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At least 577 records · Page 32Linked to original sources

PubMed1982

RO 15-1788 selectively reverses antagonism of pentylenetetrazol-induced discriminative stimuli by benzodiazepines but not by barbiturates.

The specificity of ethyl 8-fluro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a) (1,4) benzodiazepine-3-carboxylate (RO 15-1788) in reversing the effectiveness of diazepam and des-methylclobazam, but not of pentobarbital, in antagonizing discriminative stimuli produced by pentylenetetrazol is described. Male hooded rats were trained to discriminate pentylenetetrazol-induced interoceptive discriminative-stimuli (IDS) in a two-lever choice paradigm on an FR10 schedule of food reinforcement. These IDS pharmacologically model verbal report of anxiogenic activity in humans. Diazepam (1,4 benzodiazepine), des-methylclobazam (1,5 benzo-diazepine), and pentobarbital antagonized pentylenetetrazol-IDS. RO 15-1788 neither generalized to nor antagonized pentylenetetrazol-IDS. It also did not cause convulsions in pentylenetetrazol sensitized rats at doses up to 40 mg/kg. It did, however, antagonize the action of diazepam (10 mg/kg) as well as that of des-methylclobazam (160 mg/kg) but not that of pentobarbital. These data suggest that RO 15-1788 is not an anxiomimetic, anxiolytic or a convulsant drug, but it is a specific and effective antagonist of anxiolytic action of benzodiazepines.

Animals↗

PubMed1986

2-Amino-7-phosphonoheptanoic acid (AP7) produces discriminative stimuli and anticonflict effects similar to diazepam.

The N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, was evaluated in two animal test procedures known to be sensitive to the effects of diazepam. In rats trained to discriminate diazepam from vehicle, AP7 produced dose-dependent generalization to the diazepam interoceptive stimuli. This NMDA antagonist also increased the rates of conflict responding in a chronic test procedure used to identify compounds with potential anxiolytic effects. A comparison of AP7 with diazepam and two muscle relaxants (methocarbamol and baclofen) showed that excitatory amino acid antagonists (of the receptor site stimulated by NMDA) produce a muscle relaxant effect (drug discrimination) and may represent a new class of compounds for the treatment of anxiety-related disorders (conflict test).

2-Amino-5-phosphonovalerate↗

PubMed1987

N-methyl-D-aspartate produces discriminative stimuli in rats.

Male Sprague Dawley rats were trained to discriminate an interoceptive effect associated with a subconvulsant dose (30 mg/kg i.p.) of the excitatory amino acid receptor agonist, N-methyl-D-aspartate (NMDA). Approximately 60% of the rats learned to discriminate this compound from saline in 45 +/- 5 sessions, and the stimuli were dose dependent (ED50 value = 13.6 mg/kg i.p.). The specific NMDA receptor antagonist, 3-[+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), blocked NMDA-induced discriminative stimuli with an ED50 value equal to 2 mg/kg i.p., confirming that the NMDA cue is mediated by activation of NMDA receptors. Through the use of NMDA discriminative stimuli, the consequences of NMDA excitation can be studied in vivo and compounds with potential NMDA antagonist properties can be identified.

Animals↗

PubMed1987

Evidence that the stimulus properties of apomorphine are mediated by both D1 and D2 receptor activation.

Male and female rats were trained to discriminate between the stimulus properties of apomorphine (0.16 mg/kg i.p.) and saline in a two-lever, food-motivated operant procedure. Apomorphine, at doses different than the training dose, produced a similar dose-dependent relationship in both sexes. Consistent with the hypothesis that the behavioral effects of apomorphine are mediated by D2 activation, the apomorphine interoceptive cue generalized to bromocriptine, a drug considered to be a preferential D2 agonist. In addition, the dose-response curve after 5-15 mg/kg bromocriptine administration was parallel to that of apomorphine. Consistent with the biochemical evidence that apomorphine's effects are mediated, to a lesser extent, by D1 activation, the apomorphine cue partially generalized to the selective D1 agonist SKF 38393. Furthermore, the apomorphine cue was not blocked by the selective D1 antagonist SCH 23390. Somewhat surprising was the partial generalization of the apomorphine cue to SCH 23390. However, this is not the first time that the administration of SCH 23390 has resulted in unexpected behavioral responses. Other novel findings include the lack of sex differences in acquisition training to the apomorphine cue and in the generalization tests to the selective agonists. The behavioral results are consistent with previous biochemical evidence that the effects of apomorphine are mediated by both D1 and D2 activation and is further behavioral support that apomorphine's effects are not the result of D2 activation alone, as previously hypothesized.

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

PubMed1992

Comparative behavioral pharmacology and toxicology of cocaine and its ethanol-derived metabolite, cocaine ethyl-ester (cocaethylene).

The present study compared the behavioral and toxic effects of cocaine and its ethanol derived metabolite, cocaine ethyl-ester (cocaethylene). Both drugs produced qualitatively similar psychomotor stimulant effects. Cocaine and cocaethylene increased locomotor activity in mice, with cocaine approximately four times more potent than cocaethylene. The durations of action of ED75 doses of each of the drugs were comparable. Each of the drugs also produced stimulation of operant responding in rats. In rats and squirrel monkeys trained to discriminate cocaine injections from saline, cocaine was approximately three to five times more potent than cocaethylene in producing these cocaine-like interoceptive effects. In contrast to the behavioral effects, cocaine and cocaethylene were equipotent in producing convulsions, and cocaethylene was more potent than cocaine in producing lethality. These results suggest that the conversion of cocaine to cocaethylene with simultaneous cocaine and alcohol use may produce an increased risk of toxicity due to a decrease in the potency of cocaethylene in producing psychomotor stimulant effects, and its increased potency in producing toxicity.

Animals↗

PubMed1992

Withdrawal from chronic phencyclidine produces a pentylenetetrazol-like discriminative stimulus.

Rats trained to discriminate the anxiogenic compound pentylenetetrazol (PTZ) from water were implanted with osmotic mini-pumps containing 7 mg/kg/day phencyclidine (PCP) or water. Rats were tested for generalization to PTZ 24 hours prior to pump removal, and 4 to 96 hours after pump removal. While the pumps were in place, rats did not generalize to PTZ. When the pumps were removed on day 10, rats in the water group did not generalize to PTZ, but 69% of the rats in the chronic PCP group responded on the PTZ lever at 4 and/or 24 hours after pump removal, suggesting that the PCP withdrawal state mimics the interoceptive cue produced by PTZ. This withdrawal phenomenon was repeatable, in that rats that generalized once to PTZ during PCP withdrawal, generalized a second time when the procedure was repeated. In addition, the phenomenon was dose-dependent, as rats that did not generalize to PTZ after 7 mg/kg/day PCP did generalize when the chronic dose of PCP was increased to 10 mg/kg/day. These findings suggest that there is an anxiogenic component of PCP withdrawal and that tolerance does not develop to this effect.

Animals↗

PubMed1983

Discriminative stimulus properties of a small dose of cocaine.

This study characterized the interoceptive discriminative stimulus (IDS) produced by a small dose of cocaine. Rats were trained to use a dose of cocaine of 1.25 mg/kg vs saline as the basis for choosing one of two levers for food reinforcement on a fixed ratio 10 schedule. The discrimination was acquired over approx. 60 training sessions. d-Amphetamine generalized to cocaine with approximately equal potency (ED50's for cocaine and d-amphetamine were 0.07 and 0.06 mg/kg, respectively); 20 mg/kg cocaine and 10 mg/kg methylphenidate also generalized to the cocaine lever. Pentylenetetrazol, 20 mg/kg, did not generalize to the cocaine lever, and diazepam, 10 mg/kg, did not block the 1.25 mg/kg cocaine discrimination. These data indicate that when a small dose of cocaine is used as the basis of discrimination training, the discriminative stimulus that it produces is qualitatively and quantitatively similar to that produced by small doses of amphetamine, is still discriminated with a large dose of cocaine, and is dissimilar to the discriminative stimulus produced by pentylenetetrazol.

Animals↗

PubMed1993

Cross-modal associations and the human amygdala.

The role of the human amygdala in cross-modal associations was investigated in two subjects: SM-046, who had bilateral damage circumscribed to the amygdala; and the patient known as Boswell, whose damage in both temporal lobes includes the amygdala and surrounding cortices. Neither subject was impaired on Tactile-Visual or Visual-Tactile cross-modal tasks using the Arc-Circle test, suggesting that the amygdala is not involved in cross-modal associations involving perceptually "equivalent" basic stimulus properties. On the other hand, the results are compatible with the amygdala's involvement in higher-order associations between exteroceptive sensory data and interoceptive data concerned with correlated somatic states.

Adult↗

PubMed1993

Discrimination of insulin-produced hypoglycemia in rats.

Hypoglycemia is an abnormal state that can be induced by administering insulin to a fasting animal. Rats were trained to discriminate the normal state of euglycemia from the hypoglycemia produced by injection of 6 units/kg insulin. A drug discrimination procedure was used with a two-lever operant response. Insulin or water injected 25 min prior to the operant sessions determined whether left or right lever presses were reinforced. During 40 training sessions, reliable discrimination of the insulin-produced cue developed. After insulin injection, mean blood glucose levels dropped to about 75% of preinjection values. At 12 min postinsulin injection, prior to the development of hypoglycemia, noninsulin responses were made. Noninsulin responses were also made after injection with 800 mg/kg ethanol, indicating that a novel interoceptive state did not substitute for the insulin-produced cue. Insulin injections produced less severe hypoglycemia in less food-deprived rats, which again gave noninsulin responses. Animals can be trained to recognize the insulin-produced state, which presumably involves hypoglycemia, and/or counterregulatory process evoked in response to the drop in blood glucose.

Animals↗

PubMedDate not supplied

Learned taste aversions induced by hypnotic drugs.

Taste aversions reflect the association of drug-produced noxious interoceptive stimuli with distinctive tastes. In the present experiments, taste aversions to sweetened condensed milk were induced in rats by a wide range of doses of the hypnotic drugs, hexobarbital, amobarbital, chloral hydrate, flurazepam and methaqualone and by anesthetization with ethyl ether. Observation of changes in motor behavior following drug administration could not be used to predict the development of taste aversions. Despite the fact that hypnotic drugs have punishing properties, which these paradox is discussed in terms of procedural differences between taste aversion and self-administration experiments.

Animals↗

PubMed1979

Morphine withdrawal induced behavior in the Syrian hamster (Mesocricetus auratus).

The effects of morphine withdrawal on a number of behaviors was assessed using a design varying sex, amount of morphine implanted, degree of dependence at the time of testing and amount of morphine antagonist injected. Increases in two types of agonistic behavior were seen and may be related to the aversive interoceptive stimuli associated with withdrawal. Furthermore, correlations for males were found between agonistic behavior and activity, wet shakes, digging and vocalization. Agonistic behavior was correlated only with activity in females.

Animals↗

PubMed1981

Rapid acquisition of a two-drug discrimination: time of day effect upon saline state.

Rats were rapidly trained to discriminate between 0.8 mg/kd d-amphetamine and 6 mg/kg pentobarbital in a two-lever food-motivated operant task by imposing the drug states from the earliest stage of training, i.e., at the initiation of shaping to lever-press. Once trained, rats were administered each of the training drugs and were allowed to lever press without reinforcement until 10 responses were made on the lever that was not their first choice lever selection. By employing this extended schedule of responding in extinction, the amphetamine-induced interoceptive cue was observed to produce equivalent perseverance as that produced by pentobarbital. However, the administration of saline, the non-drugged state, produced significantly more pentobarbital-appropriate responding than amphetamine-appropriate responding when tested during the daytime, whereas it produced random responding when tested during the night. The results suggest that the arousal state of the rat, a nocturnal species, may differentially influence saline tests in the daytime and in the night time.

Animals↗

PubMed1983

Discriminative stimulus control with imipramine: transfer to other anti-depressants.

Discriminative stimulus control with the tricyclic anti-depressant imipramine was attempted in three groups of rats; two of which were subjected to artificially stressful conditions. Only the unstressed group were shown capable of discriminating between the stimulus properties of intraperitoneal 10 mg/kg imipramine and saline in a two-lever, food-motivated operant task. Discriminative performance with decreasing doses of imipramine was shown to be dose-responsive. The ability to discriminate the interoceptive cue produced by imipramine was observed to transfer to a 10 mg/kg dose of both amitriptyline and desmethylimipramine. The results suggest a common tricyclic anti-depressant cueing property.

Amitriptyline↗

PubMed1983

Phenytoin: similarity to tricyclic antidepressants.

Rats were trained to discriminate between the stimulus properties of intraperitoneal injections of 10 mg/kg phenytoin and its pH-adjusted vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower phenytoin doses. Administration of pentobarbital and chlordiazepoxide produced vehicle-appropriate responding, whereas injection of imipramine and amitriptyline produced intermediate results. Desipramine, at an intraperitoneal dose of 10 mg/kg, produced a pattern of responding similar to that observed after the training dose of phenytoin. These results demonstrate, for the first time, the ability of a non-disruptive dose of phenytoin to act as a behavioral discriminative stimulus in the rat and suggest the possibility of a common interoceptive cue property with tricyclic antidepressants.

Amitriptyline↗

PubMed1985

Ethanol-chlordiazepoxide interactions in the rat.

One group of rats (n = 9) was trained to discriminate between the effects induced by 600 mg/kg ethanol and saline, whereas another group (n = 5) had to discriminate between 5.0 mg/kg chlordiazepoxide (CDZ) and saline, administered intraperitoneally (IP) 15 min prior to the training sessions. Once trained, decreasing doses of ethanol in ethanol-trained rats produced decreased discriminative performance; the ED50 was 239.4 mg/kg. Likewise, decreasing doses of CDZ in CDZ-trained rats produced decreased discrimination, with an ED50 = 1.5 mg/kg. Substitution of 1.25-10.0 mg/kg CDZ in ethanol-trained rats produced a transfer of the ethanol-induced interoceptive cue in a dose-responsive manner, whereas ethanol did not substitute for CDZ in CDZ-trained rats. Analysis of dose-response curves suggested that CDZ is acting by a similar mechanism/site in both groups of rats but by a site different than ethanol. Co-administration of the ED50's for ethanol and CDZ in ethanol-trained rats did not produce additive effects. The observed one-way asymmetrical generalization of drug effects, as well as the lack of additive effects of co-administration, are discussed.

Animals↗

PubMed1985

Cathinone, cocaine and methamphetamine: similarity of behavioral effects.

The discriminative stimulus properties of (+/-)-cathinone were tested by training eight rats to discriminate between the interoceptive cues produced by 0.6 mg/kg (+/-)-cathinone and saline in a food-reinforced, two lever operant task. Doses of cocaine and methamphetamine were observed to transfer to the cathinone cue and all three drugs exhibited decreased discriminative performance with decreasing doses. The ED50 for (+/-)-cathinone, (+/-)-methamphetamine and cocaine were 0.23, 0.17, and 1.97 mg/kg, respectively, and the three curves were shown to be parallel. These data indicate the possibility of a common mechanism/site of action for these three stimulants, presumably by their actions upon central dopaminergic neurons.

Alkaloids↗

PubMed1986

Discriminative profile of MDMA.

Groups of rats were trained to discriminate the stimulus properties of dopaminergically and/or serotonergically active drugs, viz., apomorphine, fenfluramine, tetrahydro-beta-carboline (THBC) and l-cathinone. Once trained, these animals were given several doses of drugs used in training and dose-response relationships and ED50 values were generated. Subsequently, each group of trained rats was administered various doses of 3,4-methylenedioxymethamphetamine (MDMA) to test generalization of the interoceptive cue of the drug used for training to MDMA. Rats trained to fenfluramine, THBC, and l-cathinone were observed to discriminate MDMA in a manner similar to the drug state to which they had been trained. Analysis of dose-response curves suggested that MDMA may be acting both as an indirect dopaminergic agonist and as a serotonergic receptor agonist. This duality of effect of MDMA has been evidenced by other studies and may account for its present abuse potential.

3,4-Methylenedioxyamphetamine↗

PubMed1987

Interactions between stimulants: effects on DRL performance and lethality in rats.

The Controlled Substances Act of 1970 drastically reduced the supply of amphetamines available to the public. It also inadvertently prompted the emergence of a new drug industry, namely the marketing of caffeine/phenylethylamine combinations packaged to look like many of the previously available amphetamine preparations. The findings of one recent experimental study corroborate anecdotal evidence that the interoceptive "high" produced by these look-alike stimulants mimics that produced by amphetamine. The present study was designed to further characterize the behavioral effects of caffeine/phenylethylamine combinations. The present findings suggest that adding ephedrine and phenylpropanolamine to caffeine markedly enhances the disruption of DRL performance, as well as the lethality of the drug. In addition, different patterns of interactions were obtained between amphetamine and caffeine versus the caffeine/ephedrine/phenylpropanolamine combination.

Amphetamine↗