Biomedical subjects

M D Schechter

Publications and source records attributed to M D Schechter.

At least 55 records · Page 3Linked to original sources

PubMed1993

Differential training sequence effect upon psychostimulant discrimination.

1. Previous studies indicate that rats trained to discriminate either cathinone or cathine from its vehicle have a diminished discriminative performance when tested 24 hours after a drug administration when compared to tests conducted after a vehicle administration. The phenomenon of rapid tolerance may occur to produce a lessened interceptive cue on the test day following administration of the drug. It would, therefore, be probable that when rats are trained with consecutive cathinone or cathine administrations they would perform less well than if they were trained with these drugs never given in consecutive training sessions. 2. To test this hypothesis, rats were trained with 0.8 mg/kg 1-cathinone or 4.8 mg/kg d-cathine in a two-lever, food motivated operant task. Each of these groups were divided into two subgroups with the one receiving consecutive drug administrations and the second never receiving two consecutive administrations of the drug. 3. Results indicate that in the cathine-trained group, there was a significant increase in the time that was necessary to train the animals when consecutive administrations were used in training. This, however, did not occur in the cathinone-treated group. There was, however, no significant difference between the differentially trained groups as to ED50 values. 4. It, thus, appears that there may not be a correlative relationship between speed of acquisition, as documented by sessions-to-criterion, and sensitivity, as indicated by ED50 values.

Alkaloids↗

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↗

PubMed1993

Calcium channel blockade attenuates angiotensin II-induced drinking in rats.

Lateral ventricular administration of angiotensin II (ANG II) produces potent dipsogenic effects in water-sated rats. ANG II seems to require functional voltage-gated calcium channels on neurons throughout circumventricular brain sites to exert its effects. Although there are at least three types of calcium channels, only L-type calcium channel-blocking drugs have been reported to decrease drinking. (4-(4-Benzofurazanyl)-1-4-dihydro-2,6-dimethyl-3,5-pyridine-dic arb oxylic acid methyl 1-methyl-ethyl ester) [PN 200-110; isradipine (ISR)], a selective L-type calcium channel blocker, has been shown to attenuate significantly the intake of sweetened water in water-sated rats following either peripheral or ICV administration, but ISR does not affect plain-water intake in water-deprived rats. The present experiment was designed to determine whether ISR would attenuate ANG II-induced drinking that is not either motivated by palatability or dependent on deprivation. Rats, each fitted with chronic indwelling ventricular cannulae, were pretreated with ISR (0.3, 3.0, and 30 micrograms/rat; ICV). ANG II (40 ng/rat; ICV) was administered 10 min later and rats were allowed free access to water for 15 min. Injections of ANG II plus saline and ANG II plus the ISR vehicle (dimethyl sulfoxide) did not attenuate ANG II-induced polydipsia, whereas ANG II+ISR (0.3 and 3.0 micrograms) attenuated ANG II-induced drinking to 62 and 22% of control, respectively. Results with the 30-micrograms dose were not different from the 3.0 dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1993

Extinction of cocaine-induced place approach in rats: a validation of the "biased" conditioning procedure.

It has often been demonstrated that when a rat is conditioned in a cue-specific environment that has been repeatedly paired with cocaine injections, it will spend more time in that environment than it does in a saline-paired environment. This behavioral procedure is commonly known as the conditioned place preference (CPP)-test. At present, a firm theoretical understanding of the mechanisms underlying the production of a CPP are unknown. It is insufficient merely to know that a CPP can result after repeated drug pairings. Rather, it is necessary that the procedure is validated within a learning theory framework. The objective of the present study was, therefore, to establish that what is observed in place preference studies was, indeed, conditioning. This was accomplished by determining whether a cocaine-induced increase in time spent in a drug-paired environment was subject to attenuation following extinction trials. Rats were tested for their initial bias in spending more time in one of two stimulus-specific chambers of a place-conditioning apparatus. On four occasions, rats were injected with 2.5 mg/kg cocaine and confined to their less-preferred chamber whereas, on four alternating sessions, they were conditioned with saline (vehicle) in their preferred chamber. Subsequent testing in the nondrugged state revealed that these rats displayed a significant increase in the time spent in their initially least-preferred environment compared to baseline measurements. Following establishment of this cocaine-induced CPP, the rats were injected only with saline and conditioned for an equal number of sessions (i.e., four).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Trends in place preference conditioning with a cross-indexed bibliography; 1957-1991.

The purpose of this work is to present a perspective of the conditioned place preference (CPP) test by offering an overview of the empirical research from 1957-1991. The intent is not to extensively analyze the controversies inherent to any behavioral technique but rather to present a survey of research using a descriptive statistics approach to explore topical issues. The objectives of this work are three-fold: (a) to provide an exhaustive bibliography of the CPP literature including articles, journal abstracts, book chapters and critical reviews; (b) to provide a cross-index of identified key words/drugs tested; and (c) to give an overview of selected procedural issues underlying CPP testing.

Animals↗

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↗