Studies on several 7-substituted N,N-dimethyltryptamines.

Several 7-substituted derivatives of N,N-dimethyltryptamine (DMT) were prepared and evaluated in the rat fundus serotonin receptor assay and in a behavioral (discriminative stimulus) assay in rats. Both 7-Me- and 5-OMe-7-Me-DMT possess a higher pA2, and 5,7-(OMe)2-DMT a lower pA2, than that of DMT itself. Like DMT, all three of these compounds produce behavioral effects in rats which are similar to those of the hallucinogen 5-OMe-DMT. Although 7-ET- and 7-Br-DMT possess a higher serotonin receptor affinity than DMT, neither produce behavioral effects which parallel those of 5-OMe-DMT. In contrast, 6-Me-DMT and its 5-OMe derivative do not interact with the serotonin receptors in a competitive manner and are inactive in the discriminative stimulus assay.

"Go here-to there" performance after amphetamine: the importance of the response requirement in successive discrimination.

Marmosets were trained on a task involving simultaneous and successive visual discrimination performance where responses were required on all trials. Performance of this task was not affected by low doses of amphetamine. From this it is concluded that amphetamine does not cause a narrowing of attention and that the disruptive effect of amphetamine on the "go-no go" successive discrimination task already reported is due to a loss of response inhibition rather than to difficulties in the recognition of stimuli presented without a comparison stimulus.

Chlordiazepoxide-induced disruption of discrimination behaviour: a signal detection analysis.

To assess the effects of chlordiazepoxide (CDP) on a stable discrimination performance, eight rats were trained on a simple brightness discrimination and injected with three dosages (0, 5, and 10 mg/kg) once performance was stable. Signal detection analysis of the results was used to differentiate sensory from motor/responsivity effects of the drug. At 5 mg/kg, CDP increased general responsiveness which is consistent with the hypothesis that CDP disinhibits responding. At 10 mg/kg, however, this effect on responsivity was reversed and there was also a suppression of stimulus sensitivity.

Discriminative stimulus properties of intravenous morphine in the rat.

Using a single-lever operant task, rats were trained to discriminate between the effects of 1 mg/kg morphine and saline administered intravenously 15 min prior to sessions. Tests of stimulus control indicated that responding appropriate to the morphine training treatment was present at 5 min and persisted for at least 60 min following intravenous administration. Morphine administered intraperitoneally 15 min prior to sessions resulted in dose-related responding with 6 mg/kg producing stimulus control not significantly different from the intravenous training treatment. These results suggest that the discriminative stimulus properties of morphine in the rat are qualitatively similar following intraperitoneal and intravenous administration.

MDA and DOM: substituted amphetamines that do not produce amphetamine-like discriminative stimuli in the rat.

3,4-Methylenedioxyamphetamine (MDA) and 2,5-dimethoxy-4-methylamphetamine (DOM) are amphetamine congeners that produce both amphetamine-like and LSD-like effects. To evaluate whether MDA and DOM should be classed with amphetamine, their capacity to produce amphetamine-like discriminative stimuli was assessed. Rats were trained to discriminate between saline and 1.0 mg/kg d-amphetamine in a two choice, discrete trial shock avoidance paradigm. Neither MDA nor DOM produced any amphetamine-appropriate responding when tested over a 30-fold dose range. The specificity of the procedure to detect amphetamine-like effects was demonstrated by the failure of LSD to produce any amphetamine-appropriate responding. These results suggest that neither MDA nor DOM should be classed as amphetamine-like agents.

Discriminative stimulus properties of the optical isomers of nicotine.

Rats were trained to discriminate 200 or 400 microgram/kg (-)nicotine from saline in a two-bar operant paradigm. Dose-response relationships for optically pure (-)- and (+)nicotine as well as antagonistic effects were examined in both groups of rats. The natural isomer (-)nicotine was approximately nine-times more potent than (+)nicotine. Mecamylamine produced equal blockade of the (-)- and (+)nicotine cues. Hexamethonium and atropine were without effect. These data demonstrate the possible stereospecificity of the central nicotinic receptor that mediates the stimulus effect produced by nicotine.

Effects of morphine, d-amphetamine, and pentobarbital on shock and light discrimination performance in rats.

The effects of 2 and 4 mg/kg morphine sulfate, 0.5 and 1 mg/kg d-amphetamine sulfate, and 6 and 12 mg/kg pentobaribital sodium were tested in rats in two different discrete-trial two-choice discrimination tasks. The discriminative stimuli for one task were high and low intensity shocks. In the other, correct choices were signaled by the position of a brief light flash. Morphine (4 mg/kg) significantly disrupted performance of both tasks, with more reliable disturbance occurring in the shock discrimination animals. Pentobarbital (12 mg/kg), while exerting noticeable effects on gross motor behavior, had little effect on discrimination performance; d-amphetamine (1 mg/kg) was disruptive of discrimination performance in only some animals. The results indicate that much of the effect of relatively low doses of morphine on the shock discrimination performance of rats may be due not to its putative specific antinociceptive properties, but to alterations in conceptual-judgmental processes or decreases in motivation (e.g., hunger) unrelated to pain.

Discriminative response control by naloxone in morphine pretreated rats.

In an operant procedure using a lever press response 12 male, hooded rats were trained to discriminate 1.25 mg/kg naloxone from a saline injection. On certain days, according to a counterbalanced training schedule, naloxone was administered 8 h after 40 mg/kg morphine and 10 min prior to a trail in which food was available on an FR10 schedule from one of two levers in a dual lever operant chamber. On other days saline was administered 10 min prior to a trial in which food was made available by pressing the other lever. After criterion performance for acquisition of the discrimination had been reached, tests were carried out to determine its nature. Discrimination of naloxone was dose-dependent and was significantly diminished when naloxone was administered 36 h after morphine. Partial generalization of cyclazocine with naloxone was observed. Spontaneous withdrawal from morphine, tested during trials preceeded by an injection of saline instead of naloxone at various time intervals after morphine, did not generalize with the naloxone discriminative stimulus.

Drug-induced stimulus control and the concept of breaking point: LSD and quipazine.

Discriminative stimulus control was established in rats (N = 12) with LSD (100 microgram/kg) and saline using a two-lever response choice task and an FR10 schedule of water reinforcement. Subjects were then tested once per week with either LSD or quipazine (3 mg/kg) and every other week the test ratio was doubled, i.e., each drug was tested at ratios of 10, 20, 40, and 80. In contrast with LSD, which maintained stimulus control at all ratios, LSD-appropriate responding following quipazine declined significantly at FR80. In addition, five of eight subjects tested with quipazine failed to complete the FR80 in 15 min. In subsequent experiments, the breaking point, here defined as the number of LSD-appropriate responses prior to emission of ten responses on the saline-appropriate lever, was determined for LSD and for quipazine. Mean values (N = 12) for LSD and quipazine were 161 +/- 28 and 65 +/- 19, respectively.

delta 9-THC as a discriminative stimulus in rats and pigeons: generalization to THC metabolites and SP-111.

In a drug discrimination paradigm pigeons and rats were trained with an operant procedure to discriminate between the presence and absence of the effects of delta 9-THC (1.0 and 3.0 mg/kg, injected IM 90 min and I.P. 30 min before the start of the session). Once trained, various THC metabolites as well as a water-soluble derivative of THC (SP-111), were substituted for delta 9-THC to test for generalization to the training drug. Generalization to delta 9-THC occurred with the 11-hydroxy metabolites and the potency order was 11-OH-delta 9-THC > 11-OH-delta 8-THC greater than or equal to delta 9-THC. Among the other metabolites tested (8 alpha-OH-delta 9-THC, 8 alpha, 11-di-OH-delta 9-THC, 8 beta-OH-delta 9-THC, 8 beta, 11-di-OH-delta 9-THC), it was only 11-di-OH-delta 9-THC that completely substituted for delta 9-THC in pigeons, albeit at very high dose levels (rats were not tested with these metabolites). SP-111 generalized to delta 9-THC in both species. However, the onset of action of SP-111 was slower than that for delta 9-THC, especially in pigeons. These studies show the importance of obtaining complete dose-effect determinations over time when assessing structure-activity relationships with drug-discrimination procedures.

Amphetamine disrupts successive but not simultaneous visual discrimination in the monkey.

Three adolescent marmosets were trained on simultaneous and successive versions of a red-white visual discrimination task. The effects of doses of 0.2-1.2 mg/kg D-amphetamine on the performance of these tasks were assessed using a balanced design. It was found that while there was no drug effect on performance of the simultaneous task, amphetamine exerted a dose dependent disruptive effect on the successive version of the task. It is argued that amphetamine disrupts response control rather than discriminative ability and, in this respect, resembles the effect of orbitofrontal and limbic lesions in contrast to other neocortical lesions.

Morphine effects upon discriminated approach and discriminated avoidance in rats: antagonism by naloxone.

The effects of various doses of morphine (5, 10 and 20 mg/kg) alone or in combination with a constant dose of naloxone (1.25 mg/kg) were examined in rats trained on a discriminated approach schedule (in which bar pressing in the presence of a stimulus light produced food), or on a discriminated avoidance (in which the same response produced stimulus-shock termination). Since the performance of rats in the discriminated avoidance varied widely, drug effects were examined separately in groups of good, intermediate or poor performer rats. Comparable patterns of responding in the presence of light were found in the approach group and in the good performer avoidance group. Morphine induced a dose-related decrease of this responding which was identical in both cases. Other effects of morphine were a dose-related increase of escape failures in all the avoidance groups and stimulatory or depressant effects upon bar presses performed during the no light periods. All the effects of morphine were antagonized by naloxone. The data suggest that comparable patterns of responding maintained by different reinforcements can be similarly affected by morphine.

Discriminative stimulus effects of pentobarbital in pigeons.

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0--17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6--17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3--3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.

The discriminative stimulus properties of 2,5-dimethoxy-4-methylamphetamine (DOM): differentiation from amphetamine.

Rats were trained in a two-lever operant procedure to discriminate either 1.0 mg/kg (+)amphetamine or 1.5 mg/kg DOM from saline. Rats trained to discriminate DOM from saline showed generalization with the DOM training condition when tested with mescaline or 2,5-dimethoxy-4-ethylamphetamine (DOET), but not when tested with (+)amphetamine or methylphenidate. Both isomers of DOM generalized with racemic training compound, the (-)isomer being more potent. The DOM stimulus was completely blocked by the serotonin (5-HT) antagonists cinanserin and methysergide, but not by the peripheral 5-HT antagonist xylamidine nor the dopamine antagonist haloperidol. Rats trained to discriminate (+)amphetamine from saline generalized with the amphetamine training condition when tested with methylphenidate but not when tested with mescaline, DOET, racemic DOM, or either isomer of DOM. The amphetamine stimulus was blocked by pretreatment with haloperidol but not by cinanserin, methysergide, or xylamidine. The results show that, despite their structural similarity, amphetamine and DOM induce pharmacologically distinct stimuli.

Ability of 3-carboxysalsolinol to produce ethanol-like discrimination in rats.

The purpose of the present study was to investigate the possible generalization to 3-carboxysalsolinol (3C-SAL) in a group of rats trained to discriminate a low dose of ethanol (200 mg/kg IP) from the nondrug condition and in antoher group trained to discriminate 0.16 mg/kg IP apomorphine (AP) from the nondrug condition using a drug discrimination paradigm. In test sessions, ED50 for ethanol was 52.0 mg/kg and ED50 for AP was 0.01 mg/kg. In the ethanol-trained rats, 1.8 mg/kg 3C-SAL produced drug responses. In the AP-trained rats, 200 mg/kg ethanol produced drug responses whereas 1.8 mg/kg 3C-SAL produced only a partial drug response. The results are in harmony with the hypothesis that salsolinol in the central nervous system of the rat may be responsible for the discriminability of ethanol. The possible involvement of dopaminergic systems is discussed.

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.

Hallucinogenic agents as discriminative stimuli: a correlation with serotonin receptor affinities.

A choice between two levers in an operant chamber was used to train 24 rats, under a variable-interval 15 s schedule of sweetened milk reinforcement, to discriminate a hallucinogenic (psychotomimetic) agent, 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT), from saline administration. The 5-OMe DMT stimulus generalized in a dose-related manner to each of 14 tryptamine related analogs. With the exception of one compound, the effective dose for the 5-OMe DMT response correlated highly (r = -0.86) with 5-HT receptor affinity (as determined using an isolated rat fundus preparation).

Effects of the phenethylamine derivatives, BL-3912, fenfluramine, and Sch-12679, in rats trained with LSD as a discriminative stimulus.

Six rats were trained to discriminate the effects of LSD (100 micrograms/kg) and saline in a two-lever choice task. They were then tested with each of three phenethylamine derivatives, BL-3912 (2,5-dimethoxy-4-methyl-alpha-ethyl-phenethylamine), fenfluramine (N-ethyl-alpha-methyl-m-(trifluoro-methyl)phenethylamine), and Sch-12679 (N-methyl-1-phenyl-7,8-dimethoxy-2,3,4,5-tetra-hydro-3-benzazepine maleate). Fenfluramine and Sch-12679 yielded intermediate results, i.e., responding was not fully appropriate for either training condition while BL-3912 substituted completely for LSD. The LSD-like effects of each of the drugs were antagonized by pretreatment with BC-105, a serotonergic antagonist known to block the stimulus effects of indole and phenethylamine hallucinogens. The present data together with consideration of the known clinical effects of BL-3912, fenfluramine, and Sch-12679 are consistent with the following conclusions: (1) a variety of drugs may substitute in whole or in part for LSD in LSD-trained rats, and (2) even complete substitution of a drug for LSD in the rat is not necessarily associated with the production by that drug of hallucinations in man.

The effects of electroconvulsive shock on the discriminative stimulus properties of d-amphetamine and apomorphine: evidence for dopamine receptor alteration subsequent ECS.

Sprague-Dawley male rats responding for sweetened milk on a variable interval 20 s schedule of reinforcement were trained to discriminate which of two levers to press on the basis of whether they had been injected with 1.0 mg/kg of d-amphetamine or saline prior to daily training sessions. Following acquisition of the discrimination a dose-response generalization function was determined by testing animals on 0.10, 0.15, 0.25, 0.35, 0.50 and 0.75 mg/kg of amphetamine. Subjects then received either three electroconvulsive shock (ECS) treatments of sham-ECS forty-eight hours after the final treatment all subjects were injected with 0.25 mg/kg of amphetamine and retested. ECS was found to enhance the ability of the animals to discriminate amphetamine. In a second experiment it was found that ECS also facilitated the ability of animals to discriminate the cue properties of apomorphine, a direct dopamine receptor agonist. These results suggest that dopamine receptor sensitivity is altered by electroconvulsive shock.

Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon.

Separate groups of pigeons were trained to discriminate the IM injection of ketamine, cyclazocine, or dextrorphan from saline. Each of the training drugs and phencyclidine produced dose-related, drug-appropriate responding in each group of birds. In contrast, ethylketazocine and nalorphine generally produced responding appropriate for saline. These results indicate that common elements of discriminable effects exist among ketamine, cyclazocine, and dextrorphan, structurally dissimilar compounds that are generally considered to belong to distinct pharmacological classes.