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.

Lysergic acid diethylamide and stimulus generalization: rate-dependent effects.

A stimulus generalization procedure was used to investigate the effects of LSD on sensitivity to auditory stimuli in rats. The shape of the generalization gradient was changed after administration of the drug only with a dose which produced decreases in relatively high rates of responding.

Analyzing mechanism(s) of hallucinogenic drug action with drug discrimination procedures.

Some of the advantages of using drug discrimination (DD) procedure to analyze the mechanisms of action of hallucinogenic and related drugs were illustrated by reviewing research with lysergic acid diethylamide (LSD). Because they ensure that drug-induced alterations in interoceptive "state" become biologically meaningful "cues," these procedures are reliable, robust, sensitive and specific. With reference to LSD, many DD experiments suggest: (1) that while hallucinogens substitute for (mimic) LSD (in rats), such substitution does not predict hallucinogenic potency (in humans) but does predict similarities in mechanism(s) of action; (2) the behavioral (in vivo) effects of LSD, unlike those of some of its congeners, are mediated primarily by central, serotonergic (5-HT) neuronal mechanism although LSD may also have (secondary) dopamine (DA) agonist properties; (3) both the locus and the nature of these LSD-5-HT interactions are unclear: cells arising from B-7, B-8 and B-9 regions of the dorsal-medial raphe may be involved; pretreatment with agents that deplete 5-HT and increase the stereospecific binding of 3H-LSD in vitro (p-chlorophenylalanine; 5,7-dihydroxytryptamine) enhance sensitivity to LSD in vivo.

Antagonism of a PCP drug discrimination by hallucinogens and related drugs.

Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg) from saline and were then given a series of antagonist tests. It was found that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.

Effects of pentazocine and other opiates on shock detection in the rat: involvement of opiate and dopamine receptors.

The hypothesis that the antinociceptive effects of pentazocine, a mixed agonist-antagonist opiate of the benzomorphan class, are mediated by a dual opiate-dopaminergic mechanism was tested using a two-choice procedure in which rats were required to discriminate the presence or absence of shock. The results showed that pentazocine decreased shock sensitivity and speed of responding, effects that were qualitatively similar to those of morphine. However, while the antinociceptive effect of both pentazocine and morphine could be antagonized by opiate receptor blockage, that of pentazocine, but not of morphine, could also be antagonized by dopamine receptor blockade. Observations with levorphanol and phenazocine suggested further that dopamine, as well as opiate receptor agonism may be characteristic of the benzomorphans.

A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine.

Rats were trained to discriminate fenfluramine (1.0 mg/kg) from saline in a two-lever drug discrimination task. The dose-response curve for this discrimination was orderly with an ED50 of about one-half of the training dose (0.52 mg/kg). In substitution tests, indirect (p-chloroamphetamine) and direct (quipazine, MK-212, lisuride) serotonin (5-HT) agonists substituted for fenfluramine. Since none of these compounds have been reported to be hallucinogenic and the potent hallucinogen LSD did not substitute completely, it was suggested that the discriminative stimulus properties of fenfluramine are not related to its ability to produce hallucinations in humans. The fenfluramine cue, like the quipazine cue, was antagonized by the 5-HT antagonists cyproheptadine and methiothepin. Unlike quipazine, fenfluramine was also partially antagonized by the 5-HT uptake inhibitor, fluoxetine, and the 5-HT synthesis inhibitor, p-chlorophenylalanine. Thus, the fenfluramine cue differs from that of quipazine in that it is mediated via indirect actions on 5-HT receptors. Since the indirect dopamine (DA) agonist d-amphetamine failed to substitute and the DA antagonist haloperidol failed to block the fenfluramine cue, a mediating role for DA was not indicated. Another indirect DA agonist, cocaine, substituted partially for fenfluramine, a result which paralleled that seen with fluoxetine. Both of these partial substitutions were reduced by cyproheptadine; therefore, it was concluded that these effects may be due to the common ability of cocaine, fluoxetine, and fenfluramine to inhibit 5-HT uptake.

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.

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").

An analysis of some perceptual effects of morphine, chlorpromazine, and LSD.

Male albino rats were trained to detect either a pure tone or a weak footshock embedded in white noise by utilizing a discrete-trial two-choice, successive discrimination procedure. The effects of morphine, chlorpromazine (CPZ), and lysergic acid diethylamide (LSD) were then analyzed on several measures of performance. Morphine (2.5--10 mg/kg) produced a nonspecific decrease in accuracy of discrimination on trials when the stimulus was presented as well as on trials when no stimulus occurred. Morphine was also followed by dose-dependent decreased in speed to initiate trials and by increases in intersubject variability. CPZ (1.0--4.0 mg/kg) caused a decrease in accuracy only on no-stimulus trials and, like morphine decreased speed to initiate trials. LSD (0.04--0.16 mg/kg/ decreased overall accuracy in a nonspecific manner (i.e., when shock and tone discriminations were considered together) and decreased speed by producing periods of nonresponding.

Drug effects on the performance of pigeons under a negative automaintenance schedule.

Pigeons were exposed to a negative automaintenance schedule in which food was delivered following brief key illumination only if the illuminated key was not contacted; contact of the lighted key prevented food delivery. All subjects emitted some responses under this procedure when drugs were not given. However, the number of responses was less than that which occurred under an automaintenance procedure in which food followed key illumination regardless of the bird's behavior. Under the negative automaintenance procedure, acute administration of atropine (0.01--0.1 mg/kg), d-amphetamine (0.4--1.6 mg/kg), and morphine (3,8--15 mg/kg) reduced in a dose-dependent manner the percentage of key illuminations in which subjects contacted the lighted key. Diazepam (1.0--6.0 mg/kg) increased the percentage of key illuminations during contact responses occurred.

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.

Psilocybin as a discriminative stimulus: lack of specificity in an animal behavior model for 'hallucinogens'.

Fifteen rats were trained to discriminate between the tryptamine hallucinogen psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine; 1.0 mg/kg) and saline in a two-lever choice task. Dose-response and time-response curves were obtained. The psilocybin cue generalized to psilocin (the dephosphorylated congener of psilocybin) and to the prototypical indoleamine hallucinogen LSD, but not to the phenylethylamine hallucinogen mescaline. These results indicate that the hallucinogenic effects of these drugs in humans may not be identical with their discriminative stimulus functions in animals, and that these four compounds may not be members of a single drug class. The term 'hallucinogen' may thus be a misnomer in the context of drug discrimination studies in nonhumans.

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.

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).

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.

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).

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.

Drugs and visual perception: effects of LSD, morphine and chloropromazine on accuracy, bias and speed.

Ten pigeons were trained to discriminate between the intensities of two white lights (projected behind a center response "key") using a discrete trial procedure in which choice behavior involved pecking at red or green lights projected behind left or right side keys. LSD (0.02-0.08 mg/kg) did not alter the accuracy of the brightness discrimination (percent correct) although it did lower response speed and may have differentially affected spatial (position) bias. Morphine (2.5--10.0 mg/kg) decreased accuracy of discrimination as well as response speed and had greater effects on trials when the bright stimulus was presented than when the dim stimulus was presented. Chlorpromazine (7.5-3.0 mg/kg) lowered accuracy without significantly altering any other measure of performance.

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.

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.