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J B Appel

Publications and source records attributed to J B Appel.

At least 19 recordsLinked to original sources
PubMed1992

Stimulus effects of d-amphetamine 1: DA mechanisms.

As part of a continuing effort to assess the role of monoaminergic neuronal systems in the subjective effects of CNS stimulants, 10 rats trained to discriminate 1.0 mg/kg d-amphetamine from saline were treated with compounds that act through different dopaminergic mechanisms. In substitution (generalization) tests, 20 mg/kg of the dopamine (DA) uptake inhibitor GBR 12909 mimicked the training drug completely; at a dose of 15 mg/kg, GBR 12909 substituted for d-amphetamine incompletely. Neither the D1 agonist SK&F 38393 (1, 10 mg/kg) nor the D2 agonist quinpirole (LY 171555; 0.05-0.2 mg/kg) had amphetamine-like effects. When given in combination with the training drug, the D1 antagonist SCH 23390 blocked the amphetamine cue completely at a dose of 0.05 mg/kg but did not have significant effects at higher or lower doses; the D2 antagonist metoclopramide did not block d-amphetamine at any dose tested (1-5 mg/kg). These data indicate that: a) The discriminable effects of d-amphetamine are due, at least in part, to inhibition of DA uptake; b) direct stimulation of either D1 or D2 receptor sites is not sufficient to evoke d-amphetamine-like responding; and c) blockade of D1 receptors attenuates the subjective effects of d-amphetamine to a greater extent than blockade of D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine.

Evidence suggests that stimulants such as d-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D1 and D2) exist, we investigated the role of both of these receptor subtypes in mediating the internal "state" produced by these stimulants. Two groups of rats (N = 8/group) were trained to discriminate intraperitoneal (IP) injections of either d-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D1 and D2 agonists and antagonists. The D2 agonist quinpirole (0.0313-0.125 mg/kg) mimicked both stimulant cues while the D1 agonist SKF 38393 (5-20 mg/kg) substituted partially for cocaine but not d-amphetamine. Combination tests with DA antagonists indicated that both the D1 antagonist SCH 23390 (0.0063-0.25 mg/kg) and the D2 antagonist haloperidol (0.125-0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) for d-amphetamine was blocked by both DA antagonists. The ability of both D1 and D2 antagonists to attenuate the stimulus effects of d-amphetamine and cocaine raises the possibility that a synergistic ("enabling") interaction between D1 and D2 receptors may modulate stimulant cues.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice, drug discrimination procedure.

The discriminative stimulus properties of (+)-lysergic acid diethylamide (LSD) and lisuride hydrogen maleate (LHM), were compared in a three-choice, water reinforced (FR 20) situation in which rats were required to press one lever following LSD (0.08 mg/kg), a second lever following LHM (0.04 mg/kg), and a third lever following saline. Reliable drug-appropriate responding was established in 72 sessions. Dose-response tests with LSD and LHM indicated that, as dose increased, the per cent of responding on the lever associated with the particular training drug also increased; little or no cross-transfer occurred between LSD and LHM. In generalization tests, the serotonin (5-HT) agonist quipazine substituted for LSD but not LHM while the dopamine (DA) agonist apomorphine mimicked LHM but not LSD; an unrelated compound, pentylenetetrazol (PTZ), produced responding on the saline-appropriate lever. In combination tests, 5-HT antagonists (e.g., BC-105 and low doses of pirenperone) blocked responding on the LSD lever while DA antagonists (e.g., haloperidol and much higher doses of pirenperone) blocked LHM-appropriate responding. These data suggest that the three-lever (D-D-N) procedure is similar to, but can be more sensitive than the two-lever (D-N) procedure (because it can differentiate between LSD and LHM); they therefore at least partially support the hypothesis that three-choice discriminations can be conceptualized as two separate, two-choice (D-N) discriminations (Jarbe and Swedberg 1982). The results also confirm suggestion that the stimulus effects of LSD and LHM are mediated by different mechanisms; the primary action of LSD is serotonergic (5-HT2), while that of LHM is dopaminergic (White 1986).

Animals↗
PubMed1989

Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline.

In order to further evaluate the extent to which particular 5-HT receptor subtypes (5-HT1, 5-HT2) might be involved in the behavioral effects of hallucinogenic drugs, rats were trained to discriminate mescaline (10 mg/kg i.p.) from saline and were given substitution (generalization) and combination (antagonism) tests with putatively selective serotonergic and related neuroactive compounds. The mescaline cue generalized to relatively high doses of the 5-HT2 agonists, 2,5-dimethoxy-4-methylamphetamine (DOM), LSD and psilocybin; the extent of generalization to 5-HT1 agonists (8-hydroxy-2-[diethylamino]tetralin (8-OHDPAT), RU-24969 and 8-hydroxy-2-[di-n-propylamino]tetralin (TFMPP] was unclear. Combinations of the training drug and sufficiently high doses of 5-HT2 antagonists (ketanserin, LY-53857, pirenperone) were followed by saline-lever responding; less selective central 5-HT (metergoline), and DA (SCH-23390, haloperidol) antagonists, did not block the mescaline cue. These data suggest that 5-HT2 receptors are involved in the stimulus properties of mescaline.

Animals↗
PubMed1989

Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine.

The involvement of dopamine (DA) receptor subtypes in the behavioral effects of CNS stimulants was studied in rats trained to discriminate cocaine from saline. In substitution tests, the stimulus effects of 10 mg/kg of this substance generalized to d-amphetamine (0.25-1.0 mg/kg) and the selective D2 against LY-171555 (0.05-0.25 mg/kg) but not to the D1 agonist SKF-38393 (5.0-15.0 mg/kg); in combination tests, the D1 antagonist Sch-23390 (0.0625-0.5 mg/kg) significantly blocked, and the D2 antagonist spiperone (0.25-0.5 mg/kg) partially blocked the cocaine cue. These data suggest that the involvement of DA systems in the behavioral effects of cocaine is more complex than either D1 or D2 receptor activation; for example, the stimulus properties of this substance might involve both D1 and D2 receptor activation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Stimulus properties of dopaminergic drugs: comparisons involving selective agonists and antagonists.

Rats were trained to discriminate the putatively selective dopamine (DA) receptor agonists SKF 38393 (10 mg/kg) or Ly 171555 (0.025 mg/kg) from saline in a two-lever situation involving fixed-ratio (FR 20), extinction schedules of water reinforcement. During substitution tests, no dose of any compound [apomorphine, Ly 171555, lisuride, LSD, amphetamine, cocaine, (-) 3-PPP, or SKF 82526] mimicked SKF 38393, the effects of which were blocked by the D1 antagonist Sch 23390 but not by haloperidol. Postsynaptic and DA "autoreceptor" agonists [apomorphine, (-) 3-PPP], as well as dopaminergic ergot derivatives (bromocriptine, lergotrile, lisuride) and Sch 23390, substituted for Ly 171555, a partial ergoline which has behavioral effects that are blocked by haloperidol and molindone, but not by either Sch 23390 or serotonin (5-HT) antagonists (ketanserin, pizotifen). Amphetamine and cocaine did not substitute for either SKF 38393 or Ly 171555. These results suggest that the stimulus properties of a variety of neuropharmacologically important and clinically useful compounds are transduced at (pre- or postsynaptic) D2 receptors. However, this conclusion must be tempered by evidence that actions at D1 and D2 receptors may not be entirely independent. The behavioral effects of abused psychomotor stimulants probably involve mechanisms other than "direct" agonist activity at either D1 or D2 receptors.

Animals↗
PubMed1988

Differences in the stimulus properties of 3,4-methylenedioxyamphetamine and 3,4- methylenedioxymethamphetamine in animals trained to discriminate hallucinogens from saline.

The stimulus properties of 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and several related compounds were compared to those of (+)-lysergic acid diethylamide (LSD) and mescaline (3,4,5-trimethoxyphenylethylamine) in a two-lever, water-reinforced, drug discrimination task. In animals trained to discriminate LSD (0.08 mg/kg) from saline (n = 8), LSD-like responding occurred during substitution (generalization) tests with sufficiently high doses of (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline, psilocybin and (-)-MDA; saline appropriate responding occurred after (+)-MDA and both (+)- and (+)- and (-)-MDMA. In animals trained to discriminate mescaline (10 mg/kg; n = 8), (-)-MDA, (+)-MDA, (-)-MDMA and (+)-MDMA as well as (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline and psilocybin mimicked the training drug. Neither (+)-amphetamine nor cocaine produced mescaline-like responding; fenfluramine substituted partially for mescaline but not LSD. Because all of the phenylisopropylamine enantiomers mimicked the potent hallucinogen mescaline (10 mg/kg), these results do not support suggestions that similarities in the behavioral effects of "designer" drugs such as MDA and MDMA to those of hallucinogens are limited to (-)-MDA. They also indicate that, although LSD and mescaline may be pharmacologically similar (in other assays), these compounds do not have identical stimulus properties.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT): implications for understanding the actions of novel anxiolytics.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) has effects both characteristic of a serotonin (5-hydroxytryptamine; 5-HT) agonist and antagonist. To investigate the mechanism(s) of action of 8-OHDPAT in vivo, rats were trained to discriminate 8-OHDPAT (0.4 mg/kg) from saline and given various neuroactive compounds during substitution test sessions. Of the 5-HT agonists tested, d-lysergic acid diethylamide, 5-methoxy-n,n-dimethyltryptamine, quipazine, Ru 24969 and 1-(m-trifluoromethylphenyl) piperazine did not mimic the training drug; the dopamine agonists apomorphine and SKF 38393 as well as the alpha 2-adrenoceptor agonist clonidine engendered predominantly saline-lever responding. However, the novel anxiolytics buspirone and ipsapirone as well as the ergot derivative lisuride substituted completely for 8-OHDPAT. In combination tests, 5-HT (ketanserin, metergoline, methysergide, pirenperone), dopamine (haloperidol) and norepinephrine antagonists (prazosin, propranolol) failed to attenuate the 8-OHDPAT cue. The similar stimulus properties of 8-OHDPAT and the novel anxiolytics (buspirone, ipsapirone) are mirrored by the common abilities of these agents to selectively inhibit 5-HT1A binding and release punished responding. Thus, the subpopulation of 5-HT1A receptors may mediate the behavioral effects of these compounds in animals and, in turn, the anxiolytic effects of buspirone and ipsapirone in humans. Although not primarily selective for 5-HT, lisuride may also mimic 8-OHDPAT by direct or indirect stimulation of 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Neuropharmacological reassessment of the discriminative stimulus properties of d-lysergic acid diethylamide (LSD).

The neuropharmacological mechanisms underlying the behavioral effects of d-lysergic acid diethylamide (LSD) were assessed by comparing the discriminative stimulus properties of LSD with those of agonists and antagonists that act selectively at putative serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes (5-HT1 and 5-HT2). Male Sprague-Dawley rats (N = 23) were trained to discriminate LSD (0.08 mg/kg) from saline and given substitution tests with the following agents: 8-hydroxy-2(di-n-propyl-amino) tetralin (8-OHDPAT; 0.02-0.64 mg/kg), Ru 24969 (0.2-3.2 mg/kg), m-chlorophenylpiperazine (MCPP; 0.1-1.6 mg/kg), 1-(m-trifluoromethylphenyl)piperazine (TFMPP; 0.1-1.6 mg/kg), and quipazine (0.2-3.2 mg/kg). Only quipazine mimicked LSD. In combination tests, BC 105 (0.2-3.2 mg/kg), 2-bromolysergic acid diethylamide (BOL; 0.1-1.6 mg/kg), Ly 53857 (0.4-3.2 mg/kg), metergoline (0.05-0.8 mg/kg), ketanserin (0.2-3.2 mg/kg), and pipenperone (0.0025-0.08 mg/kg), all of which act as 5-HT2 antagonists, blocked the LSD cue; only spiperone (0.02-0.32 mg/kg) was without effect. Although commonalities may exist among "5-HT agonists", the present results demonstrate that such "agonists" are not identical. Since putative 5-HT1 agonists do not mimic LSD and the LSD cue is potently blocked by 5-HT2 antagonists, it appears that 5-HT2 neuronal systems are of greater importance than 5-HT1 systems in mediating the discriminative stimulus and, perhaps, other effects of LSD.

Animals↗
PubMed1987

Discriminative stimulus properties of lisuride revisited: involvement of dopamine D2 receptors.

Although the discriminative stimulus effects of the clinically useful ergot derivative lisuride have previously been related to dopamine (DA) neuronal systems, the involvement of DA D1 and D2 receptor subtypes in the lisuride cue has been characterized for the first time in the present experiment. In rats trained to discriminate lisuride (0.04 mg/kg) from saline, appropriate doses of the putative D2 agonist LY 171555 (0.008-0.063 mg/kg) substituted completely whereas the D1 agonist SKF 38393 (2.0-16.0 mg/kg) evoked primarily saline-lever responding. When given in combination with lisuride (0.04 mg/kg), the D2 antagonist (-)-sulpiride (5-30 mg/kg), but not the D1 antagonist SCH 23390 (0.125-0.5 mg/kg), blocked the lisuride cue. Combination tests also suggested that bromuride and pirenperone have DA antagonist properties. Although the specificity of these agents is not fully known, these results support the conclusion that D2 but not D1 receptors play an important role in the stimulus effects of lisuride. Although a role for serotonin in the similar stimulus properties of lisuride and SCH 23390 cannot be ruled out, partial substitution of SCH 23390 (0.0625-0.35 mg/kg; administered alone) for lisuride complements previous observations which suggest that the two DA subtypes may be functionally linked in vivo.

Animals↗
PubMed1986

Dopamine D2 receptor mediation of the discriminative stimulus properties of LY 171555 (quinpirole).

The mechanisms subserving the behavioral effects of the putatively selective dopamine D2 agonist LY 171555 (0.025 mg/kg) were analyzed in rats (N = 23) using a two-lever, water-reinforced drug discrimination task. Substitution (generalization) tests showed that the DA agonist apomorphine mimicked LY 171555 while the selective D1 agonist SKF 38393 did not. When given in combination with the training drug, haloperidol but not the D1 antagonist Sch 23390 dose dependently blocked the LY 171555 cue; given alone, Sch 23390 mimicked LY 171555 and haloperidol elicited responding on the saline-appropriate lever. These results suggest that stimulus properties of LY 171555 are mediated primarily by D2-containing neuronal systems but that the effects of stimulating either D1 or D2 receptor subtypes in vivo are complex and interdependent.

Animals↗
PubMed1986

Effects of repeated administration of the monoamine oxidase inhibitor phenelzine on the discriminability of d-lysergic acid diethylamide (LSD) and 1-(m-trifluoromethylphenyl) piperazine (TFMPP).

Rats trained to discriminate d-lysergic acid diethylamide (LSD; 0.08 mg/kg) or 1-(m-trifluoromethylphenyl) piperazine (TFMPP; 0.8 mg/kg) were treated with the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg/day) for 7 days. After a 24 h "washout" period, they were challenged with the training drug (and dose) or saline, during extinction test sessions. Following 0.08 mg/kg LSD, LSD-trained rats responded primarily on the saline lever (29% drug-appropriate responding) while, after TFMPP (0.8 mg/kg), TFMPP-trained animals responded on the drug lever (75% drug-appropriate responding). These preliminary data suggest that, if serotonin receptors are involved in the behavioral effects of TFMPP, these receptors differ from those involved in the effects of LSD.

Animals↗
PubMed1986

Discriminative stimulus properties of the serotonin agonist MK 212.

In an attempt to clarify the role of 5-hydroxytryptamine (5-HT) in the discriminative stimulus properties of MK 212 (6-chloro-2[1-piperazinyl]pyrazine), male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg of this compound from saline. While the putative 5-HT agonists fenfluramine and m-chlorophenylpiperazine (MCPP) mimicked MK 212 in a dose-related manner, d-lysergic acid diethylamide (LSD), 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, Ru 24969, and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) failed to substitute completely. The 5-HT1/5-HT2 antagonists BC 105, metergoline, and methysergide completely blocked the MK 212 cue, while the selective 5-HT2 antagonists ketanserin and pirenperone, the dopamine antagonists haloperidol and spiperone, and the beta-noradrenergic antagonist propranolol were without effect. The substitutions of fenfluramine and MCPP for MK 212 support a role for 5-HT in the MK 212 cue; however, the lack of substitution of many other 5-HT agonists is difficult to explain. The complete antagonism by 5-HT1/5-HT2 but not by selective 5-HT2, antagonists suggests the possibility that 5-HT1 receptors mediate the stimulus properties of MK 212. Further research is needed to support this hypothesis and to investigate the relative role of 5-HT and other neurotransmitters in the stimulus effects of MK 212.

Animals↗
PubMed1986

Possible 5-hydroxytryptamine1 (5-HT1) receptor involvement in the stimulus properties of 1-(m-trifluoromethylphenyl)piperazine (TFMPP).

Male rats (N = 24) were trained to discriminate 1-(m-trifluoromethylphenyl)piperazine (TFMPP) (0.8 mg/kg) from saline in a two-lever, drug discrimination situation. 5-Hydroxytryptamine (5-HT) agonists such as fenfluramine (0.8-1.6 mg/kg), m-chlorophenylpiperazine (0.1-1.6 mg/kg) and RU 24969 (0.1-1.6 mg/kg) mimicked TFMPP; 8-hydroxy-2-(di-n-propylamino)tetralin (0.02-0.32 mg/kg) and quipazine (0.2-3.2 mg/kg) elicited saline lever responding; d-lysergic acid diethylamide (0.1-0.16 mg/kg) produced intermediate results. The 5-HT antagonists BC 105 (1.6-12.8 mg/kg), bromolysergic diethylamide (0.8-1.28 mg/kg), ketanserin (0.8-6.4 mg/kg), Ly 53857 (0.2-1.6 mg/kg) and pirenperone (0.08-0.64 mg/kg) failed to attenuate the TFMPP cue; metergoline (0.4-6.4 mg/kg) and spiperone (0.08-1.28 mg/kg) decreased drug lever responding by as much as 60%. These data suggest that 5-HT agonists are not identical and that drug discrimination procedures can differentiate among them. Given that there is strong evidence to support the existence of heterogeneous 5-HT receptors, the present results also suggest that TFMPP acts through mechanism(s) similar to those of the novel 5-HT1 agonists m-chlorophenylpiperazine and RU 24969; these actions can be differentiated from those underlying d-lysergic acid diethylamide, quipazine and 2,5-dimethoxy-4-methylamphetamine, which are attenuated by putative 5-HT2 antagonists. Thus, the authors propose a role for 5-HT1 receptors in mediating the stimulus effects of TFMPP, although further research is necessary to identify functional antagonists of such systems.

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1985

Discriminative stimulus properties of clonidine: substitution by ergot derivatives.

Bromocriptine, lergotrile and lisuride but not apomorphine, ergonovine or lysergic acid diethylamide (LSD) mimicked clonidine in rats trained to discriminate this compound (0.02 mg/kg) from saline. BC 105, ketanserin and haloperidol failed to block the clonidine cue. Yohimbine was an effective antagonist of clonidine but not of the lisuride substitution for clonidine. Since dopamine does not appear to be involved in the stimulus effects of clonidine, the behavioral similarities between clonidine and some ergots may be related to alpha-adrenoceptor stimulation; however, the role of blood pressure changes in the stimulus effects of all of these compounds should not be overlooked.

Adrenergic alpha-Agonists↗
PubMed1985

Dopamine D1 receptor mediation of the discriminative stimulus properties of SKF 38393.

Dopaminergic mediation of the stimulus properties of SKF 38393 was analyzed in a two-lever, drug discrimination task. After acquiring the ability to discriminate SKF 38393 (10 mg/kg) from saline, rats (N = 12) were given substitution (generalization) and combination (antagonism) tests with selective D1 and D2 receptor agonists and antagonists. The D2 agonists apomorphine and Ly 171555 (levo-isomer of Ly 141865) produced predominantly saline-lever responding; the D1 antagonist Sch 23390, but not the D2 antagonist haloperidol, dose dependently antagonized the SKF 38393 cue. These data support previous neurochemical and behavioral research which suggest that SKF 38393 may act by stimulating D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗