摘要:

Growing attention has been directed towards the potential involvement of the dopamine D3 receptor (D3R) in modulating effects of psychomotor stimulants. BP 897 (N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-2-naphthylcarboxamide; aka BP 4.897 and DO897) is amongst the most selective partial agonists for the D3R receptor thus far reported. BP 897 was tested for its ability to support self-administration in rhesus monkeys (0.3–30 μg/kg) and for its ability to produce cocaine- and d -amphetamine-like discriminative stimulus effects in mice (0.01–17 mg/kg i.p.). BP 897 was not self-administered above vehicle and saline levels in any of the four monkeys tested, and produced less than 30% generalization from either the cocaine or d -amphetamine stimulus. When BP 897 was administered before administrations of cocaine or d -amphetamine, percent drug-lever selections were reduced. These results suggest that BP 897 has a profile of activity suitable for consideration as a potential treatment for cocaine dependency disorders.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Psychostimulant‐induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non‐preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine‐sensitized animals exhibited markedly enhanced LI compared to saline‐treated animals, due to the fact that NPE–cocaine animals spent more time freezing during the tone CS than NPE–saline animals, whereas PE–cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine‐withdrawn NPE animals, the absence of this effect in cocaine‐withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Acquisition and dose-related self-administration of heroin (H)/cocaine (C) combinations in C57BL/6 × SJL mice were studied in nose-poke or lever-press operant responding procedures. C57BL/6 × SJL mice readily acquired self-administration in both operant procedures with a combination of doses known to be ineffective when each drug was used alone (H:15 μg/kg and C:150 μg/kg per injection). Similar numbers of infusions were obtained under conditions of fixed-ratio (FR) 3 versus 1 for the nose-poke and lever-press responses, respectively. Dose–effect curves for heroin:cocaine combinations revealed a pattern corresponding to a leftward shift of the dose-response for intravenous cocaine self-administration. Curves were similar whether generated with 1 or 3 days of availability per dose, or including subjects that did not respond preferentially (>70% responses) to the hole or lever associated with drug delivery, along with those that did. Motor activity induced by a combination of low doses for each drug was examined (H: 0.375 mg/kg and C: 3.75 mg/kg, i.p.). Under these conditions, the combination of both drugs induced an initial cocaine-like stimulation of horizontal activity, in contrast to the tendency of heroin to decrease activity. It is concluded that heroin:cocaine combinations used in the present study had reinforcing effects in C57BL/6 × SJL mice, and produced a cocaine-like effect in the early part of drug-induced activity sessions, followed by a locomotor profile corresponding to the average of both drugs.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Smokers often report that the first cigarette of the day is the most rewarding, and subsequent smoking is less rewarding. Reduction in smoking enjoyment later in the day may be related to acute tolerance to the discriminative stimulus effects of nicotine. We examined changes in nicotine discrimination behaviour in humans as a function of acute nicotine pretreatment. Male and female dependent smokers (n = 15) were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0 μg/kg) without nicotine pretreatment. They then were tested on generalization of discrimination across a range of spray doses from 0–20 μg/kg following pretreatment with placebo, moderate dose (14–21 mg) or high dose (28–42 mg) transdermal nicotine. Generalization testing involved both two- and three-response (‘novel’ option) quantitative procedures. Subjects also engaged in a self-administration phase at the end of each session, involving choices between nicotine (20 μg/kg) and placebo spray. Nicotine pretreatment significantly attenuated nicotine-appropriate responding at higher nicotine spray doses, suggesting acute tolerance, but only in women. Similar results were seen for subjective ‘head rush’, suggesting this effect may be related to discrimination behaviour in women. However, nicotine pretreatment also increased novel-appropriate responding, especially in men, following intermediate generalization doses, suggesting qualitatively different stimulus effects. Although differences were not significant, nicotine self-administration tended to be inversely associated with nicotine pretreatment dose in men but not in women. These results only modestly support the notion of acute tolerance to the discriminative stimulus effects of nicotine, and even then only in women and not in men.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Prepulse inhibition (PPI), a measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. Animal studies have revealed drug effects on PPI that may be relevant to understanding the biology of gating deficits in human populations. Recent efforts have examined similarities and differences in drug effects on PPI between rodents and humans. Experimental designs are needed that most effectively translate these drug studies across species. In the course of a larger set of studies of drug effects on startle in normal human subjects, we examined the potential utility of one design element that is utilized in rodent PPI drug studies: pre-testing to diminish variability across dose groups. Startle was measured during a screening session; 7–10 days later, 20 subjects were retested after consuming a placebo pill. Acoustic and tactile startle, and unimodal and cross-modal PPI, were measured in five sessions over a period of 3 hours post-placebo. There were significant and robust correlations between levels of startle magnitude and PPI during pre-testing and testing, for both left and right eyeblink measures. Comparable correlations were evident for both unimodal and cross-modal testing. Pre-testing values were most predictive of test performance early in the 3-hour test session, and predictive strength diminished or disappeared towards the end of testing. The utility of a pre-testing design could be seen clearly by comparing groups ‘matched’, based on pre-test data, versus groups created by alternating or random group assignments. It is concluded that pre-test designs can effectively match groups with comparable levels of startle or PPI, and thereby diminish between-group variability in human PPI drug studies. For studies using repeated testing to assess drug time course, the predictive value of pre-testing is greatest in early test sessions.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

This study assessed the effects of acute amphetamine and ketamine on the performance of rats in a serial negative patterning procedure. A 5 s auditory target stimulus and a 5 s visual feature cue were each followed by food, but the target stimulus was not followed by food if preceded by the feature. There was a 5 s empty gap between feature termination and target onset in the latter, non-reinforced trials. Thus, the feature functioned as a cue signalling the non-reinforcement of the target. The interval between the feature and the target was varied in the non-reinforced trials following pretreatment with subcutaneous saline, d -amphetamine (0.5 mg/kg) or ketamine (5 mg/kg). The main behaviour measured was visits to the place of food delivery during target presentation. Under saline, the response frequency during the target was lowest when the interval between the feature and the target exactly matched the interval used during training. Either shortening or lengthening the interval enhanced responding. Neither d -amphetamine nor ketamine disturbed this temporal pattern, although d -amphetamine and ketamine non-specifically increased and decreased response frequencies, respectively, in all the trial types. The results are discussed in the framework of the amphetamine and ketamine models of schizophrenia.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Differences in locomotor response to an inescapable novel environment have previously been shown to predict sensitivity to amphetamine reward, where high responders (HR), compared to low responders (LR), showed greater initial sensitivity to amphetamine self-administration. The present experiments sought to extend these findings and assessed the relationship between locomotor response to an inescapable novel environment and conditioned taste aversion (CTA) with amphetamine and lithium chloride (LiCl). Male Sprague–Dawley rats were tested for their locomotor response to an inescapable novel environment and divided into high (HR) or low (LR) responders, based on whether their locomotor scores were above or below the median activity level of the subject sample. After several days, the animals were tested in a CTA procedure and conditioned with either amphetamine or lithium chloride. Compared to HR rats, LR rats showed greater sensitivity to amphetamine CTA at the doses tested. In contrast, the results with LiCl showed no relationship between locomotor response to an inescapable novel environment and CTA. Taken together, the present results suggest that LR, compared to HR, rats show less sensitivity to the rewarding effects of amphetamine because they are more sensitive to aversive effects of amphetamine, as reflected in CTA. In contrast, HR rats display less sensitivity to aversive effects of amphetamine, which may explain their greater propensity to self-administer amphetamine.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The antidepressant effect of sulpiride has been generally explained as the result of its preferential blocking effect on self‐inhibitory presynaptic dopamine autoreceptors at low doses. Low dose haloperidol has the same blocking effect. In rats with unilateral ablation of the frontal cortex, methamphetamine administration induced mild contralateral rotation 10 days after the operation. We examined whether low dose sulpiride and haloperidol would have the same effect on this rotational model. High dose sulpiride (100 mg/kg) or low dose haloperidol (0.05 mg/kg) prevented this methamphetamine‐induced rotation. However, low dose (15 mg/kg) sulpiride clearly reversed the direction of rotation. This reversal effect of low dose sulpiride is not explained by the preferential blocking effect on dopamine autoreceptors. The results suggest that low dose sulpiride, unlike low dose haloperidol, has a prominent blocking effect on D2 receptors in the frontal cortex. This unique effect of sulpiride may be relevant to its clinical antidepressant and anxiolytic effects at low doses.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

In previous studies we have demonstrated a possible interaction between the GABAergic and opioid systems involved in the antinociceptive effect of the GABABagonist, baclofen (BAC). On the other hand, sex differences have been observed for the antinociceptive effect of morphine (MOR). In the present study, we analyzed sex-related differences in the MOR abstinence syndrome and its prevention with BAC. Prepubertal male and female Swiss–Webster albino mice (27–33 g) were rendered dependent by intraperitoneal (i.p.) injection of MOR (2, 4 and 8 mg/kg), twice daily for 9 days. On the tenth day the dependent animals were divided into two groups: one received naloxone (NAL) (6 mg/kg, i.p.) 60 min after the last dose of MOR, to precipitate the abstinence syndrome; the other group received BAC (2 mg/kg, i.p.) followed by NAL (6 mg/kg, i.p.), injected 30 and 60 min after the last dose of MOR, respectively. Behavioral signs were recorded in the open field for 30 min. Although there were sex differences in the MOR withdrawal syndrome, we found a lack of sex differences in the prevention of the MOR abstinence syndrome by BAC.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID