摘要:

Evidence is mounting that prenatal protein malnutrition affects the physiological properties of the GABAergic neurotransmitter system in rats. To investigate the functional behavioral consequences of these changes, chlordiazepoxide (CDP, a positive modulator of the GABAAreceptor) was applied directly to the medial septum and the amnestic response appraised. In adulthood, male offspring of rats provided with a protein‐deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy underwent stereotaxic surgery to implant steel cannulae aimed at the medial septum. After recovery, spatial learning performance in the submerged platform version of the Morris water maze task was assessed immediately following a 1 μl infusion of either artificial cerebrospinal fluid (aCSF), or one of three doses of CDP (15, 30 and 60 nmol). Well‐nourished control rats demonstrated a robust amnestic response to intraseptal CDP. During task acquisition, well‐nourished rats administered each of the doses exhibited significantly longer escape latencies than those given aCSF. On the probe trial (platform removed) a lower proportion of time was spent in the target quadrant (all three doses) at a greater average distance from the former platform location (30 and 60 nmol doses). In contrast, prenatally malnourished rats exhibited a muted sensitivity to CDP, most notable at the 30 nmol dose. These findings provide further support for functional changes within the GABAergic system consequent to malnutrition.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Recent work has shown that transport of food items from open, exposed food sources to a covered shelter is reduced by drugs thought to have anxiolytic properties in rodents and humans. We studied the effects of amphetamine and the dopamine D2/3-receptor antagonist, raclopride, in this test of food transport that pits immediate food consumption against exposure in an open space. Rats traveled from a home cage along an elevated beam to obtain single food items of varying sizes located at one of 12 distances from the home cage. Large food items and items located close to the home cage were carried back and consumed inside the cage. Small items and items located farther from the cage were eaten immediately at the food source while sitting on the beam. Amphetamine sulfate (0.001–2.0 mg/kg, i.p.) decreased eating on the beam and increased carrying of food items to the home cage. Raclopride (0.005–0.2 mg/kg, i.p.) tended to reduce carrying of food to the home cage, but 0.05 mg/kg raclopride did not block the increase in food carrying seen with amphetamine treatment (2 mg/kg). The increased food carrying seen with amphetamine is opposite to the effect produced by anxiolytic drugs, raising the possibility that amphetamine promotes carrying by increasing defense or ‘anxiety’. Consistent with this hypothesis, amphetamine (2 mg/kg; the maximally effective dose in the food-carrying experiment) decreased open-arm exploration in the elevated plus-maze, considered to be an anxiogenic effect. These results indicate that stimulation of monoaminergic neurotransmission increases food transport from exposed food sources to a shelter; D2/3-receptor blockade tends to reduce it. The food-carrying test provides a rich, ethologically valid paradigm to assess the effects of psychoactive drugs on species-specific, defensive behaviors in rodents.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

It has been suggested that the locomotor response of rats to novelty is positively correlated with motor stimulant effects of acute injections with psychomotor stimulants, and liability to self-administer these drugs. In addition, response to novelty appears to be inversely correlated with an individual's susceptibility to develop behavioural sensitization (an increase in the behavioural response to a given dose of stimulant after repeated treatments). To test some of these putative relationships, 96 rats were allocated to one of two subgroups based on a median split of locomotor responses to novelty. Animals then received 10 successive injections of either vehicle, cocaine (10 mg/kg), or the direct D2agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO: 15 μg/kg), and locomotor activity was monitored. Conditioning tests and additional sensitization and cross-sensitization tests were conducted. Results showed that locomotor responses to novelty are not significantly correlated with locomotor effects of either acute injection with cocaine or PHNO, or rate of development of behavioural sensitization to these drugs. However, locomotor responses to novelty did predict level of locomotor and stereotypy responses to cocaine, and to a lessor extent to PHNO. Cocaine-treated, but not PHNO-treated, rats exhibited drug-conditioned-like effects. Cross-sensitization between cocaine and PHNO was not observed, indicating independent mechanisms for sensitization. It is concluded that the locomotor response to novelty can predict level of locomotion and stereotypy produced by cocaine and PHNO, but does not predict the degree or rate of behavioural sensitization to either of these drugs.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Prior experience of withdrawal from chronic diazepam treatment reduces the aversiveness of withdrawal when precipitated withdrawal is made the unconditioned stimulus in a conditioned taste aversion (CTA) paradigm. Accounts of the mechanism by which unconditioned stimulus pre-exposure reduces its effectiveness in CTA postulate that unconditioned stimulus pre-exposure leads to the formation of associations with the environment, resulting in blocking of taste conditioning. We tested whether a blocking explanation accounted for the reduced effectiveness of withdrawal as a unconditioned stimulus in a CTA following prior exposure. Mice received chronic diazepam (15 mg/kg/day, s.c. in sesame oil), or sesame oil vehicle, for three periods of 7 days, interspersed with 3-day withdrawal periods. The first two withdrawals occurred either in the home cage, or in one compartment of a place-conditioning apparatus (PCA). Animals which experienced withdrawal in the home cage were given equivalent experience of the PCA outside the withdrawal period. The third withdrawal was precipitated by i.p. administration of flumazenil (20 mg/kg). Thirty minutes before injection, all animals were placed individually in the compartment of the PCA to which they had been previously exposed, allowed to drink a novel 10% sucrose solution, injected with flumazenil, and replaced in the PCA for 2 h, before being returned to the home cage. When sucrose consumption was measured 24 h later, only that group which had experienced all three withdrawals in the PCA showed evidence of a CTA. These animals (but not those that had experienced withdrawal in the home cage, or vehicle-treated mice) also showed strong avoidance of the chamber in which they had experienced withdrawal. Thus, no evidence was adduced that prior conditioning of an environment-conditioned stimulus to a withdrawal unconditioned stimulus blocked the formation of a CTA. When the CTA conditioning was repeated in the home cage, again only the mice that had experienced withdrawal in the place-conditioning apparatus showed evidence of conditioning. These observations are discussed in the context of blocking explanations of unconditioned stimulus pre-exposure.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Three separate groups of rats were trained to discriminate the putative D3 dopamine receptor agonists (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT) (0.03 mg/kg), PD 128,907 (1.0 mg/kg) and quinpirole (0.03 mg/kg) from saline. Food was presented after each 10 (7-OH-DPAT and PD 128,907) or 20 (quinpirole) consecutive responses on one lever after administration of the training drug, and the other lever after the administration of saline. Once stable performances were obtained, the effects of various doses of several dopaminergic agonists were assessed during test sessions in which responses on either lever were reinforced. The substitution tests were conducted to determine if differences in potencies would be obtained, which would be suggestive of differences in the mechanisms underlying the discriminative effects of the training drugs. Non-selective agonists with activity at both D2 and D3 dopamine receptors (D2-like agonists) substituted for each of the three training drugs. In addition, the selective D2 dopamine receptor agonist U91356A also generalized to both 7-OH-DPAT and PD 128,907. The potencies of the D2-like agonists in substituting for each training drug were highly correlated with potencies in substituting for the others. SKF 82958 and SKF 81297, agonists with selectivity for D1 and D5 dopamine receptors (D1-like agonists), partially substituted for 7-OH-DPAT but not PD 128,907. The D1-like partial agonist SKF 38393 did not substitute for any of the training drugs for which it was tested. Cocaine produced intermediate substitution in 7-OH-DPAT- and PD 128,907-trained subjects and did not substitute at all in quinpirole-trained subjects. The dopamine D1-like antagonist SCH 39166 (0.001–0.03 mg/kg) did not alter the discriminative stimulus effects of PD 128,907, whereas the D2-like dopamine antagonist spiperone (0.001–0.1 mg/kg) produced at the highest dose an insurmountable antagonism of the discriminative effects of PD 128,907. In contrast, there was no appreciable antagonism of the effects of PD 128,907 on response rates. The data collected are consistent with a distinction between the effects of each of these training drugs and the indirectly acting agonist cocaine. Further, these data indicate that there are differences in the mechanisms underlying the discriminative effects of PD 128,907 and its effects on response rates. Moreover, these data indicate that each of the training drugs is distinct from drugs acting through D1 dopaminergic mechanisms. However, there were no data that clearly distinguished these training drugs from each other or from drugs acting through D2 dopaminergic mechanisms.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

In the rat, fear-potentiated startle (FPS) test animals are first trained to associate brief light presentations with a mild electric footshock and then tested for startle responses to acoustic stimuli, delivered either in darkness (i.e. baseline startle) or after the conditioning stimulus. Following light presentation the magnitude of the startle response is markedly increased, and the test is commonly used to distinguish anxiolytic drug effects (i.e. a reduction in FPS) from non-specific effects such as sedation/muscle relaxation. However, recent studies suggest that the environment in which the animal is trained may also contribute towards the acquisition of a conditioned fear response (i.e. contextual fear conditioning) and that this may elevate startle responses recorded in the dark. In the present study, therefore, we have compared the benzodiazepine/γ-aminobutyric acid-A receptor agonist chlordiazepoxide with the partial agonists FG 8205 and bretazenil, which are known to have a reduced propensity to produce sedation/myorelaxation, using two different FPS procedures: (i) conditioning and testing in stabilimeter chambers, and (ii) conditioning and testing in different environments. The results show that FPS can be demonstrated in both procedures and that treatment with chlordiazepoxide, FG 8205 or bretazenil dose-dependently attenuates the response. However, animals conditioned and tested in stabilimeter chambers also showed a significant increase in dark-startle amplitudes compared with non-shocked rats, suggesting that this response was elevated by contextual fear conditioning. Furthermore, despite clear differences in side-effect liabilities, FG 8205 and bretazenil significantly reduced dark-startle responses, suggesting that this measure is also sensitive to the anxiolytic effects of benzodiazepines. In contrast, when animals were conditioned and tested in different environments, dark-startle responses were not significantly different from those recorded in non-shocked rats and treatment with FG 8205 or bretazenil had no effect. Thus, conditioning and testing animals in different environments may provide a more effective means of distinguishing anxiolytic from non-specific drug effects in the rat FPS test.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Nicotine produces dose-dependent enhancement of performance in an active avoidance test, and also increases the levels of NO2−and NO3−, which are stable metabolites of nitric oxide (NO), in various brain regions of rats. On the basis of these two observations, we hypothesized that the beneficial effect of nicotine on learning could result from increased NO in relevant brain regions. We therefore tested active avoidance performance in rats given l-Nω-nitroarginine (l-NA) to inhibit NO synthetase (NOS) prior to nicotine administration. Male Sprague-Dawley rats received l-NA (30 or 50 mg/kg), nicotine (0.4 mg/kg), saline or combinations of these treatments before learning trials. Rats were also tested on the inclined plane, to assess the possible effects due to impairment of motor function by drug treatments on active avoidance learning. l-NA treatment impaired the acquisition of active avoidance learning, and this defect was partially overcome by the co-administration of nicotine. Nicotine facilitated learning and significantly increased the number of correct responses. The threshold for the effect of NOS inhibition on performance exceeded 30 mg/kg l-NA, whereas 50 mg/kg impaired learning and also eliminated the nicotine-induced enhancement of learning. On the fifth day of learning trials, no facilitation of learning by nicotine was observed in rats receiving either dose of l-NA. Our results suggest that NO is involved in the facilitation of active avoidance learning by nicotine.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

In the development of medications for the treatment of cocaine abuse, the drug discrimination paradigm can be used to identify medications that can attenuate the discriminative stimulus effects of cocaine. To ascertain that participants are basing the discrimination on the drug's central effects, this paradigm requires that the drug and placebo administrations do not produce any peripheral effects on which the discrimination can be based. This study examined whether intranasal cocaine (50 mg) can be discriminated from placebo (46 mg lactose + 4 mg cocaine), how quickly this discrimination can be made, and whether pretreatment with intranasal benzocaine can affect this discrimination. Results showed that subjects were generally able to discriminate the drug conditions correctly 15 s after administration, and this was unaffected by benzocaine. These results suggest that subjects base the discrimination on peripheral drug effects (e.g. taste) that are not affected by anaesthesia of the nasal passage, and that the intranasal route of cocaine administration is unlikely to be feasible with a drug discrimination paradigm.

ISSN:0955-8810    

出版商:OVID    

年代:2000

数据来源: OVID