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At least 595 records · Page 33Linked to original sources

PubMed1988

Discriminative stimulus control by the anxiogenic beta-carboline FG 7142: generalization to a physiological stressor.

Drug discrimination was employed to investigate the similarities between FG 7142-induced anxiogenesis and the stress produced by exposure to either a novel environment or to footshock. Eight rats were trained to discriminate between the stimulus properties of the beta-carboline FG 7142 (5.0 mg/kg) and its vehicle in a two-lever, food motivated operant task. Once trained, decreasing doses of FG 7142 produced fewer FG 7142-appropriate responses and the dose-response relationship yielded an ED50 of 1.45 mg/kg. Rats were subsequently subjected to two physiological/environmental stressors, footshock and novelty, and then tested in the discriminative paradigm. Exposure to novelty resulted in partial FG 7142-appropriate responding, whereas footshock sessions produced responding predominately on the FG 7142-appropriate lever. This is the first report of stimulus control by FG 7142 and it is likely that the interoceptive cue state produced by this compound is anxiogenic in nature, as reported to occur in man. The anxiogenic nature of the FG 7142 discriminative stimulus is supported by the generalization of FG 7142 to the state produced following stressful environmental manipulation.

Animals↗

PubMed1989

Phosphodiesterase inhibitors potentiate opiate-antagonist discrimination by morphine-dependent rats.

This study was performed to examine the relevance of the quasi-withdrawal syndrome in nondependent rats to the syndrome precipitated by naltrexone in rats physically dependent upon morphine. Morphine-dependent rats trained to discriminate between SC injections of naltrexone (0.1 mg/kg) and saline were pretreated with 10 mg/kg of a phosphodiesterase inhibitor: 3-isobutyl-1-methylxanthine (IBMX), Ro 20-1724, or papaverine. The naltrexone stimulus-generalization curve and dose-response curve for loss of body weight were shifted to the left by IBMX and Ro 20-1724, which produce quasi-withdrawal, but not by papaverine, which does not. IBMX also potentiated the naltrexone-like discriminative effects and loss of body weight induced by cyclazocine, an opioid agonist-antagonist. Butorphanol, another agonist-antagonist, occasioned choice responding appropriate for saline when tested alone but engendered more than 50% naltrexone-appropriate choice responses in rats pretreated with IBMX. Thus, phosphodiesterase inhibitors that produce an opiate quasi-withdrawal syndrome potentiate interoceptive stimuli and weight loss associated with the withdrawal syndrome precipitated by naltrexone in morphine-dependent rats. Furthermore, they appear to enhance the opiate-antagonist activity of opioids with mixed agonist and antagonist properties.

1-Methyl-3-isobutylxanthine↗

PubMed1990

N-modified fluorophenyltropane analogs of cocaine with high affinity for cocaine receptors.

The binding properties of three N-modified fluorophenyltropane analogs of cocaine were compared in competition experiments with [3H]cocaine. All three analogs displaced specifically bound [3H]cocaine from caudate-putamen membranes of cynomolgus monkeys with affinities exceeding that of cocaine. The compound with the highest affinity, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-N-allyl-nortropane, (N-allyl-CFNT) was about three times more potent than cocaine. N-Allyl-CFNT also had cocaine-like interoceptive effects and was about three times more potent than cocaine in squirrel monkeys trained to discriminate cocaine from vehicle in an operant drug discrimination procedure. The results suggest that N-modified fluorophenyltropane derivatives may be useful precursors for development of pharmacological probes for cocaine receptors.

Animals↗

PubMed1991

Cross-generalization between an ethologically [correction of ecologically] relevant stimulus and a pentylenetetrazole-discriminative cue.

Twelve male Sprague-Dawley rats were trained in a two-choice pentylenetetrazole vs. saline drug discrimination (DD) task under an FR10 schedule of food reinforcement. Two-minute reinforced test sessions with the two training stimuli engendered exclusive injection-appropriate responding. Rats were injected with saline and then exposed for 20 min to the presence of a domestic cat pretreated with catnip. Immediately following the predator exposure, rats were tested for stimulus generalization in the DD task. The predator/prey interaction engendered 92% PTZ-appropriate responding. These data suggest that the interoceptive state associated with species-specific defense reactions in rats is similar to the cues produced by a pharmacological agent within a behavioral assay which has been suggested as an animal model of human anxiety.

Animals↗

PubMed1991

Effect of learned behavior upon conditioned place preference to cathinone.

The purpose of this study was to examine whether first training rats to discriminate the stimulus cues produced by an indirect dopamine agonist, cathinone, would influence a subsequent test of preference. The conditioned place preference (CPP) paradigm was used to evaluate the reinforcing effects of l-cathinone in four differently treated groups of rats. Half of the animals were trained to discriminate the interoceptive cues produced by 0.8 mg/kg cathinone in a two-lever, food-motivated operant task. The other animals were equally divided between two groups, one receiving saline and noncontingent reinforcements on the same schedule as those trained to discriminate cathinone; the other group, the "yoked-control" rats, received the same cathinone and saline regimen of administration as the discrimination-trained animals. Results of CPP testing indicate that cathinone produced a statistically significant conditioned place preference only in the group trained to discriminate cathinone and not in the saline or yoked control groups. Furthermore, when half of the cathinone discrimination-trained rats were pretreated with the dopamine release inhibitor CGS 10746B, the conditioned place preference to cathinone was attenuated. The results would indicate that pairing cathinone with a nonpreferred environment tended to make the rat spend more time in that environment and the amount of time spent in the cathinone-associated environment can be increased by prior discrimination training and decreased by diminished dopamine function in the brain.

Alkaloids↗

PubMed1992

Further evidence for the mechanisms that may mediate nicotine discrimination.

Rats were trained to discriminate the interoceptive stimuli produced by subcutaneously administered 0.4 mg/kg nicotine in a two-lever, food-motivated, operant task. Once criterion performance was attained, dose-response experiments indicated an ED50 value of 0.1 mg/kg and subsequent time course experiments showed a maximal effect between 10 and 30 min postadministration with a return to saline-like responding at 2 h. Pretreatment with the presynaptic dopamine release inhibitors CGS 10746B (30 mg/kg), as well as with the dihydropyridine calcium blocker isradipine (15 mg/kg), each produced a significant blockade of nicotine discrimination. In contrast, the 5-hydroxytryptamine (5-HT) receptor 5-HT3 antagonist ICS-205930 did not produce any effect upon nicotine discrimination. Thus, drugs that interfere with calcium influx, viz., isradipine, or with dopamine release (CGS 10746B) also interfere with nicotine discrimination and these results suggest that calcium influx and dopamine release may be necessary conditions for nicotine discrimination.

Animals↗

PubMed1993

P and NP rats respond differently to the discriminative stimulus effects of nicotine.

Rats selectively bred for ethanol preference, that is, alcohol-preferring (P) and -nonpreferring (NP) rats, were trained to discriminate the interoceptive stimuli produced by IP-administered 1,000 mg/kg ethanol (10% v/v) in a two-lever, food-motivated, operant task. Once criterion performance was attained, dose-response experiments indicated an ED50 value for P rats = 354.1 mg/kg, whereas NP rats generated an ED50 value of 495.1 mg/kg, not significantly different from each other. In contrast to these similar sensitivities to ethanol, administration of doses of nicotine (0.4-1.2 mg/kg, SC) indicated that P rats were significantly more sensitive to the ethanol-like effects of nicotine than were NP rats. The results provide additional evidence for a possible hereditary co-occurrence of alcohol and nicotine sensitivity.

Alcoholism↗

PubMedDate not supplied

Cocaethylene produces discriminative stimulus properties in the rat: effect of cocaine and ethanol coadministration.

Experimentally naive Sprague-Dawley male rats were trained to discriminate the interoceptive stimulus cues produced by either 10.0 mg/kg cocaine or 10.0 mg/kg cocaethylene from their saline vehicles. Although it required more sessions to train the cocaethylene rats, once they were trained to criterion performance the ED50 value for cocaethylene (2.89 mg/kg) was very similar to that of cocaine (3.04 mg/kg). Coadministration of a 300-mg/kg dose of ethanol that produced saline-like responding in cocaethylene-trained rats with 2.5 mg/kg cocaine allowed for 88.9% of first lever selections being made on the cocaethylene-appropriate lever. Time-course evidence using coadministered (1.25-mg/kg) cocaine and (300-mg/kg) ethanol indicated that the formation of cocaethylene was highest, as indicated by discriminative performance, at 15 min and progressively decreased as the postinjection interval was increased to 30, 60, and 120 min. The results are discussed in light of rapid formation of cocaethylene from cotreatment with ethanol and cocaine in the mouse, rat, and human subject. The suggestion is made as to the prevalent, and growing, use of this drug combination in the human population of cocaine abusers.

Animals↗

PubMed1994

Cocaine-induced conditioned place approach in rats: the role of dose and route of administration.

The hedonic valence of the interoceptive stimuli associated with a wide range of cocaine doses administered by either SC or intraperitoneal injections was assessed in rats. Ninety-six male Sprague-Dawley rats were randomly assigned to different dose- and route-of-administration dependent groups (n = 8/group) and conditioned in a place learning task. During half of the conditioning trials, rats received either SC or intraperitoneal injections of saline or an individual dose of cocaine from 0.32 to 32 mg/kg (10 groups, 0.5 log common log unit increments), and were immediately placed in the initially nonpreferred compartment of a straight alley-way place-conditioning chamber. Prior to the other conditioning trials, rats received equivalent volumes of saline injections via the same routes of administration and were immediately placed in the initially preferred compartment. Two additional control groups received saline injections on both sides. Each rat received eight conditioning trials (four on each side). Significant conditioned place approach was produced by both SC- and IP-injected cocaine. However, the IP route of cocaine administration required a dose of 10 mg/kg cocaine to elicit a conditioned place approach, whereas a 0.32 mg/kg SC cocaine injection produced a CPP. Saline injections alone did not change the initial preference scores, and conditioned place aversions were not produced by any cocaine dose. The results of the present study demonstrate the relative safety of SC cocaine administration in the rat and a behavioral potency difference between these two routes of administration relative to the hedonic valence of the associated subjective states.

Animals↗

PubMed1994

A three-choice haloperidol-saline-cocaine drug discrimination task in rats.

This study was conducted to test whether rats could be trained and successfully maintain a three-choice drug discrimination task using 0.1 mg/kg haloperidol (SC, 2-h pretreatment), saline (IP or SC, 2 h and 15 min pretreatment), and 10 mg/kg cocaine (IP, 15-min pretreatment) as training stimuli. Six male Sprague-Dawley rats achieved criterion performance for stimulus control by these training stimuli under a fixed-ratio-5 schedule of food reinforced lever-press responding in an average of 164 training sessions. Dose-response functions for cocaine and haloperidol demonstrated both quantitative and qualitative specificity of the training stimuli. The data also are presented along a single pharmacological continuum (agonist-antagonist) that we hypothesize to represent a parallel subjective or interoceptive stimulus continuum associated with the drug injections. Based on the previous multidimensional model of drug stimuli dimensionality (3), this specific stimulus dimension is characterized as an unidimensional bipolar continuum represented by the hypothetical states of hedonia or euphoria on one end (cocaine) and anhedonia or depression on the opponent end (haloperidol), with a neutral (saline) centroid region. We propose that this specific three-choice drug discrimination task in rats may function as an animal analog of the subjective states associated with cocaine abuse and the subsequent withdrawal or, crash, in humans (7,8,21).

Animals↗

PubMedDate not supplied

Clozapine but not haloperidol antagonizes an MK-801 discriminative stimulus cue.

The noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) produced an interoceptive stimulus cue in rats trained to discriminate between MK-801 (0.075 mg/kg) and saline in a two-choice, discrete trial avoidance paradigm. Haloperidol (0.03-0.3 mg/kg) failed to antagonize the discriminative stimulus cue of MK-801, with all rats choosing the MK-801-appropriate choice lever. Higher doses of haloperidol (1.0 mg/kg) produced significant sedation such that the rats were unable to complete all the trials. In contrast, clozapine dose dependently antagoinzed the discriminative stimulus cue produced by MK-801. Clozapine at a dose of 3.0 mg/kg completely antagonized the stimulus cue produced by MK-801. Therefore, the discriminative stimulus cue produced by the noncompetitive NMDA antagonist MK-801 may be useful as an animal model for selecting novel drugs with potential efficacy for treatment-resistant schizophrenia.

Animals↗

PubMed1994

An investigation into the discriminative stimulus and reinforcing properties of the CCKB-receptor antagonist, L-365,260 in rats.

The discriminative stimulus properties of the selective CCKB-receptor antagonist, L-365,260 were evaluated in rats trained to discriminate diazepam (2 mg/kg) or morphine (5 mg/kg) from vehicle, using a two-lever food reinforced technique. In the diazepam drug discrimination, the benzodiazepine-receptor agonist FG8205 (0.063-2 mg/kg) produced dose-related drug associated responding, whereas L-365,260 (0.125-4 mg/kg) treated animals showed vehicle appropriate behaviour. In rats trained to discriminate morphine from saline, L-365,260 (0.063-4 mg/kg) produced saline lever responding. When a dose of 1 mg/kg L-365,260 was administered in combination with morphine, the dose response curve for drug lever responding was not significantly affected. This was in contrast to the effect produced by the opiate antagonist naloxone (0.3 mg/kg) which shifted the dose-response curve to the right. Another group of rats underwent training to discriminate a dose of 6 mg/kg L-365,260 from vehicle. None of the animals learned the discrimination within 50 daily training sessions. In addition, unlike morphine (3 mg/kg), or changing the training dose of cocaine, intravenous administration of L-365,260 (0.3-10 mg/kg) did not modify lever pressing or the number of injections received by rats trained to self administer cocaine (0.25 mg/injection). L-365,260 (0.1-3 mg/kg) produced a dose-related inhibition of pentagastrin-stimulated gastric acid secretion in vivo. When administered dissolved in a mixture of ethanol/propylene glycol/saline, the ID50 was 0.83 mg/kg, and when suspended in an ethanol/carboxymethylcellulose vehicle, it was 0.7 mg/kg. It was concluded: 1) that L-365,260 does not produce discriminative stimuli similar to either diazepam or morphine; 2) that the potentiation of morphine-induced behaviour by L-365,260 does not extend to the discriminative stimulus properties of morphine; 3) that L-365,260 itself does not produce readily discriminable interoceptive stimuli in rats; and 4) that L-365,260 does not substitute for the reinforcing drug cocaine.

Animals↗

PubMed1982

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.

Animals↗

PubMed1984

Neuroregulators and the reinforcement of smoking: towards a biobehavioral explanation.

This paper examines findings on the neuroregulatory effects of nicotine in an effort to formulate a unified hypothesis that can explain the remarkable persistence of smoking behavior. Because nicotine alters the bioavailability of several behaviorally active neuroregulators, including acetylcholine, norepinephrine, dopamine, beta-endorphin, and vasopressin, we propose that nicotine is "used" by smokers to produce temporary improvements in performance or affect. Under this formulation, a potential large number of exteroceptive and interoceptive cues unrelated to the nicotine-dependence cycle may serve as discriminative stimuli for smoking, over and above smoking to terminate or avoid withdrawal. The rapid action of nicotine, and its diverse neuroregulatory effects, render it particularly effective as a "coping response" to the demands of daily living. Of special interest in this regard is a biphasic pattern of arousal/catecholaminergic activation followed by cholinergic blockade or beta-endorphin release. Apparently smokers can adjust nicotine intake to enhance these effects selectively, which may add considerably to the appeal of smoking.

Analgesics↗

PubMed1993

Activation of an apomorphine behavior pattern by cocaine: a new behavioral test for drug substitution.

In current tests for drug substitution using the 2-choice operant bar press paradigm, an animal can be trained to respond differentially between an interoceptive drug state stimulus vs. saline. Despite the long history and extensive number of investigations, the interpretation of such test results, nevertheless, is limited by number of potential sources of stimulus drug effects which can occur with repeated drug administration but which cannot be distinguished by this paradigm: (1) local effects at the injection site; (2) peripheral effects; (3) central activity effects; and/or (4) sensory-motor dysfunctional effects. By using a video-image analysis of behavior in an intact animal model and a pavlovian drug treatment protocol, new, spontaneous but environmentally contingent and stable behavior patterns emerge selectively in the paired treatment group with repeated drug administration which can be used as a behavioral marker to assess dose-response effects and drug substitution test results with a novel drug. A study with repeated administration of the DA agonist apomorphine and with a drug substitution assessment by a cocaine drug test is presented as a reference example to illustrate the new response-based methodological approach to the study of central mechanisms mediating the stimulus and response effects of drugs. Additionally, the observed efficacy of cocaine to activate a complex acquired behavioral pattern unique to repeated apomorphine treatment supports a critical role for dopaminergic mechanisms in the mediation of cocaine induced stereotypy.

Animals↗

PubMed1996

Effects of repeated treatment with methamphetamine plus scopolamine and methamphetamine on behavioral sensitization and conditioning.

This study compared repeated treatment with methamphetamine (4.0 mg/kg, i.p.) plus scopolamine (0.5 mg/kg, i.p.) and methamphetamine alone in behavioral sensitization and drug conditioning with respect to a reciprocal balance between the dopaminergic and cholinergic systems. Repeated methamphetamine plus scopolamine treatment induced a more progressive and enduring enhancement of stereotyped behavior than repeated methamphetamine treatment. Methamphetamine plus scopolamine-induced stereotyped behavior was reproduced by challenge injections of not only methamphetamine plus scopolamine and methamphetamine, but also, to a lesser extent, by scopolamine challenges. The methamphetamine plus scopolamine-sensitized rats were conditioned to a low-frequency tone (300 Hz, 100 dB) as conditioned stimulus associated with the drug state. They responded to pairings of the tone and placebo injections, but not to the tone alone or the placebo alone. The methamphetamine-sensitized rats failed to exhibit conditioning. These results suggest that methamphetamine plus scopolamine-induced pronounced behavioral sensitization may produce an enhanced conditioning. Exteroceptive conditioned stimulus-interoceptive unconditioned stimulus associations may provide an important source for drug conditioning. We concluded that behavioral sensitization may be mediated via a reciprocal balance between the dopaminergic and cholinergic systems, in favor of a dopaminergic dominance. Conditioning to the drug-associated tone may operate via a reciprocal balance between the dopaminergic and cholinergic systems.

Animals↗

PubMed1984

Cerebral asymmetry and the psychophysiology of attention.

The literature relevant to psychophysiological aspects of the lateralized control of attention is reviewed. It is argued that the description of attention as a dynamic process tends to obscure examination of the structural determinants of attentional asymmetries. Psychophysiological evidence suggests that a right hemispheric predominance in attention is quite possibly the natural outcome of a similar asymmetry in activational, interoceptive and early visual processes.

Arousal↗

PubMedDate not supplied

Can ACTH analogs support discriminative learning in rats?

Ten rats were trained to discriminate between the stimulus properties of subcutaneously (SC) administered MSH/ACTH4-10 and saline in a two-lever, food-motivated operant task. After 12 weeks of discriminative training with 100 micrograms/kg MSH/ACTH4-10, half the rats received 200 micrograms/kg MSH/ATCH4-10, whereas the other half were administered 400 micrograms/kg, for 6 additional weeks. Subsequently, all rats continued training on 50 micrograms/kg ORG 2766 (SC) and, after 12 weeks of training, were randomly assigned to receive either 100 or 200 micrograms/kg ORG 2766. The results of this extensive 36 week training schedule indicate that only 1 of the 10 rats learned to discriminate the interoceptive cues produced by the ACTH analogs. However, this rat's performance was so sustained and errorless that the possibility exists that it was relatively more sensitive to the effects of MSH/ACTH4-10 and its analogs and that these substances may support discriminative learning in the rat.

Adrenocorticotropic Hormone↗