotic doses (3.0-3.6 g/kg) of ethanol were tested for differential responses to the aversive effects of 1.0 g/kg ethanol in a conditioned place preference task. Likewise, the effects of 0.3-1.0 g/kg ethanol on spontaneous locomotor activity over a 30-min period, as well as the loss of righting reflex with a higher ethanol dose (3.0 g/kg), were determined in these animals. The LAS rats reacted more aversively to 1.0 g/kg during conditioned place aversion testing than the HAS animals and also had a shorter mean sleeping time following 3.0 g/kg ethanol. Furthermore, dose-related depression of spontaneous motor activity was seen in the HAS animals and not in the LAS animals over a 30-min period using doses of 0.3, 0.6, or 1.0 g/kg (10% w/v) ethanol. Taken together, the results indicate that the intoxicating sequelae of high ethanol doses, such as ataxia and sedation, may not be correlated with the aversive effects of low ethanol doses.

Animals↗

PubMed1992

Place conditioning reveals the rewarding aspect of social interaction in juvenile rats.

Rewards, as diverse as food, sweetened solutions, copulation, electrical brain stimulation, and drugs abused by humans, have been shown to condition place preferences in rats. Juvenile rats will readily learn to traverse a T-maze for the opportunity to interact with another similar-aged rat. This suggests that play behavior is rewarding. Experiment 1 examined whether play (as quantified by rough-and-tumble pinning) would act as a sufficient reward to condition a place preference (CPP). Experiment 2 examined whether pairings with a nonplaying partner would decrease the time spent in the preferred side and thus suggest a conditioned place aversion (CPA). In Experiment 1, dominant juvenile rats were given free access to a CPP apparatus and a side preference for one of the two physically distinct sides was determined. Dominant rats were then conditioned twice daily over four days in the CPP apparatus. They spent their first session confined in their preferred side with a scopolamine-treated partner (that rendered the partner unable to respond to play solicitations) and during the second session, dominant rats were confined to their less preferred side with a submissive play partner. The number of dorsal contacts, as well as frequency and duration of pinning, were recorded. Following conditioning, side preference was redetermined. A similar procedure was used in Experiment 2 except that the subjects underwent conditioning on their less-preferred side without a play partner. Results of Experiment 1 demonstrated that the dominant rats significantly increased (198.6%) the time spent on the originally less-preferred side after play conditioning.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Direct microinjection of cathinone into the rat brain produces discriminative stimuli.

Rats were trained to discriminate IP administration of 800 micrograms/kg cathinone using a food-motivated, two-lever discrimination procedure. Following training, 800 micrograms/kg cathinone discrimination was produced (generalized) by lower cathinone doses in a dose-responsive manner after IP administration; an ED50 value of 330 micrograms/kg was calculated. Subsequently, guide cannulae were implanted into the lateral ventricle and bilaterally into the nucleus accumbens. After recovery, injections were made via cannulae that extended 0.5 mm past the tip of the guide cannulae. ICV administration of 256 micrograms cathinone/rat produced discriminative responding on the cathinone-appropriate lever to the same degree as did the peripherally administered training dose of cathinone. Decreasing ICV doses produced decreased discriminative performance and allowed the calculation of an ED50 value of 90.5 micrograms. Likewise, administration of 64 micrograms cathinone/nucleus accumbens (for a total of 128 micrograms/rat) substituted for the IP training dose of cathinone. These results evidence the central mediation of the cathinone-induced discriminative stimulus cue and show that administration of cathinone into the nucleus accumbens is sufficient to produce these stimuli. Thus, these data suggest that receptors in the nucleus accumbens are important for the discrimination of this psychostimulant.

Alkaloids↗

PubMed1992

Effect of altering dopamine or serotonin neurotransmitters upon cathinone discrimination.

Rats were trained to discriminate between the stimulus properties of 0.8 mg/kg l-cathinone 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 cathinone doses. An analysis of the dose-response curve indicated an ED50 value of 0.23 mg/kg. Pretreatment with CGS 10746B (5-20 mg/kg) resulted in a dose-related decrease in cathinone discrimination with the highest dose blocking cathinone discrimination. In contrast to the ability of this dopamine release inhibitor to decrease cathinone discrimination, pretreatment with three doses of the calcium channel blocker isradipine (2.5-10 mg/kg) or with the 5-HT3 antagonist MDL 72222 (0.1-0.4 mg/kg) had no effect upon cathinone discrimination. The results suggest that cathinone controls differential responding in a discriminative stimulus task by a mechanism involving presynaptic release of dopamine, which may not be regulated by either neuronal calcium influx through L-type calcium channels or by serotonergic neurons.

Alkaloids↗

PubMed1992

Further evidence for the mechanisms that may mediate nicotine discrimination.

Rats were trained to discriminate the interoceptive stimuli produced by subcutaneously administered 0.4 mg/kg nicotine in a two-lever, food-motivated, operant task. Once criterion performance was attained, dose-response experiments indicated an ED50 value of 0.1 mg/kg and subsequent time course experiments showed a maximal effect between 10 and 30 min postadministration with a return to saline-like responding at 2 h. Pretreatment with the presynaptic dopamine release inhibitors CGS 10746B (30 mg/kg), as well as with the dihydropyridine calcium blocker isradipine (15 mg/kg), each produced a significant blockade of nicotine discrimination. In contrast, the 5-hydroxytryptamine (5-HT) receptor 5-HT3 antagonist ICS-205930 did not produce any effect upon nicotine discrimination. Thus, drugs that interfere with calcium influx, viz., isradipine, or with dopamine release (CGS 10746B) also interfere with nicotine discrimination and these results suggest that calcium influx and dopamine release may be necessary conditions for nicotine discrimination.

Animals↗

PubMed1992

Rats bred for differences in preference to cocaine: other behavioral measurements.

Cocaine has repeatedly been shown to produce conditioned place preference (CPP) in the rat. The present study employed the heterogenous N/Nih rat stock to produce a selectively bred rat line determined by individual place preference to a conditioning dose of 2.5 mg/kg cocaine. As each of three generations of rats were exposed to the CPP task, cocaine-preferring (CP) males were mated with CP females whereas cocaine-nonpreferring (CNP) male rats were paired with their female counterparts. Rats in litters of the third generation of these selectively bred rats were used in two collateral studies: one involving the discriminative stimulus properties of cocaine and the other to investigate the ability of cocaine to stimulate activity. Results indicate that the continued breeding of CP animals has resulted in rats that prefer cocaine, whereas the breeding of CNP rats is defining a line of rats that actually find cocaine aversive. In testing the discriminative stimulus performance of five male CP and five male CNP rats, the learning rates and dose-response relationship to cocaine were not significantly different between these two groups. In contrast, administration of 5.0 and 7.5 mg/kg cocaine to male and female CP and CNP rats indicated that, although all groups were stimulated by cocaine when compared to vehicle administration, male CNP rats showed a significantly decreased reaction to these two doses of cocaine. The possibility that conditioned place preference and locomotor stimulation are subserved by the same neural substrates, that is, most probably the dopaminergic systems in the nucleus accumbens of the brain, is discussed.

Animals↗

PubMed1992

Psychostimulant-induced activity is attenuated by two putative dopamine release inhibitors.

Centrally administered amphetamine (AMPH), cathinone, (CATH), or cocaine (COC) have each been shown to produce elevated activity in rats and this effect is dose responsive. The question remains whether these psychostimulants share a common mechanism of action (i.e., do these psychostimulants act by releasing dopamine to increase activity levels?). Experiments were, therefore, conducted to measure the spontaneous activity of these three centrally administered psychostimulants in rats following pretreatment with two putative dopamine release inhibitors, viz., 5-(4-methyl-1 piperazinyl)imidazol(2,1-b) (1,3,5)-benzothiadiazepine maleate [CGS 10746B (CGS); 20 mg/kg)] and 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicar boxylic acid methyl 1-methyl-ethyl ester [isradipine (ISR); 2.5 mg/kg)]. Rats fitted with chronic indwelling ventricular cannulae received a single dose of ICV-administered CATH (32 micrograms), AMPH (16 micrograms), COC (100 micrograms), or vehicle. Selection of these ICV doses of stimulant drugs was based upon results obtained in preliminary studies that indicated similar elevations of activity. ICV administration of each of these drugs/doses was preceded (20 min) by peripherally administered CGS, ISR, or vehicle. Results show that ICV CATH (32 micrograms), AMPH (16 micrograms), COC (100 micrograms) equieffectively elevate activity (two- to threefold) and that, in each case, this increase was significantly attenuated by pretreatment with CGS or ISR.

Alkaloids↗

PubMed1992

Evidence for noradrenergic involvement in mediating the FG 7142 discriminative stimulus.

Rats were trained to discriminate the stimulus properties of the benzodiazepine receptor partial inverse agonist beta-carboline-3-carboxylate acid methyl amide (FG 7142) (5.0 mg/kg) or the alpha 2-adrenergic receptor antagonist 17 alpha-hydroxyyohimban-16 alpha-carboxylic acid methyl ester (yohimbine) (3.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. These compounds have in common a beta-carboline structure and anxiogenic behavioral profiles. The yohimbine discriminative stimulus was mimicked by the alpha 2-adrenergic receptor antagonist idazoxan and antagonized by the alpha 2-adrenergic receptor agonist clonidine, indicating that the yohimbine stimulus was mediated through the alpha 2-adrenergic receptor. The anxiogenic beta-carbolines FG 7142, 1,2,3,4-tetrahydro-beta-carboline (THBC), and norharmane, the anxiogenic/convulsant agent pentylenetetrazole (PTZ), and two physiological stressors failed to mimic the yohimbine discriminative stimulus. In contrast, both yohimbine and idazoxan dose responsively mimicked the anxiogenic FG 7142 stimulus. The present results demonstrate that an asymmetrical generalization exists between the discriminative stimuli produced by yohimbine and FG 7142. Furthermore, these data suggest that yohimbine can produce a multicomponent discriminative stimulus, part of which may be anxiogenic in nature. The ability of alpha 2-adrenergic receptor antagonists to mimic the FG 7142 cue suggests that activation of the noradrenergic system may underlie cues produced by benzodiazepine receptor inverse agonists.

Adrenergic alpha-Antagonists↗