摘要:

The phenotype of NK1R−/− mice was compared with that of acute pharmacological blockade of the tachykinin NK1receptor on sensorimotor function and in assays relevant to depressive illness and anxiety. The dose range for L‐760735 and GR205171 that was associated with functional blockade of central NK1receptors in the target species was established by antagonism of the behavioural effects of intracerebroventricular NK1agonist challenge in gerbils, mice and rats. The caudal grooming and scratching response to GR73632 was absent in NK1R−/− mice, confirming that the receptor had been genetically ablated. There was no evidence of sedation or motor impairment in NK1R−/− mice or following administration of L‐760735 to gerbils, even at doses in excess of those required for central NK1receptor occupancy. In the resident–intruder and forced swim test, the behaviour of NK1R−/− mice, or animals treated acutely with L‐760735 or GR205171, resembled that seen with the clinically used antidepressant drug fluoxetine. However, the effects of GR205171 were not clearly enantioselective in mice. In contrast, although NK1R−/− mice also exhibited an increase in the duration of struggle behaviour in the tail suspension test, this was not observed following pharmacological blockade with L‐760735 in gerbils or GR205171 in mice, suggesting that this may reflect a developmental alteration in the knockout mouse. There was no effect of NK1receptor blockade with L‐760735 in guinea‐pigs or GR205171 in rats, or deletion of the NK1receptor in mice, on behaviour in the elevated plus‐maze test for anxiolytic activity. These findings extend previous observations on the phenotype of the NK1R−/− mouse and establish a broadly similar profile following acute pharmacological blockade of the receptor. These studies also serve to underscore the limitations of currently available antagonists that are suitable for use in rat and mouse behavioural assays.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

HDS and LDS rats are the result of selective breeding for differences in the hypothermic effects of the 5‐hydroxytryptamine‐1A (5‐HT1A) agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT); HDS (high DPAT sensitivity) rats exhibit a much greater hypothermic response than do LDS (low DPAT sensitivity) rats. It is possible that this genetically‐based difference in sensitivity to the hypothermic effects of the 5‐HT1Aagonist is associated with a change in other behaviours modulated by 5‐HT neurotransmission. The present study examined the acoustic startle response, the classically conditioned enhancement of startle, and the effects of 8‐OH‐DPAT and buspirone treatments on these measures, in HDS and LDS rats. On four test sessions, HDS and LDS rats were exposed to 20 acoustic startle stimuli (115 dB; 40 ms in duration). For each test session, 10 trials were presented in the dark (Noise Alone trials) and 10 were presented at the end of a 3500 ms presentation of a 15 W signal light (Light + Noise trials). LDS rats exhibited greater startle amplitude than did HDS rats on Noise Alone trials. Initially, there was no difference in startle amplitude on the Light + Noise versus Noise Alone trials in either LDS or HDS rats. By the end of the first test session, however, and continuing throughout the remainder of the four test sessions, startle amplitude on the Light + Noise trials was significantly greater than in the Noise Alone trials. The magnitude of this startle‐potentiated startle (SPS) effect did not differ in HDS versus LDS rats. SPS testing was continued for three additional sessions; in these sessions the effects of acute treatment with the 8‐OH‐DPAT (125 μg/kg, subcutaneously (s.c.)), the novel anxiolytic buspirone (4 mg/kg, intraperitoneally (i.p.)) or vehicle (distilled water) were determined. Both 8‐OH‐DPAT and buspirone treatment increased baseline (Noise Alone) startle amplitude in LDS rats but not in HDS rats. With respect to the conditioned enhancement of startle, buspirone reduced the SPS effect in both HDS and LDS rats, whereas 8‐OH‐DPAT did not change the conditioned enhancement effect in either rat line. These findings suggest that the selective breeding for differences in 8‐OH‐DPAT‐induced hypothermia has resulted in changes in other behaviours and also changes in the response to 5‐HT1Aagonist treatment. Moreover, these findings are consistent with the hypotheses that: (a) 5‐HT1Aagonist actions underlie the buspirone‐induced and 8‐OH‐DPAT‐induced increases in Noise Alone startle amplitude; whereas (b) the buspirone‐induced reduction in potentiated startle is not the result of 5‐HT1Aagonist actions of this compound.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Rat genotypes differ in their susceptibility to spontaneously occurring spike‐wave discharges and in their dopaminergic properties. In a previous study, it was found that spike‐wave discharge incidence decreased in the following order in four rat genotypes during baseline and following injection with the dopamine antagonist haloperidol: apomorphine‐susceptible (APO‐SUS) > WAG/Rij > apomorphine‐unsusceptible (APO‐UNSUS) and ACI rats. The question in the present study was to what extent certain dopaminergic properties are pathognomonic for epileptic rats. Therefore, behavioral responses were assessed in order to investigate the dopaminergic properties in the four rat genotypes. Apomorphine‐induced gnawing data imply that the dopamine activity of the nigrostriatal system in the WAG/Rij rats is higher than in APO‐SUS but lower than in the ACI and APO‐UNSUS rats. Furthermore, in previous studies APO‐SUS have been shown to have a higher novelty/amphetamine‐induced locomotion, indicative of a higher dopamine reactivity of the mesolimbic system as compared to APO‐UNSUS rats. Results from the present study showed that WAG/Rij rats have a higher locomotor responsiveness to novelty/amphetamine, indicating a higher dopamine reactivity of the mesolimbic system in comparison to the ACI rats. It is suggested that the functional dopaminergic mesolimbic dominance is an important factor in the susceptibility to show spontaneously occurring spike‐wave discharges.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Rat genotypes tentatively identified as addiction‐prone or addiction‐resistant on the basis of alcohol preference and locomotor responsiveness to novelty – Lewis versus Fischer strains and Nijmegen high versus low responder lines – differed in time to develop intravenous cocaine self‐administration habits, but did not differ in sensitivity to the ability of cocaine reward to summate with lateral hypothalamic brain stimulation reward. Moreover, rats from the Nijmegen low‐responder line that initiated self‐administration came to do so compulsively and to the same degree as did the Nijmegen high‐responder rats. Thus the differences between both sets of genotypes appeared to reflect differences in reactions to the testing situation more than differences in reaction to the reinforcing drugper se.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Sensitization to the locomotor‐stimulant effects of drugs is thought to play an important role in the development of drug‐seeking behaviour. We hypothesized that the ability of acamprosate to reduce alcohol relapse rates in recovering alcoholics, and alcohol consumption in rodents, may be related to its ability to reduce sensitization to the locomotor‐stimulant effects of alcohol. The purpose of the present study was to determine whether acamprosate reduces the expression of sensitization to the locomotor‐stimulant effects of alcohol in lines of mice selectively bred for high (HAP) and low (LAP) alcohol preference. Mice were given six intraperitoneal (i.p.) injections of alcohol (3 g/kg) or saline at 48 h intervals. The test for sensitization to the locomotor‐stimulant effects of alcohol consisted of a challenge dose of 2 g/kg i.p. alcohol followed immediately by assessment of locomotor activity for 20 min. Mice were pretreated with either saline or acamprosate (400 mg/kg) at 14 h and again at 2 h before the alcohol challenge. Both HAP and LAP mice showed sensitization to the locomotor‐stimulant effects of alcohol. Acamprosate reduced the expression of sensitization to the locomotor‐stimulant effects of alcohol in HAP but not LAP mice. These data suggest complex effects of acamprosate on alcohol‐stimulated locomotor activity that depend on genotype.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

High‐alcohol drinking (HAD1) and low‐alcohol drinking (LAD1) rats were trained to discriminate among 0.75 g/kg ethanol, 1.5 g/kg ethanol and saline under a fixed‐ratio 10 schedule. LAD rats learned the discrimination more rapidly than HAD rats, and asymptotic performance by LAD rats was better than that of HAD rats. The 0.75 g/kg dose of ethanol failed to control the responding of HAD rats, both when baseline responding stabilized and during the determination of an ethanol dose–response curve. These differences between LAD and HAD rats in ethanol discrimination were not observed in previous experiments using a two‐choice procedure. The three‐choice procedure may be useful for establishing strain differences in ethanol discrimination. These and previous experiments with alcohol‐preferring rats suggest that the learning of an ethanol discrimination may be dissociable from voluntary ethanol consumption in rat strains bred selectively to consume ethanol.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Knockout mice lacking serotonin1B(5‐hydroxytryptamine1B; 5‐HT1B) receptors (1BKO) exhibit increased sensitivity to the stimulant and reinforcing effects of indirect dopamine (DA) agonists and are more reactive to mild stressors such as handling and the injection procedures that commonly occur when using the intraperitoneal (i.p.) route of drug administration. Since the intravenous (i.v.) route of administration allows minimal handling and injection‐induced stress, the present study was designed to evaluate the effect of the administration route on amphetamine‐induced locomotor activation and behavioural sensitization in 1BKO mice. For this purpose, 1BKO and wild‐type (WT) control mice were administered i.p. or i.v. amphetamine in a within‐session design, which allows evaluation of a complete dose–response curve within a single session. The locomotor stimulant effects of i.p. (0.5–4.0 mg/kg) and i.v. (0.6–1.2 mg/kg) amphetamine were investigated both acutely and following repeated treatments (four treatments at 48 h intervals). The results showed that acute i.p. amphetamine injection induced a significant higher horizontal activity peak effect in 1BKO mice, while this difference was less profound after acute i.v. injection. However, repeated i.p. or i.v. administration of amphetamine induced significantly higher locomotion in 1BKO mice. We conclude that the stimulant effects of amphetamine can be influenced by the route of administration in a genotype‐dependent manner, and that route of drug administration (and associated variables) should be considered an important factor in studies of psychostimulant action in knockout mice.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID