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J B Appel

Publications and source records attributed to J B Appel.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1985

Differentiation between the stimulus effects of l-5-hydroxytryptophan and LSD.

The stimulus properties of the serotonin precursor 1-5-hydroxytryptophan (5-HTP) and the hallucinogen d-lysergic acid diethylamide (LSD) were compared in a two-lever, water-reinforced drug discrimination task. 5-HTP (in combination with the peripheral decarboxylase inhibitor Ro 4-4602) elicited no more than 50% drug-lever responding in rats trained to discriminate LSD (0.08 mg/kg) from saline while LSD substituted completely in animals trained to discriminate 5-HTP (50 mg/kg) from saline. Combination tests indicated that, while the 5-HTP cue was unaffected by pretreatment with various serotonin antagonists, the substitution of LSD for 5-HTP was abolished by the putative serotonin-2 antagonist ketanserin. It was concluded that LSD mimics 5-HTP by stimulating a subset of serotonin receptors activated by 5-HTP which are sensitive to ketanserin (serotonin-2?).

5-Hydroxytryptophan↗
PubMed1985

The effect of drugs on the acquisition of stimulus control in a conditioned suppression procedure.

Rats were trained to press a lever under a variable-interval (VI) schedule of water reinforcement. After stable responding had developed, a 4.5-KHz tone (CS) was conditioned classically to a 2.5-mA electric shock (US) in groups of animals which had been given various psychoactive drugs or saline. Twenty-four hours later, a stimulus generalization test was conducted in the absence of drug; during this session, tones that varied in frequency around 4.5 KHz were presented while the animals were responding under the VI schedule. In animals conditioned under saline, all tones (non-differentially) suppressed responding which, however, recovered gradually over time. This suppressive effect was eliminated by lysergic acid diethylamide (LSD; 0.2 and 0.32 mg/kg), cocaine (20 mg/kg), diazepam (2.5 mg/kg), lisuride (0.08 mg/kg), mescaline (20 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (4 mg/kg), and was attenuated by amphetamine (4 mg/kg), pentobarbital (15 mg/kg) and morphine (4 mg/kg). Atropine (10 mg/kg), scopolamine (1 mg/kg), clonazepam (0.5 mg/kg), and chlorpromazine (4 mg/kg) did not alter the suppressive effect of the tone. The serotonin antagonist BC-105 (6 mg/kg) reversed the effect of 0.2 mg/kg of LSD. These results suggest (1) that drug-induced stimuli may "overshadow" other (e.g., external) stimuli during classical conditioning and, (2) that drugs might affect behavior by altering processes (stimulus control or others) that do not simultaneously involve response or motor control.

Animals↗
PubMed1985

Antagonism of the LSD cue by putative serotonin antagonists: relationship to inhibition of in vivo [3H]spiroperidol binding.

In two groups of rats trained to discriminate 0.08 or 0.16 mg/kg of lysergic acid diethylamide (LSD) from saline, pirenperone and ketanserin completely blocked the stimulus effect of LSD. Pizotifen (BC-105) blocked the LSD cue when the training dose was 0.08 mg/kg, but had variable effects in the 0.16 mg/kg of LSD-trained group. The antagonism of the 0.08 mg/kg cue occurred at doses of the antagonists which blocked [3H]spiroperidol labeled 5-HT2 receptors in the frontal cortex in vivo; binding in the striatum was unaffected by the LSD antagonists. However, in doses which produce the LSD cue, neither LSD nor the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine, which substitutes for LSD, inhibited the binding in either the cortex or the striatum. The results are discussed in relation to the possible neuropharmacological basis for the LSD cue.

Animals↗
PubMed1985

Monoaminergic involvement in the behavioral effects of ergot derivatives.

Monoaminergic neuronal systems have been implicated in the mechanisms of action of most ergot derivatives (including those that are clinically useful and those that are "hallucinogenic"). Among the various assays that have been useful in determining the extent of such involvement is drug discrimination. In this procedure, animals are trained to respond in one way (e.g., press the right lever) following saline and to respond differently (e.g., press the left lever) after either a particular ergot or a neurotransmitter agonist, and are subsequently tested with other ergots, transmitter agonists or antagonists (alone or in combination with the training drug). The results to date indicate that: 1) There are similarities in the discriminable effects of lergotrile, lisuride and bromocriptine, which probably involve catecholaminergic neuronal systems (DA or NE). 2) These effects are clearly separable from those of ergonovine and LSD, which may be relatively more serotonergic. More precise delineation of the mechanisms underlying these cues (e.g., D1, D2-selective agonism, antagonism, etc.) awaits further testing with highly specific pharmacological interventions.

Animals↗
PubMed1984

Drug effects on the repeated generalization of a visual discrimination acquired under one trial per day conditions.

Six pigeons were trained to respond under concurrent fixed-ratio extinction schedules of food reinforcement (FR 50) on the side keys of a three key chamber. Presence or absence of continuously-flashing, colored lights on the center key signalled which key pecking response (left or right) would be reinforced over the course of an entire experimental session; thus, the lights were analogous to a drug cue in drug-discrimination situations. In test (generalization) sessions of one FR in duration, the percentage of light on the center key was varied from 0 to 100%. During these sessions, saline, lysergic acid diethylamide (LSD; 0.04-0.20 mg/kg) and morphine (3.75 mg/kg) produced orderly, log-linear light generalization gradients, but only LSD shifted the gradient to the right (by approximately 50%). These results demonstrate the potential value of the method for assessing the effects of drugs on both exteroceptive (light) and interoceptive (drug) stimulus control. The method has the additional advantage that the effects of drugs on such control (i.e., on stimulus generalization) are relatively unaffected by corresponding effects on response control (e.g., rate of responding).

Animals↗
PubMed1984

Discriminative stimulus properties of lergotrile.

Although withdrawn from clinical trials because of liver toxicity, the ergot derivative lergotrile has been useful in the treatment of disorders involving dopaminergic systems (e.g., parkinsonism). In various biochemical and behavioral assays, this compound acts most potently as a dopamine (DA) agonist but also has DA antagonist as well as serotonin (5-HT) agonist properties. To elucidate further its effects in vivo, rats were trained to discriminate 0.5 mg/kg of lergotrile from saline in a two-lever water-reinforced task. In tests for similarities to other ergolines, dose-related substitutions were observed with lisuride (0.003-0.04 mg/kg) and d-lysergic acid diethylamide (0.01-0.08 mg/kg); partial substitution occurred with ergonovine (0.063-0.5 mg/kg). The DA agonist apomorphine (0.016-0.5 mg/kg) also substituted for lergotrile whereas the 5-HT agonist quipazine (0.25-2.0 mg/kg) elicited primarily saline-appropriate responding. Tests involving drug combinations indicated that the DA antagonist haloperidol (0.016-0.5 mg/kg) attenuated responding on the drug-appropriate lever; however, neither the DA (D2) antagonist sulpiride (2.0-16.0 mg/kg) nor the 5-HT antagonist BC-105 (1.0-4.0 mg/kg) had an effect upon the lergotrile cue. These results indicate that DA neuronal systems are probably more important than 5-HT neuronal systems in mediating the discriminative stimulus properties of lergotrile; however, the contribution of other neurotransmitter systems (e.g., norepinephrine) to these effects still must be evaluated.

Animals↗
PubMed1983

Benzodiazepine receptor mediated discriminative cues: effects of GABA-ergic drugs and inverse agonists.

Rats were exposed to a two-lever drug discrimination procedure using the benzodiazepine (BZ) receptor inverse agonists N'-methyl-beta-carboline-3-carboxamide (FG 7142) or methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). FG 7142 (30 mg/kg) failed to acquire discriminative stimulus control, although it did suppress responding. The same group of animals was trained successfully to discriminate diazepam (DZP, 2.5 mg/kg) from vehicle. The DZP cue was potentiated by the GABA agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol (THIP, 1,3 mg/kg); THIP alone produced vehicle-appropriate responding. In addition, clonazepam (0.2 mg/kg) and chlordiazepoxide (5 mg/kg) substituted for DZP (with potencies of 7.5 and 0.25 times that of DZP, respectively). In antagonism tests, FG 7142 (5-17.5 mg/kg), methyl-beta-carboline-3-carboxylate (beta-CCM, 2.5 mg/kg) did not effect, bicuculline (2 mg/kg) and DMCM (1 mg/kg) partially blocked, and the BZ receptor antagonist Ro 15-1788 (40 mg/kg) completely blocked the discriminative stimulus effects of DZP. In animals trained to discriminate DMCM (0.2 mg/kg) from vehicle, 95.2% substitution occurred with bicuculline (2 mg/kg); DZP (1-5 mg/kg) completely antagonized DMCM. These results indicate that the DZP cue is mediated by GABA-coupled BZ receptors and that GABA may modulate the efficacy of a BZ at its receptor site. However, since inverse BZ receptor agonists (FG 7142, DMCM and beta-CCM) were, at best, only marginally effective in antagonizing DZP, the DZP cue may be mediated by a distinct subclass of BZ receptors.

Animals↗
PubMed1983

The effects of drugs on the discrimination of color following a variable delay period: a signal detection analysis.

Six pigeons were trained in a chamber with three response keys. Following an observing response on the center key, either colored or noncolored (white) lights were projected on that key. A second center key observing response provided an opportunity to respond on one of the side keys, appropriate to the stimuli presented, to obtain food; responding on the incorrect side produced a 30-s time-out. A delay period of varying duration with no stimuli followed stimulus presentation; the length of the delay was determined 'on-line', such that performance would be maintained at about 80% correct. Lysergic acid diethylamide (LSD, 0.04-0.2 mg/kg) had no significant effect on the accuracy of the discrimination (overall percent correct responses), even at doses that produced cessation of responding in some animals. Amphetamine (1-4 mg/kg) and morphine (0.5-4 mg/kg) decreased accuracy by decreasing sensitivity (A') and had little effect on reaction time. Haloperidol (0.5-2 mg/kg) had no significant effect on any measure of performance. None of the drugs altered response bias (B").

Amphetamine↗
PubMed1983

Antagonism of a behavioral effect of LSD and lisuride in the cat.

These experiments investigated the role of serotonin 5-HT) and dopamine (DA) receptors in the limb-flick (LF) response elicited by the hallucinogenic ergot LSD and its nonhallucinogenic structural congener lisuride. Pretreatment with either the 5-HT antagonist pizotifen (BC-105) or the DA antagonist haloperidol significantly attenuated LF elicited by either LSD or lisuride. Thus, the LF model failed to differentiate the neuropharmacological actions of LSD and lisuride. Cocaine also prevented LSD- and lisuride-elicited LF simply by reducing the activity of cats (response competition) suggesting the need for caution in interpreting 'antagonism' of the LF response.

Animals↗
PubMed1982

Behavioral and biochemical evidence for serotonergic actions of tetrahydro-beta-carbolines.

In two groups of rats trained to discriminate LSD (0.1 mg/kg or 0.24 mg/kg) from saline, tetrahydro-beta-carboline (THBC; 1-12 mg/kg as free base) and its derivative 6-methoxy-THBC (1-12 mg/kg as free base) substituted partially for LSD. The substitution of THBC for 0.1 mg/kg of LSD was analyzed further with antagonism tests in 16 animals and was attenuated by the serotonin (5-HT) antagonist BC-105 (pizotifen; 3 mg/kg) but not by the dopamine (DA) antagonist haloperidol (0.1 mg/kg). It was abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (100 mg/kg/day for 3 days). In addition, THBC was found to inhibit 3H-LSD binding to homogenates of rat frontal cortex with an IC50 value of 4 microM which is similar to that previously reported for other 5-HT agonists. These data indicate that THBCs exert potent 5-HT agonist actions. Since THBCs have recently been found in mammalian brain and other tissues, the present results are of interest in relation to a possible role of these substances in endogenous psychosis.

Animals↗
PubMed1982

Dopaminergic and serotonergic mediation of the discriminable effects of ergot alkaloids.

The involvement of dopamine (DA) and serotonin (5-HT) neuronal systems in the discriminative stimulus effects of various ergot derivatives was assessed by administering four ergots to 36 rats which had been trained to discriminate either apomorphine (APO) or d-lysergic acid diethylamide (LSD) from saline. Lergotrile, lisuride and LSD substituted for APO (0.25 mg/kg) while bromocriptine and ergonovine (ergometrine) did not; only lisuride mimicked LSD (0.08 mg/kg). Antagonism tests showed that the DA antagonist haloperidol but not the 5-HT antagonist BC-105 (pizotifen) blocked the APO cue; both the LSD cue and the substitution of LSD for APO were blocked by BC-105 but not by haloperidol. It was concluded that DA receptor activation plays a prominent role in the discriminative stimulus effects of lergotrile and lisuride as well as APO and a secondary role in the LSD cue; 5-HT seems to be of major importance in the mediation of the effects of LSD and, to a lesser extent, lisuride. The functions of the two monoamines in the discriminable effects of bromocriptine and, particularly, ergonovine are less clear.

Animals↗
PubMed1982

Lysergic acid diethylamide (LSD) and lisuride: differentiation of their neuropharmacological actions.

The nonhallucinogenic ergot derivative lisuride exerts many pharmacological effects that are similar to those of its hallucinogenic congener, lysergic acid diethylamide (LSD). Animals trained to discriminate between the presence of one drug and the other can be used to differentiate the actions of these compounds on a neuronal level. The discriminative stimulus effect of LSD (the LSD cue) is similar to that of the serotonin agonist quipazine, whereas the lisuride cue is similar to that of the dopamine agonist apomorphine. These data support the hypothesis that serotonin is intricately involved in the hallucinogenic effects of LSD.

Animals↗
PubMed1982

Morphine may mimic the apomorphine cue by inhibiting dopaminergic autoinhibition.

Rats were trained to discriminate the cue produced by 0.25 mg/kg apomorphine from that produced by saline, using a two-lever, drug discrimination task. This cue was blocked by haloperidol but not by DPI, ergometrine, bromocriptine, sulpiride, naloxone or naltrexone; none of these agents substituted for (mimicked) apomorphine. Morphine and levorphanol did, however, mimic apomorphine, whereas dextrorphan did not; pentazocine induced responding unlike either apomorphine or saline. The substitution of morphine for apomorphine was blocked by naltrexone or bromocriptone, and was partially antagonized by a low of ergometrine, but was unaffected by haloperidol or sulpiride. To explain these results, it was proposed that morphine mimics apomorphine by inhibiting dopaminergic autoregulation involving D2-receptors.

Animals↗
PubMed1982

Training dose as a factor in LSD-saline discrimination.

To assess the effects of training dose on the discriminative stimulus properties of LSD, groups of rats (eight/group) were trained to discriminate each of three doses of LSD (0.02, 0.08 or 0.32 mg/kg) from saline. This was accomplished by using a method of progressively altering dose ("fading"). Dose-response tests revealed that the three LSD cues were specific to the dose used during training and that, as the training dose declined, the slope of the LSD dose-response curve became less steep. Substitution tests with direct serotonin (5-HT) agonists (quipazine, MK-212, 5-methoxy-N,N-dimethyltryptamine) and antagonism tests with central 5-HT antagonists (methiothepin and cyproheptadine) indicated that 5-HT is involved in mediating the in vivo effects of LSD and that training dose co-determines (along with the dose of the test compound) the extent of substitution or antagonism. In addition, substitution tests with the peripherally-active 5-HT agonist 5-methoxytryptamine and 5-HT antagonist xylamidine suggested that the peripheral serotonergic actions of LSD may be involved (in part) in the low dose (0.02 mg/kg) LSD cue. In contrast to 5-HT, dopamine (DA) did not appear to be involved in the discriminative stimulus properties of LSD, because no significant dose or group effects were seen during tests with the DA agonists apomorphine and d-amphetamine or the DA antagonist haloperidol.

Animals↗