摘要:

The effects of several drugs acting at central benzodiazepine receptors on performance of a differential reinforcement of low rate (DRL) 15 s schedule of reinforcement for food reward were studied in rats. The non-selective full agonists diazepam (0.1, 1.25,5 and 10 mg/kg) and lorazepam (0,1, 0.25, 0.375 and 0.5 mg/kg) increased total numbers of responses and decreased the numbers of reinforcements received, increased burst responding (responding within 3 s of a previous response), and produced a shift in the interresponse time (IRT) distribution of responses towards shorter intervals. The β-carboline anxiolytic abecarnil (0.039, 0.156, 0.313 and 0.625 mg/kg) was more potent than the two benzodiazepines, but otherwise gave rise to similar changes in performance. Bretazenil (0.1, 1.0, 10 and 30 mg/kg), a non-selective partial agonist, and CL 218872 (3, 10, and 30 mg/kg), a partial agonist showing preference for the BZ1 receptor subtype, also increased response rates and decreased numbers of reinforcements, but failed to increase significantly burst responding, and had only weak effects in shifting the IRT distribution. Alpidem (1, 3, 10, 30 and 100 mg/kg) and zolpidem (0.33, 1, 3 and 10 mg/kg), two imidazopyridines showing BZ1 preference, but classified respectively as an anxiolytic and a selective hypnotic agent, non-significantly reduced response rates and significantly reduced the numbers of reinforcements, but did not influence burst responding, and had effects on IRT distribution only at single doses. Thus, in general, the effects of these compounds on DRL performance reflect their activity in conflict models. The differential effects on DEL performance of the benzodiazepine receptor ligands tested may be attributable to their abilities to interact selectively as agonists or partial agonists at different benzodiazepine receptor subtypes.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Discriminative control was established among morphine, saline and naitrexone in rhesus monkeys receiving morphine every other day. Three hours prior to sessions subjects received saline or 3.2 mg/kg morphine; immediately prior to sessions they received saline or 0.01 mg/kg of naitrexone. There were dose-related generalizations to each training condition: morphine generalized to the morphine plus saline lever; small doses of naitrexone reversed effects of morphine and larger doses occasioned responding on the morphine plus naitrexone lever; in one monkey still larger doses occasioned responding on the saline plus saline lever. When saline was administered 3h earlier, naitrexone had no effect in one subject and occasioned responding on the morphine plus naitrexone lever in a second subject. Nalbuphine substituted for morphine plus saline in one monkey and for morphine plus naitrexone in a second monkey; ketamine did not substitute for either training drug. That stimulus control was established between no drug and a combination of morphine and naitrexone suggests the latter condition did not represent the absence of morphine. In addition to demonstrating stimulus control for three conditions in rhesus monkeys, the current study suggests opioid antagonists might have novel discriminative stimulus effects at opioid receptors even under conditions where signs of withdrawal are not evident.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Modulation of the discriminative stimulus effects of cocaine by the μ agonist morphine, the K agonist U 50,488, and the δ agonist BW 373U86 was investigated in squirrel monkeys using a two-lever drug discrimination procedure. Monkeys initially were trained to discriminate intramuscular injections of 0.3 or 0.56 mg/kg cocaine from vehicle and subsequently retrained to discriminate a 3− to 5.6-fold lower dose of cocaine (0.1 or 0.18 mg/kg). After retraining, dose-response functions for the discriminative stimulus effects of cocaine were shifted to the left and ED50values were reduced 2− to 6-fold compared to values obtained with the higher training doses. In drug substitution experiments, morphine (0.03–1.0 mg/kg), U 50,488 (0.1–3.0 mg/kg) and BW 373U86 (0.001–0.1 mg/kg) did not reproduce the discriminative stimulus effects of the low training doses of cocaine, although U 50,488 engendered a majority of responses on the cocaine-associated lever in two of three monkeys. In drug interaction experiments, pretreatment with morphine (0.3 mg/kg) potentiated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the left and ED50values were reduced 3− to 7-fold. Pretreatment with U 50,488 (0.3 mg/kg), on the other hand, attenuated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the right and ED50values were increased approximately 4-fold. The cocaine-modulating effects of morphine and U 50,488 in these experiments were qualitatively similar to those observed previously when the monkeys were trained to discriminate higher doses of cocaine. In contrast to the effects of the μ and K agonists, pretreatment with BW 373U86 (0.01 or 0.03 mg/kg) did not systematically alter the discriminative stimulus effects of cocaine regardless of training dose.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The effects of amphetamine, phencyclidine, dopaminergic blockers and atypical neuroleptics on the acquisition of schedule-induced polydipsia in rats were compared in a chronic dose regime followed by 7 days of withdrawal. All compounds suppressed water intake. However, different mechanisms were responsible. The antidopaminergic compounds inhibited the initiation of drinking, as the temporal pattern of licking was shifted to the right. Phencyclidine inhibited the maintenance of drinking as the number of licks/ml water consumed war; increased. The suppressing effect of amphetamine may have been due to the reduction of high rates of licking and/or a competition between licking and locomotor or other amphetamine-induced activities. The number of panel entries were increased by amphetamine and phenryclidine. The typical antidopaminergic compounds decreased the number of panel pushes, whereas the atypical antidopaminergic compounds were without effect on this parameter. In conclusion, it was possible to differentiate between the types of compounds investigated by comparing their effects on water intake, panel pressing, drinking efficiency and the temporal patterns of licking and panel pressing.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The purpose of this study was to analyse adrenergic and serotonergic interactions in the anxiolytic effects of several 5-HT1Aagonists including ipsapirone, buspirone, indorenate and 8-OH-DPAT. To this end, the effects of different closes of the adrenergic compounds clonidine (0.015–0.0625 mg/kg), yohimbine (0.125–0.5 mg/kg), prazosin (0.5–2.0 mg/kg), pindolol (1.55–6.2mg/kg) and practolol (0.25–1.0 mg/kg) on defensive burying behaviour were established. Clonidine (0.015–0.0625 mg/kg), prazosin (1.0 and 2.0 mg/kg), pindolol (1.55 and 6.2 mg/kg) and all 5-HT1Aagonists reduced burying behaviour by themselves. In contrast, yohimbine (0.250 and 0.5 mg/kg) increased, while practolol did not modify, this behaviour. Additionally, the actions of yohimbine (0.125 mg/kg), prazosin (0.5 mg/kg), pindolol (3.1 mg/kg) and practolol (0.5 mg/kg) on the effects of ipsapirone (5.0 mg/kg), buspirone (5.0 mg/kg), indorenate (5.0 mg/kg) and 8-OH-DPAT (0.25 mg/kg) were examined. Prazosin enhanced the effects of ipsapirone, indorenate and buspirone, while yohimbine antagonized the actions of indorenate and 8-OH-DPAT. Pindolol enhanced the effects of indorenate while practolol antagonized the actions of ipsapirone, buspirone and 8-OH-DPAT. Only buspirone (5.0 mg/kg) affected motor coordination, an effect that was not counteracted by the antagonists. Based on these data an interaction between 5-HT1Aagonists and the noradrenergic system in the regulation of anxiety is proposed.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In the framework of the well-known regulatory role of the GABA-benzodiazepine (BZ) mechanisms of the brain in response to social and environmental challenges, we tested the hypothesis that developmental manipulation of this neurochemical system by prenatal BZ exposure can affect the social repertoire and neophobia level in infant mice. Outbred CD-1 mire were treated with either vehicle or oxazepam (15 mg/kg p.o. to the dam, twice a day on Days 12–16 of foetal life), and fostered at birth to untreated dams. Two males plus two females were observed in the home cage, in the presence of a novel object, on Postnatal Days 16, 20 and 24. The expression of social and non-social behaviours increased with age. Prenatal oxazepam exposure reduced sex differences by having a more pronounced effect on males than on females; it also produced fairly specific, though subtle, behavioural changes. Oxazepam-exposed mice appeared more involved than prenatal controls in behaviours related to the achievement and maintenance of a “passive” proximity with littermates. By contrast, they performed less active investigation and solicitation of littermates, and non-social behaviours such as locomotor-rotational play, cage exploration, and maintenance activities; they also showed a reduced frequency of approaching and making contact wish the novel object. Analysis of social interactions of infant mice seems to represent a sensitive tool for early detection of subtle developmental changes in the CNS.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Substitution and antagonism patterns of butorphanol, meperidine and profadol were examined in pigeons trained to discriminate either a 0.056 (low) or 0.18 (high) mg/kg dose of fentanyl from saline. In the low dose group, fentanyl, meperidine, profadol and butorphanol substituted completely (≥ 85% fentanyl-appropriate responding) for the fentanyl stimulus. For fentanyl and butorphanol, complete substitution was obtained at doses that had little effect on rates of responding, whereas profadol substituted at doses that moderately decreased rates and meperidine substituted at doses that markedly decreased rates. Although naloxone antagonized the stimulus effects of meperidine and profadol, it failed to alter their rate-decreasing effects. In the high-dose group, fentanyl and butorphanol substituted completely and meperidine and profadol partially (approximately 50% fentanyl-appropriate responding) for the fentanyl stimulus. During antagonism tests, meperidine and profadol produced only small decreases (less than 15%) in the percentage of fentanyl-appropriate responding produced by the training dose of fentanyl. Analysis of individual data indicated that meperidine and profadol produced three patterns of substitution and antagonism. In one subgroup of pigeons, meperidine and profadol substituted completely for but failed to antagonize the fentanyl stimulus; in another, these opioids failed to substitute for but did antagonize the fentanyl stimulus; and in another, these opioids failed to substitute for or antagonize the fentanyl stimulus. In this latter subgroup, meperidine and profadol produced leftward shifts in the dose effect function for the stimulus effects of fentanyl and butorphanol. The present findings suggest that the failure of meperidine and profadol to substitute completely for the high-dose fentanyl stimulus was a direct consequence of their rate-decreasing effects rather than low efficacy at the mu receptor.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

This study assessed the acute effects of Δ9-tetrahydrocannabinol (THC) on learning and performance, using a repeated acquisition and performance paradigm, in eight healthy adult humans. Subjective ratings of drug effects were also collected. In each component of a multiple schedule, subjects completed a different sequence of 10 responses using three keys of a numeric keypad. In the acquisition component, subjects learned a new sequence with each series of 20 trials. In the performance component, the sequence remained constant throughout the study. The multiple schedule and rating scales were presented pre-drug, post-drug and at 30 min intervals thereafter for 5h. THC (10–20 mg, p.o.) increased the peak percentage of errors during the acquisition component from 7.0% to 9.3% but responding during the performance component was unchanged. THC decreased Digit Symbol Substitution Test performance, increased Profile of Mood State ratings of confusion, depression and general mood disturbance and Visual Analog Scale ratings of strength of drug effect, good and bad effects, but did not alter Addiction Research Center Inventory ratings. In summary, THC in humans caused a slight learning deficit at behaviorally active doses under the repeated acquisition procedure.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Seven male research volunteers reporting intravenous cocaine and morphine use participated in 12 cocaine self-administration sessions. A session consisted of sublingual buprenorphine pretreatment (0, 2, 4 mg) 50 min before seven self-administration trials. The first three trials were sampling trials, in which subjects were given each of the three reinforcers available for that session; the remaining four trials were choice trials in which subjects could choose between two doses of cocaine and tokens exchangeable for special privileges. Each buprenorphine dose was tested for four consecutive days under different cocaine dose/token combinations (e.g. 8 mg vs 16 mg vs two tokens). Following placebo, under all choice conditions, subjects reliably chose higher doses of cocaine over lower doses, and tokens about as often as high cocaine doses. Buprenorphine (4 mg) significantly decreased high-dose cocaine choice and increased token choice, when the available cocaine doses were 16 and 32mg/70 kg. Both buprenorphine doses significantly increased ratings of “sedated” and opiate symptoms and decreased ratings of “bad drug effect” following all cocaine doses. Both buprenorphine doses, in combination with cocaine doses greater than 8 mg, significantly increased self-reported “high” and occasionally increased “stimulated” scores above values seen following cocaine alone. The results demonstrate that in the presence of non-drug alternatives to cocaine (tokens), buprenorphine decreased high-dose cocaine choice. Despite the decrease, subjects were clearly intoxicated from a drug combination that mimicked a cocaine-heroin (“speedball”) effect. Although buprenorphine may be useful in reducing cocaine use, the complex relationship between this reduction in use, behavioral alternatives, and the subjective effects of the drug combination remains unclear.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Social olfactory recognition in rodents has been shown to assess short-term memory and to be sensitive to cholinergic drugs. It is based on the investigation of a juvenile by an adult rat and is measured by a reduction in duration of exploration during the second of two successive exposures lasting 5 min. The present experiments further characterize rodent social recognition in pathophysiological models known to impair memory. Social recognition was disrupted by ageing in both rats and mice, by vincristine-induced septal lesion and by damaging the CA1 hippocampal layer after cerebral ischaemia in rats. These memory deficits could be compensated by reducing the time interval between the two presentations of the juvenile and/or by prolonging the juvenile encounter. Similarly, muscarinic agonists (arecoline, SR 46559A) counterbalanced the memory impairment in the three models. The present results indicate that the hippocampus plays a key role in social recognition. They suggest that in the three pathophysiological models, memory ability is still present although it is of very short duration; however, it can still be improved by pharmacological treatments.

ISSN:0955-8810    

出版商:OVID    

年代:1994

数据来源: OVID