摘要:

Discrimination of a mixture of an agonist plus an antagonist has been analysed by training rats to discriminate ( – (-nicotine (0.32 mg/kg s.c.) from saline; in different groups of rats (n = 8), nicotine was administered either alone or in combination with the non-competitive nicotine antagonist mecamylamine (0.1–0.8 mg/kg s.c). Rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. After 50 sessions, rats trained with nicotine alone had acquired the discrimination with an accuracy of about 85%. In combination, mecamylamine blocked accuracy during acquisition in a dose-related manner. In generalization tests, rats trained with nicotine alone yielded a typical dose-response curve for nicotine (ED50, = 0.082 mg/kg), without depression of response rate. In rats trained with nicotine plus 0.2 mg/kg of mecamylamine, the ED50for the discriminative effect of nicotine was lowered (ED50= 0.036 mg/kg), again without depression of response rate. In rats trained with nicotine plus 0.4–0.8 mg/kg of mecamylamine, nicotine did not acquire stimulus control over behaviour (flat dose-response relationships), but in these animals, nicotine had a pronounced response rate-decreasing effect. These characteristics of discriminations based on nicotine plus mecamylamine differed substantially from those of previously described discriminations of nicotine plus midazolam, supporting the hypothesis that interactions between the latter drugs were based on a behavioural mechanism (overshadowing) rather than on interactions at the level of receptors

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The acute behavioral and cardiac effects of alcohol (0, 0.5 and 1.0 g/kg) and caffeine (0, 250 and 500 mg/70 kg), administered alone and in combination, were assessed in eight adult humans. Subjects received all possible combinations twice. Alcohol administered alone disrupted responding in the Digit-Symbol Substitution Test and the Repeated Acquisition and Performance Procedure, increased heart rate, decreased blood pressure, and increased subject ratings of drunkenness. Caffeine administered alone offset performance decrements that emerged across the test session on the Digit-Symbol Substitution Test performance and accuracy of responding in the Repeated Acquisition and Performance Procedure, but never actually enhanced performance and learning. Caffeine administered alone increased blood pressure and increased subjective ratings of drug strength. The most notable effect of the drug combinations was that caffeine partially attenuated the disruptive behavioral effects of alcohol. Combining alcohol and caffeine generally offset the pressor effects observed with the drugs administered alone. By contrast, alcohol-caffeine combinations did not significantly alter breath alcohol levels, heart rate or subject-rated drug effects, relative to the effects of the drugs alone. Across all measures except heart rate, these effects are qualitatively similar to those observed previously with cocaine and -amphetamine in combination with alcohol, documenting a high degree of consistency in the behavioral pharmacology of alcohol-stimulant combinations in humans

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The effects of chlordiazepoxide (2.5–15.0 mg/kg), a full benzodiazepine receptor agonist, and bretazenil (5.0–30.0 mg/kg), a partial benzodiazepine receptor agonist, were examined in the murine elevated plus-maze paradigm. Behaviours recorded comprised the traditional indices of anxiety as well as a number of ethologically derived measures. Results show that chlordiazepoxide (10–15 mg/kg) and bretazenil (5–30 mg/kg) not only decreased traditional indices of anxiety but also reduced risk assessment behaviours such as head-dipping and stretch attend postures from secure areas of the maze. Both compounds produced these effects without adversely affecting general activity levels. While traditional indices of anxiety did not clearly discriminate between the two compounds, some differences were apparent on the ethological measures. The dose-response curves for bretazenil were generally shallower than those for chlordiazepoxide, confirming its partial agonist profile. Together, these data support the view that benzodiazepine receptor partial agonists may have utility in the management of human anxiety disorders

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Although tolerance to a variety of behavioral and physiological effects of Δ9-tetrahydrocannabinol (Δ9-THC) has been demonstrated, previous studies have reported that tolerance to the discriminative stimulus effects of Δ9-THC does not develop when discrimination training is continued during repeated administration. The present study investigated development of tolerance to the discriminative stimulus effects of Δ9-THC under conditions of supplemental administration during suspended training. Rats, trained to discriminate Δ9-THC (3 mg/kg) from vehicle in a two-lever drug discrimination procedure, under a fixed-ratio 10 schedule of food reinforcement, were tested with cumulative doses of Δ9-THC before and after repeated administration of vehicle and of high doses of Δ9-THC. Following suspended training with repeated vehicle injection, the Δ9-THC dose-effect curve for percentage of drug lever responding showed little change from the prevehicle curve. After supplemental administration of Δ9-THC, the degree of rightward shift in the post-THC dose-effect curve was 40-fold. Recovery to pre-THC levels of percentage of drug lever responding was observed during a second post-THC dose-effect curve administered 23 days later. The large reversible shift in the dose-effect curve following supplemental administration of Δ9-THC suggests that tolerance developed to the discriminative stimulus effects of Δ9-THC under suspended training conditions.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

In a study examining the effects of pharmacological manipulations on “demand” for food, responding of six adult male baboons (Papio c. anubis)was maintained under a fixed-ratio schedule of food reinforcement during daily 22 h experimental sessions. Increasing the response requirement decreased daily food intake. Administration of anorectic drugs (amphetamine, fenfluramine, diethylpropion, phenmetrazine, phenylpropanolamine and mazindol) produced parallel dose-dependent downward shifts in responding at all response costs. In contrast, administration of the anxiolytic, diazepam, produced parallel dose-dependent upward shifts in responding at all response costs. Oral phencyclidine decreased intake during the first 8 h of the session, but compensatory feeding later in the day eliminated this effect. Changes in pellet intake were fitted to a theoretical equation derived by Hurshet at.(1988) to describe changes in demand for a commodity. When responding increases as a result of increasing cost, demand is said to be inelastic, but when responding decreases as a result of increasing cost, demand is said to be elastic. Administration of anorectic drugs, while decreasing maximal intake at minimal cost, had no effect on the elasticity of demand for food. Similarly, diazepam increased maximal intake at minimal cost without affecting the elasticity of demand for food. The effect of anorectic drugs differs from the previously reported effects of caloric substitutes which increase the elasticity of demand for food. Thus, anorectic drugs do not function as caloric substitutes, in an economic sense, for food

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Schedule-induced polydipsia in rats was established in daily, 3h sessions with a fixed-interval 1 min food schedule, and continued with two fluids available on concurrent fixed-ratio 6 schedules. A 2% ethanol solution was preferred to water, and succeeding drug solutions (0.16mg/ml cocaine, 0.1 mg/ml caffeine, 0.01 mg/ml nicotine, 0.11 mg/ml lidocaine) also were preferred. Except for lidocaine, these drugs are known to function as reinforcers. Drug solution position was alternated daily, with location indicated by a discriminative stimulus (SD) light. Subsequent SD manipulations indicated that lidocaine and cocaine preferences were attributable to the prior association of the SD with ethanol rather than to the pharmacological effects of the currently accessible drug. Furthermore, when concurrent water choices were instituted, animals continued to choose the water source indicated by the SD. The effectiveness and durability of the SD in determining polydipsic choice attests to the importance of the associative history of environmental SDs in triggering and maintaining drug seeking and drug taking. A model is outlined which suggests that drug abuse is a special case of a more general set of excessive behaviors induced by current environmental conditions, with choice of behavior remaining under SD control determined, in part, by the associative history of the SD.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Separate groups of rats were trained to discriminate either 0.1 mg/kg (low dose; L) or 2.5 mg/kg (high dose; H) of 8-OH-DPAT from saline, in a standard operant task. Both cues were found to be dose, time and route dependent and generalized completely to the 5-HTuagonists ipsapirone and flesinoxan. Buspirone substituted completely for 8-OH-DPAT in L and partially in H, whereas the 5-HT]A,1Breceptor agonist eltoprazine substituted completely for 8-OH-DPAT in H but only partially in L. The 5-HT1A/1Breceptor agonist RU24969, the 5-HTIB/2chAreceptor agonist TFMPP and the 5-HT reuptake blocker fluvoxamine did not completely mimic the effect of 8-OH-DPAT in either L or H and the 5-HT,Amixed agonists/antagonists BMY 7378 and NAN-190 produced partial generalization in L, but no generalization in H. In antagonism tests, NAN-190 and BMY 7378 only partially blocked the 8-OH-DPAT cue in both groups. The non-selective 5-HT receptor antagonist methysergide did not completely block the 8-OH-DPAT cue in L or H. However, in generalization studies, it completely mimicked the 8-OH-DPAT cue in L and produced partial generalization in H. The /8-adrenergic/5-HTIA/1Breceptor antagonist pindolol completely blocked the 8-OH-DPAT cue in L and H and did not mimic the 8-OH-DPAT cue in either condition. The a2-adrenoceptor blocker yohimbine substituted fully for the 8-OH-DPAT cue in L and partially in H. Idazoxan did not substitute for the cue of 8-OH-DPAT in H, but produced nearly 80% generalization in L. The dopamine receptor antagonist pimozide neither blocked nor mimicked the cue of 8-OH-DPAT in either group. A number of other drugs (i.e. m-CPP, S (-propranolol, DOI, ketanserin, clonidine and apomorphine) were only tested in H.S( -(-Propranolol blocked the 8-OH-DPAT cue but the other compounds produced neither stimulus generalization nor antagonism. The present study demonstrates that the cues produced by the low and the high training dose of 8-OH-DPAT are quantitatively different and mediated by the agonistic activity of 8-OH-DPAT at 5-HT1Areceptors. Although the results suggest that the 8-OH-DPAT cue (both L and H) is mediated via postsynaptic 5-HT,Areceptors, the involvement of presynaptic 5-HT,Areceptors cannot yet be ruled out.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

In the rat forced swimming test, systemic application of the serotonin 1A (5-HT1A) receptor agonist 8-OH-DPAT reduced immobility (ID500.17–1.37 mg/kg, depending on route of application and application schedule). Intracerebroventricular (i.c.v.) or local application into the dorsal raphe nucleus (DRN), a brain area rich in presynaptic 5-HT1Areceptors, resulted in a parallel shift of the dose-response curve to the left (ID505.1 and 3.9 μg/rat, respectively). Systemic application of the 5-HT1Areceptor partial agonist ipsapirone resulted in a U-shaped dose-response curve (maximal effect about 30% immobility reduction at 3–10 mg/kg). Local application of ipsapirone in the DRN reduced immobility (maximal effect 40% at 60 μg/rat). However, 8-OH-DPAT and ipsapirone were still effective after depletion of brain 5-HT by means of 5,7-DHT (150 μg, i.e. v.) or pCPA (either 2 ± 150 mg/kg or ± 350 mg/kg, i.p.) Additionally, in non-lesioned rats: (1) the putative (postsynaptic) 5-HT1Aantagonist NAN-190, but not spiperone, haloperidol, prazosin or 1-PP, was able to block the anti-immobility effects of 8-OH-DPAT in a behaviorally specific manner; (2) local application of 8-OH-DPAT and ipsapirone in the lateral septum (a brain area rich in postsynaptic 5-HT1Areceptors) reduced immobility (8-OH-DPAT: ID5011.4 μg/rat; ipsapirone: maximal effect at 30 μg/rat 38%); and (3) pretreatment with ipsapirone resulted in an attenuation of the effect of 8-OH-DPAT when both compounds were administered either systemically or in the lateral septum but not when both compounds were microinjected into the DRN. It is hypothesized that the anti-immobility effects of 5-HT1Areceptor agonists are mediated by pre- and postsynaptic 5-HT1Areceptors and that they closely reflect the intrinsic activity of these compounds at these receptors.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

When given the opportunity to choose between a novel and a familiar compartment (free-exploratory paradigm), BALB/c mice exhibited a preference for familiar places and a marked number of attempts at entry into the novel compartment followed by avoidance responses. In contrast, C57BL/6 mice showed a preference for novel places and very few avoidance responses towards novelty. When novelty was reduced by two familiar odours, fresh sawdust or urine of conspecifics, the neophobia of the BALB/c mice was reversed and the animals clearly showed a preference for the novel compartment. This experimental paradigm can be proposed as an effective animal model for investigating drugs potentially able to reduce neophobia in BALB/c mice. The effects of anxiolytics, effective in the usual animal models of “state” anxiety, were investigated in the free-exploratory paradigm which may model another type of anxiety termed by Lister (1990) “trait” anxiety. Thus, the behavioural effects of two benzodiazepine full agonists, chlordiazepoxide and diazepam, two non-benzodiazepine partial agonists at benzodiazepine receptors, Ro 19–8022 and alpidem, the 5-HT1Areceptor agonist, 8-OH-DPAT, and the 5-HT, receptor antagonist, zacopride, were assessed in BALB/c and C57BL/6 mice. Chlordiazepoxide, diazepam and Ro 19–8022 completely reversed the preference of BALB/c mice for the familiar compartment, treated animals exhibiting a significant preference for novel places. In contrast, alpidem, 8-OH-DPAT and zacopride did not significantly modify their behaviour. Moreover, the same drugs did not modify the specific responses of C57BL/6 mice toward novelty. These results demonstrate that drugs which bind in a non-selective manner to heterogeneous benzodiazepine recognition sites were very effective in reducing neophobia in BALB/c mice, whereas 5-HT-interacting drugs were unable to counteract their neophobic behaviour. Thus, the free-exploratory paradigm can be proposed as an effective method for testing potential neophobia- (“trait” anxiety) reducing drugs.

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Microinjection of the mu opioid, [D-Ala2,JV-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) into the ventral pallidum (VP) elicits a motor stimulant response. The coadministration of dopamine (DA) antagonists with DAMGO into the VP was used to determine the role of DA transmission in the motor response. The mixed D1/D2 antagonist, fluphenazine, was found to produce a partial reduction in DAMGO-induced motor activity. To evaluate the role of DA receptor subtypes, the Dl and D2 selective antagonists, SCH-23390 and raclopride, respectively, were coadministered with DAMGO into the VP. SCH-23390 was found to produce a dose-dependent reduction in both horizontal and vertical motor activity with a minimum effective dose of 0.3 nmol/side. However, only a partial reduction in horizontal activity occurred with a dose of SCH-23390 as high as 6.0 nmol/side. Raclopride was without effect at any dose examined, and an equimolar mixture of SCH-23390 and raclopride did not alter the minimum effective dose nor the maximum reduction in motor activity produced by SCH-23390 alone. It is concluded that stimulation of Dl receptors is permissive to the motor stimulant effect elicited by DAMGO in the VP

ISSN:0955-8810    

出版商:OVID    

年代:1993

数据来源: OVID