摘要:

The present study reports on the development of a multiple schedule procedure of oral ethanol self‐administration in cynomolgus macaques. Six adult cynomolgus macaques (four female, two male) were trained to self‐administer ethanol and water under a 60 min, four‐component multiple schedule of ethanol and water access with 1 g food pellets presented every 900 s (fixed‐time 900 s). Water was available for the first and third 15 min components, ethanol in the second and fourth components. Total ethanol dose was stable at between 1–1.25 g/kg at ethanol concentration of 4%, 6% and 8%. Subsequently water was replaced with a sweetened drink (sugar‐free Tang powder, General Foods). Ethanol and Tang were self‐administered in similar volumes and both served as reinforcers compared with water. Acute pretreatment with 0.25 to 1.5 g/kg of intragastrically gavaged (i.g.) ethanol failed to alter ethanol or Tang self‐administration significantly despite producing mean blood ethanol levels of up to 199 mg/dl when combined with self‐administered ethanol. However, 1.0 g/kg i.g. ethanol administered for 15 consecutive days significantly decreased ethanol self‐administration by 23%. The results suggest that ethanol self‐administration under a multiple schedule is insensitive to alteration by acute ethanol pretreatment, but can be decreased by more prolonged chronic ethanol pretreatment.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Although it is recognized that retrieval may be state-dependent, only recently has a paradigm been identified that allows state-dependence in rats to be demonstrated reliably and at relevant doses of CNS agents. In humans, the effects of scopolamine constitute a valuable model of disordered memory. We used this paradigm to analyze the effects of scopolamine on different memory processes. Rats treated with either saline or 0.01–10 mg/kg doses of scopolamine learned to lever press for milk reward, and were then tested for retrieval while given the same or a different treatment. Saline-to-scopolamine as well as scopolamine-to-saline state changes produced robust failures to retrieve the response. Remarkably, the state produced by 2.5 mg/kg scopolamine, like that produced by saline, produced little intrinsic effect on learning or any other memory process (i.e. when the prevailing state was left unchanged). However, changing the implemented state from one to the other between two different processes, disrupted not only retrieval, but also learning, encoding and retention. We also determined whether the graded state changes produced by 0.01–10 mg/kg doses of scopolamine could mimic the peculiar and poorly understood temporally graded retrograde amnesia that occurs in Alzheimer's disease. In rats that had acquired a complex drug-discrimination task over a 6-month period, scopolamine-induced state changes seemed to produce dose-dependent deficits in the retrieval of recent information while preserving those abilities that had been acquired in the increasingly remote past. Beyond its role in retrieval, the findings implicate state dependence in learning, encoding and retention, and suggest that physiologically defined mnesic states govern each of these. The changes of mnesic state that are likely associated with excessively labile cholinergic neurotransmission may conceivably cause the complex disabilities of Alzheimer's disease.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

This study was conducted to determine whether sex differences in opioid antinociception may be explained by sex differences in opioid receptor activation. The time course, dose–effect and selectivity of antagonists that have been previously shown to be relatively mu (β-funaltrexamine, β-FNA), kappa (norbinaltorphimine, norBNI), or delta (naltrindole, NTI) receptor selective in male animals were compared in female and male Sprague-Dawley rats using a 52°C hotplate test. In both sexes, β-FNA (10 or 20 μg intracerebroventricularly [i.c.v.]) dose-dependently blocked the antinociceptive effects of fentanyl (0.056 mg/kg subcutaneously); antagonism was observed 24 h after β-FNA, and diminished within 7–14 days. In both sexes, norBNI (1 or 10 μg i.c.v.) dose-dependently blocked the antinociceptive effects of U69,593 (1.0 mg/kg subcutaneously); antagonism was maximal by 1–3 days post-norBNI and lasted longer than 56 days. NTI (1 or 10 μg i.c.v.) dose-dependently blocked the antinociceptive effects of [d-Pen2, d-Pen5]enkephalin (DPDPE, 100 nmol i.c.v.) in both sexes; however, the duration of action of NTI was shorter in females than in males. The antinociceptive effects of the mu receptor-preferring agonists fentanyl, morphine and buprenorphine were significantly and dose-dependently antagonized by β-FNA, but not by norBNI or NTI, in both sexes. β-FNA antagonism was significantly greater in females compared with males given morphine, but not fentanyl or buprenorphine. The antinociceptive effects of the kappa receptor-preferring agonists U69,593 and U50,488 were significantly and dose-dependently antagonized by norBNI; U50,488 but not U69,593 was also antagonized to a lesser extent by NTI and β-FNA, in both sexes. The antinociceptive effect of the delta receptor-preferring agonist SNC 80 was significantly antagonized by NTI, but not by norBNI or β-FNA, in both sexes. The sex difference in β-FNA antagonism of morphine suggests that there may be sex differences in functional mu opioid receptor reserve or signal transduction; however, the lack of consistency across all mu agonists weakens this hypothesis. Overall, the opioids tested had very similar receptor selectivity in male and female subjects.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Neuronal substrates that mediate the conditioned effects of cocaine have not been well characterized. To examine dopaminergic mechanisms, three antagonists were tested for their capacity to inhibit the expression of conditioned locomotor activity and conditioned place preference in rats. Antagonists were also assessed against acute cocaine-stimulated locomotor activity for comparison. For locomotor activity conditioning, six conditioning sessions were conducted over a 10-day period. Paired rats received 10 mg/kg cocaine prior to activity sessions and saline after; unpaired controls received saline prior and cocaine after. For place preference conditioning, eight conditioning sessions were conducted over a 13-day period; rats received 10 mg/kg cocaine while restricted to one of two distinct chambers and, on alternate days, they received saline in the other. Antagonists (haloperidol, raclopride and SCH23390; 0.03–0.1 mg/kg) were given only on test days for conditioned effects. All three antagonists significantly and dose-dependently attenuated the direct stimulatory effect of cocaine. SCH23390 showed a tendency to reduce the expression of conditioned locomotor activity, and only haloperidol blocked the expression of conditioned place preference. Thus, direct and conditioned stimulant effects of cocaine were shown to be differentially sensitive to dopamine receptor blockade. Further, conditioned stimulant effects differed from conditioned reinforcing effects in this regard.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The ability of m-CPP [1-(m-chlorophenyl)piperazine] to produce hypolocomotion is well documented. This effect has been postulated to be due to activation of the 5-HT2Creceptor. It is only recently that the tools necessary to clearly delineate which serotonin receptors are involved in the mediation of m-CPP hypolocomotion have become available. We investigated the effects of the selective 5-HT2Aantagonists, MDL 100,907 and ketanserin, the selective 5-HT2Bantagonists, LY 202146 and LY 266097, the 5-HT2B/2Cantagonist, SB 206553, and the selective 5-HT2Cantagonist, SB 242084 on m-CPP-induced hypolocomotion and spontaneous locomotor activity in mice. Furthermore, we investigated the effects of the non-selective serotonin antagonists, ritanserin, LY 53857, mianserin and cyproheptadine on m-CPP hypolocomotion. Additionally, receptor-binding studies were employed as anin vitroassessment of relative affinities at the 5-HT2A, 5-HT2Band 5-HT2Creceptors. Antagonists tested alone were without effect on spontaneous activity, with the sole exception of ketanserin, which decreased spontaneous activity at the high dose of 1 mg/kg. m-CPP-induced hypolocomotion was not significantly attenuated by various doses of MDL 100,907, ketanserin, LY 202146, LY 266097, ritanserin or cyproheptadine. In contrast, SB 206553, SB 242084, LY 53857 and mianserin were capable of reversing m-CPP-induced hypolocomotion. Consistent with previous suggestions, a detailed pharmacological evaluation with selective antagonists for the 5-HT2family of receptors supports a primary role for the 5-HT2Creceptor, and not 5-HT2Aor 5-HT2Breceptors, in mediating the hypolocomotion produced by m-CPP.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

(+)Amphetamine was added as a training stimulus for pigeons previously trained to discriminate among pentobarbital, morphine and saline using a three-choice procedure. Pigeons quickly learned the four-choice drug discrimination. Generalization from the training drugs was similar to that established with simpler drug discriminations; pentobarbital generalized to chlordiazepoxide, morphine generalized to methadone, and (+)amphetamine generalized to cocaine and methamphetamine. Low doses of phencyclidine generalized to saline, while higher doses partially generalized to pentobarbital and (+)amphetamine. When dose–response curves were redetermined with a cumulative-dosing procedure, the same pattern of generalization occurred as under single-dose procedures. Dose–response curves were quantal under both the single-dose and the cumulative-dosing procedures. The four-choice procedure offers some important advantages for studying the discriminative stimulus effects of drugs that interact with multiple receptor subtypes and for studying drug mixtures.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the CA1 region of the dorsal hippocampus. Once recovered from surgery, animals were submitted to one session of step-down inhibitory avoidance training (3.0 s, 0.4 mA footshock). Animals received a 0.5-μl infusion of saline, or of LY294002 (5, 50 or 500 μM), an inhibitor of the phosphoinositide 3-kinase (PI 3-K) family. Infusions were given 10 min before training, immediately post-training or 10 min prior to a 24-h retention test. In the pre- and post-training groups, the animals were tested twice: at 1.5 and 24 h after training, for short- (STM) and long-term memory (LTM), respectively. Pre- and post-training infusion of the drug inhibited both STM and LTM. Pre-test infusions impaired LTM retrieval. The effects can not be attributed to influences on locomotor, exploratory, pro- or anti-conflict behaviour, since LY294002 had no influence on elevated plus-maze behaviour. The results suggest that hippocampal PI 3-K is necessary for memory acquisition, consolidation and retrieval of the consolidation of step-down inhibitory avoidance in rats. This could be due to an interaction with theN-methyl-d-aspartate (NMDA) receptor complex or with activity of the extracellularly regulated protein kinase (ERK)–Ras signalling pathway.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Research has indicated that the herb St John's Wort (Hypericum perforatum) has comparable efficacy to conventional antidepressants in the treatment of depression. Although clinical studies have demonstrated that hypericum has a superior side‐effect profile compared to standard antidepressants, no study has directly compared the cognitive and psychomotor effects of hypericum with those of other antidepressants. The aim of the current study was to examine the acute effects of hypericum on cognitive and psychomotor function, and to compare its effects with those of amitriptyline. Thirteen healthy volunteers received an acute dose of placebo, amitriptyline (25 mg, positive control) or hypericum (900 mg or 1800 mg) in a double‐blind, placebo‐controlled design. Cognitive and psychomotor tests and subjective measures of sedation were administered before and 1, 2 and 4 hours after drug administration. Amitriptyline impaired performance on a battery of psychological tests, which included critical flicker fusion (CFF), choice reaction time (CRT), digit symbol substitution test (DSST), profile of mood states (POMS) and the line analogue rating scale (LARS), while hypericum had neutral effects on performance in these tests. However, hypericum induced a dose‐related impairment on DSST. Current findings suggest that clinical doses of hypericum do not impair attention, sensorimotor function or information processing.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Cannabinoids increase food intake, via CB1 receptors. The CB1 antagonist, SH141716, has been reported to decrease palatable food consumption in both operant and non-operant procedures. Similarly, CB1 receptor blockade diminished responding for normal food pellets under a fixed-ratio 15 (FR-15) schedule of reinforcement. The present experiment investigated whether the control of a continuous schedule of reinforcement (CRF) for sucrose pellets would be sensitive to the CB1 antagonist in mildly deprived rats. SH141716 dose-dependently reduced responding in a CRF procedure, by increasing post-reinforcement pauses. Together with formerly published conclusions, the data suggest that CB1 blockade reduces the rewarding efficacy of both palatable and non-palatable food.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID