摘要:

Lever pressing by rats was maintained under a fixed-ratio 30 schedule of food presentation. The response rate-decreasing effects of several opioid compounds that vary in selectivity for, and activity at, μ and non-opioid receptors, were examined alone and in combination with the opioid antagonist naltrexone. Naltrexone (0.01–1.0 mg/kg) produced dose-dependent and generally parallel rightward shifts in the dose-effect curves for morphine, fentanyl, butorphanol and nalbuphine. Apparent pA2values for naltrexone against these agonists ranged from 7.05 to 7.29, and the slopes of the regression lines fitted to the Schild plots approximated theoretical unity (-1.0), suggesting a competitive interaction at μ-opioid receptors. In contrast, although at least one dose of naltrexone (0.01–10.0 mg/kg) antagonized the response rate-decreasing effects of bremazocine, U50,488, (-)-pentazocine and nalorphine, suggesting some opioid activity, these effects differed from those of the μ agonists in that: (a) they were less sensitive to naltrexone antagonism; (b) maximal rightward shifts were smaller; (c) antagonism patterns were not directly related to naltrexone dose and, in some cases, were influenced by the response rate-decreasing effects of the larger naltrexone doses; and (d) there were considerable between-subjects differences in sensitivity to naltrexone antagonism. Naltrexone (0.1–10.0 mg/kg) did not antagonize the effects of the non-opioid control compound pentobarbital. The present results suggest that patterns of naltrexone antagonism can provide a basis for making inferences about receptor activity related to the effects of some opioids on rate of schedule-controlled behavior. With some opioids, however, such inferences are limited by the direct response rate-decreasing effects of naltrexone itself and by differences in patterns of antagonism across subjects.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Pre-clinical studies have suggested that 5-HT3antagonists such as GR 68755 oppose mesocorticolimbic dopamine release, which may mediate the important effects ofd-amphetamine on positive subjective mood, anorexia, and performance. Twenty-six healthy male volunteers received each of the following treatments in a double-blind, randomized, cross-over design separated by a period of four to seven days: (a)d-amphetamine (20 mg orally); (b) placebo; (c) GR 68755 (2 mg orally); and (d) GR 68755 plusd-amphetamine. Subjects completed subjective measures of mood, hunger, and satiety. Caloric and macronutrient intake were measured using a test meal. Performance and attention were assessed using standardized computerized tasks. GR 68755 enhanced accuracy on the computerized attention task but failed to reverse significantly any of the effects ofd-amphetamine. These results suggest that at these doses GR 68755 pre-treatment does not significantly reduce the effects ofd-amphetamine.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The present study was designed to characterize the degree of cross-tolerance between the response rate-decreasing effects of morphine and threemuopioids with varying relative intrinsic efficacies at themureceptor, buprenorphine, butorphanol and fentanyl, and a non-opioid (+)-amphetamine, in a behavioral-tolerance paradigm. Lever pressing of rats was maintained by a fixed-ratio 20 schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine in separate groups of rats administered morphine either before (pre-session) or after (post-session) experimental sessions. Each of themuopioids and the non-opioid (+)-amphetamine dose-dependently decreased response rates. In the pre-session group, daily administration of morphine shifted the morphine dose-effect curve 0.33 log unit rightward, indicating that tolerance had developed, and shifted the butorphanol dose-effect curve 0.96 log unit rightward. Daily pre-session administrations of morphine did not shift the dose-effect curves for buprenorphine, fentanyl, or (+)-amphetamine. In the post-session group, daily administration of morphine did not shift the morphine, butorphanol, buprenorphine, fentanyl, or (+)-amphetamine dose-effect curves. These data suggest that pharmacological variables, such as the drug's relative intrinsic efficacy at themureceptor, can play a role in behavioral tolerance and cross-tolerance.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The present study used a computerised technique to assess the behavioural effects on locomotor activity of i.p. cocaine administration in the rat. This computerised method provides considerable information about various behavioural responses, as well as accuracy by measuring the frequency and duration of every behavioural event. Cocaine induced an increase in behavioural events related to motor activity, such as moving, sniffing and rearing, while standing was reduced. Cocaine increased the frequency of the behavioural responses recorded, but decreased their mean duration. No stereotyped behavioural element, such as head swinging, head bobbing, licking, stereotyped mouth moving or stereotyped sniffing, was recorded after cocaine treatment. Cocaine, unliked-amphetamine, induced a specific behavioural pattern characterised predominantly at all doses by a stimulated motor activation involving an increase in moving and sniffing and a decrease in standing behaviour.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Two experiments were performed to study the effects of age and repeated administration of alpha-phenyl-tert-butyl-nitrone (PBN), the free radical spin-trapping agent, upon spontaneous motor activity levels and radial arm maze performance in normal young (3 month old) and normal aged (15 month old) C57 B1/6 mice. In Experiment 1, the aged mice were found to show reduced locomotor and rearing behaviour in comparison with the young mice. In the radial eight-arm maze learning task, the aged mice performed at a comparable level to the young mice during the first learning trial (Day 1) but made significantly more errors and showed longer total latencies during the second trial presented 24 h later. In Experiment 2, the aged and young mice were subchronically administered either PBN at a dose of 50 mg/kg, s.c. over 12 days, or saline. Spontaneous motor activity was tested 72 h after the last injection. 36 h later the first test trial in the radial arm maze was presented; this was followed after a further 24 h by the second test trial. Subchronic treatment with PBN increased locomotion counts in the aged (15 month old) mice during the 60 min test period, but decreased rearing during the first 30 min of the test period. In the radial arm maze, the performance deficit shown during the second test trial by the aged mice was abolished by repeated PBN administration; both the number of errors and the latencies to all eight pellets were significantly reduced in the aged mice that received PBN. PBN did not exert any effects upon the performance of the young mice. These results, considered in conjunction with other studies using gerbils or rats, implicate the involvement of free radical species in the deterioration of function in the aged C57 B1/6 mouse.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Male Swiss mice were tested 48 h after training in a one-trial step-through inhibitory avoidance task. Immediately post-training i.p. injection of the GABA antagonist picrotoxin (0.3–3.0 mg/kg), at nonconvulsive doses, induced a dose-dependent modification of retention performance. The lower doses of picrotoxin (0.1–1.0 mg/kg) enhanced retention, whereas the highest dose (3.0 mg/kg) impaired retention. Picrotoxin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of picrotoxin on retention performance were not due to nonspecific proactive effects on response latencies. The enhancing effects of picrotoxin (1.0 mg/kg) on retention were time-dependent, which suggests that picrotoxin enhanced storage of recently acquired information. The enhancement of retention induced by picrotoxin (1.0 mg/kg) was prevented by the vasopressin receptor antagonist, AAVP (0.01 μg/kg, s.c.) administered immediately after training, but prior to picrotoxin treatment. This dose of AAVP did not affect retention by itself, either under the standard experimental conditions, or in mice trained with a high footshock. Low subeffective doses of picrotoxin (0.1 mg/kg, s.c.) administered immediately after training, and hypertonic saline (1 ml of 0.5 M NaCl, i.p.), given 10 min after training, interacted to improve retention. Considered together, these findings suggest that the better retention performance induced by post-training administration of picrotoxin could result, at least in part, from an endogenous release of vasopressin.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Rats were trained to discriminate 3.0 mg/kg morphine from water in a standard two-lever drug discrimination procedure and tested in a hot water tail-withdrawal procedure. When tested with morphine, fentanyl, buprenorphine and butorphanol, individual animals showed a three- to ten-fold difference in the lowest dose that substituted completely for morphine, whereas 30− to 1000-fold differences were obtained with nalbuphine and levallorphan, respectively. Across repeated determinations, the dose-effect curves for morphine and nalbuphine remained relatively stable within an individual, suggesting that the profound individual differences with nalbuphine were not a consequence of variability in the dose-effect curve. In addition, despite the extremely shallow group dose-effect curves obtained with nalbuphine and levallorphan, intermediate levels of drug-appropriate responding were not evidenced in individual animals. In the tail withdrawal procedure, the doses of morphine and fentanyl required to produce the maximal levels of antinociception varied by approximately three-fold across individual rats. With butorphanol and nalbuphine, differences across animals were greater than 30-fold and 300-fold, respectively, whereas with levallorphan, substantial individual differences were observed in the maximal level of antinociception. Further analyses indicated that animals sensitive to the stimulus effects of nalbuphine and levallorphan were also sensitive to the antinociceptive effects of nalbuphine, levallorphan and butorphanol. In contrast to the individual differences obtained with the stimulus and antinociceptive effects of these opioids, the potency of these drugs for decreasing rate of responding was similar across animals. These findings indicate that the relative efficacy of an opioid at themureceptor is an important determinant of individual differences in responsiveness to its stimulus and antinociceptive effects, but not to its rate-decreasing effects.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Anandamide was recently discovered to be an endogenous substance that acts as a partial agonist at cannabinoid receptors in the central nervous system. Because exogenous cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive ingredient of marijuana, have been found to impair memory, we undertook the present study to examine the mnemonic effects of anandamide. Memory was assessed in rats well-trained in a two-component instrumental discrimination task with a conditional discrimination to test reference memory and a delayed nonmatch-to-position to test working memory. Since anandamide has a short metabolic half-life, we examined the mnemonic effects of anandamide (0.0–2.0 mg/kg) in rats pretreated with the protease inhibitor phenylmethylsulfonyl fluoride (2.0 mg/kg), serving to increase the metabolic half-life of anandamide. Under these conditions, a dose-dependent impairment of the nonmatch-to-position, but not the conditional discrimination component, was found, closely resembling that observed following Δ9-THC (0.0–4.0 mg/kg). This is the first report that anandamide impairs memory; results suggest that endogenous cannabinoids may be involved in cognitive processes influencing memory.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Pigeons were trained to discriminate 5 mg/kg pentobarbital from saline under several multiple fixed-ratio fixed-interval schedules of food presentation. The following schedules were studied: multiple fixed-ratio 40 fixed-interval 18 s (mult FR40 FI18), mult FR10 FI18 s, mult FR10 FI180 s and mult FR90 FI10 s. After responding stabilized under each multiple schedule, generalization curves were determined for pentobarbital, amobarbital, diazepam, phencyclidine andd-amphetamine. Pentobarbital generated dose-dependent increases in responding under all schedule components; however, there was more responding on the drug key after low doses of pentobarbital under FI components than under FR components, except for the FR90 component of the mult FR90 FI10 schedule. This tendency for more responding on the drug key after low doses of pentobarbital under FI components than under FR components generally was observed for low doses of all of the drugs. Examination of data from individual subjects revealed that there was a greater tendency for birds to distribute responding on both keys (mixed responding) under FI components than under FR components, where responding after each dose was confined largely to one of the two response keys. Analysis of local rates of responding within the FI component of the schedules showed that responding under the FI components developed the typical FI scallop at all Fl-component durations. These data suggest that FI schedules with values between 10 and 180 s generate similar dose-effect curves with higher rates of responding on the drug key after low doses of drugs than under FR schedules with low response requirements; however, under schedules with higher FR requirements, the dose-effect curves for some drugs begin to look more like those under FI schedules.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

This experiment examined the influence of mianserin, a 5-HT2receptor antagonist, on the rewarding effect of ethanol in a place conditioning paradigm. Swiss-Webster mice received four pairings of a tactile stimulus with drug treatment consisting of two i.p. injections separated by a 30 min interval. Drug treatment groups were as follows: saline (10 ml/kg) followed by ethanol (2 g/kg); mianserin (10 mg/kg) followed by ethanol; mianserin followed by saline. A different stimulus was paired with two saline injections. During conditioning, ethanol produced increases in locomotor activity that were reduced by mianserin. Mianserin alone reduced activity levels. As expected, group saline-ethanol showed a nonsignificant trend towards conditioned place preference. However, mianserin enhanced the acquisition of ethanol preference, whereas mianserin alone did not produce either place preference or aversion. The results are consistent with the notion that serotonergic systems are important in the response to ethanol, and further suggest that S-HT2receptor blockade increases the rewarding effects of ethanol.

ISSN:0955-8810    

出版商:OVID    

年代:1996

数据来源: OVID