Biomedical subjects

M D Schechter

Publications and source records attributed to M D Schechter.

At least 19 recordsLinked to original sources

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↗

PubMed1992

Reducing the time needed to conduct conditioned place preference testing.

The objective of the present experiment was to demonstrate whether four days of twice-a-day conditioned place conditioning produces a preference that is equivalent to that produced by using eight days of once-a-day training. Two doses of the amphetamine-like stimulant drug cathinone (0.2 and 1.6 mg/kg) were selected to demonstrate the effectiveness of twice-a-day (morning-vehicle; afternoon-drug pairings) conditioning. The 0.2 mg/kg dose of cathinone failed to affect the expression of place preference, whereas the 1.6 mg/kg dose produced a significant (p less than 0.002) shift in CPP from baseline when compared to previous measurements. These results demonstrate that twice-a-day pairings over four days effectively shorten the total duration of training without changing the development of place preference produced by once-a-day over eight conditioning day schedule.

Alkaloids↗

PubMed1992

Increases in the locomotor activity of rats after intracerebral administration of cathinone.

There is a widespread practice among people living in Eastern Africa and Southern Arabia of chewing the leaves of the Khat shrub so as to produce pharmacological effects that are practically indistinguishable from those produced by amphetamine (AMPH). Cathinone (CATH) has been identified as the psychostimulant constituent of this plant and, although the locomotor elevating effects of centrally administered AMPH and cocaine (COC) in rats are well known, there is a paucity of data regarding CATH. Three experiments were, therefore, conducted to measure locomotor activity following central administration of CATH in rats. The first experiment determined the dose-dependent effects of CATH on activity following intracerebroventricular (ICV) administration. As psychostimulant effects are believed, at least in part, to be mediated by dopaminergic systems, in Experiment 2 CATH was injected into the dopamine nerve terminals of the nucleus accumbens. Experiment 3 examined the effects of CATH injection into the dopamine cell body region of the substantia nigra, and activity was measured. Results of the ICV injection of CATH revealed a dose-dependent increase of activity. The highest dose tested (64 micrograms) yielded a 117% increase in activity when compared to baseline, whereas a 20 micrograms bilateral nucleus accumbens (NA) injection of CATH increased activity fivefold. These findings evidence the hypothesis that the effects of CATH are dopaminergically mediated. Substantia nigra (SN) injections of CATH were without effect.

Alkaloids↗

PubMed1992

Attenuation of drinking sweetened water following calcium channel blockade.

Recent reports cite results that both cocaine-induced conditioned place preference and activity stimulation are attenuated by pretreatment with the calcium channel blocker isradipine (ISR) in rats. By blocking voltage-dependent L-type calcium channels, ISR may regulate neural dopamine release that, in turn, decreases the putative rewarding effects mediated by dopaminergic mechanisms. It is known that nonfluid deprived rats avidly consume sweetened fluids; this suggests that the sweet taste is rewarding. Three experiments were conducted to determine the effects of ISR on drinking sweetened and nonflavored water. Experiment 1 was designed to test whether ISR would attenuate the intake of a palatable solution in a dose-dependent manner. To this end, ISR was administered both peripherally (3.0-30 mg/kg) and centrally (0.3-30 micrograms/rat) prior to a solution of saccharin and d-glucose (S + G) being made available to rats (15 min/day) and intake was recorded. ISR produced dose-dependent decreases (38%-81%) in S + G intake dependent on the route of administration. In Experiment 2, water intake was measured in 18 h water-deprived rats following ISR (10 mg/kg) administration as well as comparing S + G drinking. The effect of two ISR vehicles, dimethyl sulfoxide and Tween 80, upon fluid intake was also determined. ISR injection did not attenuate water intake in 18 h water-deprived rats and the choice of vehicle did not affect the ISR-induced attenuation of S + G drinking. In Experiment 3, a single dose (30 micrograms) of ICV administered ISR, that attenuated S + G intake by approximately 44%, did not attenuate water intake in 18 h water-deprived rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Possible serotonergic and dopaminergic mediation of the N-ethyl-3,4-methylenedioxyamphetamine discriminative stimulus.

Eight male rats previously trained to discriminate 2.0 mg/kg N-ethyl-3,4-methylenedioxyamphetamine (MDE) from its vehicle in a two-lever, food motivated task were utilized to characterize the stimulus properties of MDE. The 5-HT receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP), quipazine and 6-methoxy-1,2,3,4 tetrahydro-beta-carboline were able to generalize to the stimulus produced by MDE. However, the 5-HT receptor agonists m-chlorophenylpiperazine (mCPP), buspirone and norfenfluramine, the dopamine receptor agonist amphetamine, as well as the acetylcholine receptor agonist arecoline did not completely generalize. In addition, the simultaneous administration of norfenfluramine and amphetamine generalized to MDE. Pretreatment with the serotonin receptor antagonists cinanserin and metergoline or the dopamine receptor antagonist haloperidol failed to completely inhibit the discriminative stimulus produced by MDE. Multiple p-chlorophenylalanine (PCPA) pretreatments significantly reduced MDE discrimination, whereas vehicle discrimination was unaffected. Five days following cessation of PCPA pretreatment, MDE discrimination returned to criterion levels and remained at that level. These results suggest that the stimulus produced by MDE involve a complex interaction of various neurotransmitters, with both serotonergic and dopaminergic components.

3,4-Methylenedioxyamphetamine↗

PubMed1991

Inverse agonist properties of the THBC discriminative stimulus: asymmetrical generalization with FG 7142.

Male rats were trained to discriminate the stimulus properties of the beta-carbolines 1,2,3,4-tetrahydro-beta-carboline (THBC) (15.0 mg/kg) or FG 7142 (5.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. Consistent with the serotonergic properties of THBC, administration of the 5HT1B agonists TFMPP and mCPP to THBC-trained rats resulted in THBC-appropriate responding. Norharmane, a beta-carboline metabolite of THBC, also mimicked the THBC discriminative stimulus. In contrast, the benzodiazepine receptor partial inverse agonist FG 7142, the anxiogenic/convulsant pentylenetetrazole (PTZ), two physiological stressors and the alpha 2 adrenergic antagonists yohimbine and idazoxan failed to produce THBC-appropriate responding. In the FG 7142-trained rats, THBC and norharmane dose-dependently mimicked the FG 7142 discriminative stimulus. This generalization was not based upon the serotonergic properties of THBC and norharmane since administration of the serotonin agonist mCPP to FG 7142-trained rats failed to produce FG 7142-appropriate responding. The ability of THBC to substitute for the FG 7142 discriminative stimulus was antagonized by the benzodiazepine receptor mixed agonist/antagonist CGS 9896 and the benzodiazepine receptor antagonist RO 15-1788, indicating that THBC produces an inverse agonist stimulus in FG 7142-trained rats. These results suggest that THBC produces a discriminative stimulus which consists of both serotonergic and inverse agonist components.

Animals↗

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↗