一次阿扑吗啡注射对大鼠视觉辨别学习和工作记忆的影响

目的探讨多巴胺受体激动剂 -阿扑吗啡对大鼠视觉辨别学习和工作记忆的影响。方法利用旋转T迷宫装置 ,通过食物强化 ,分别训练大鼠正常和逆反的视觉辨别学习任务。动物达到规定的标准次数后 ,腹腔注射 2mg/kg体重的阿扑吗啡 ,3 0分钟后观察药物对工作记忆的影响。 结果对于正常学习 ,阿扑吗啡注射组动物的正确次数与生理盐水对照组相比无显著性差异 ,且两组动物继续进行逆反学习训练 ,达到学习标准所需的总次数亦无显著性差异 ;对于逆反学习 ,阿扑吗啡注射组动物的正确次数较对照组显著降低。结论单独一次阿扑吗啡注射可能干扰大鼠逆反学习的工作记忆 ,但不影响正常学习的工作记忆和逆反学习的过程。     

Characteristics of tetrahydrocannabinol (THC)-produced discrimination in rats

Rats were trained in a T-shaped maze to discriminate the effects produced by i.p. injections of tetrahydrocannabinol (THC) and the no-drug state (state-dependency, StD). Several doses of both ⁸-THC (range: 0.75–5.0 mg/kg) and ⁹-THC (range: 0.75–10.0 mg/kg) were used in order to compare the number of sessions required by the animals until reaching criterion performance. An additional group of rats had to discriminate pentobarbital sodium (20.0 mg/kg) from the no-drug state.Results: THC discrimination was proportional to dose i.e., animals that had to differentiate high doses of THC from no drug acquired the T-maize task faster than animals trained with the lower doses of THC. Acquisition data further suggest that ⁸-THC is somewhat less potent than the ⁹-isomer. ⁹-THC (10.0 mg/kg) produces strong StD, as defined by Overton (1971), since both this group and the barbiturate group reached the criterion within the first 10 training sessions. Time and dose testings suggest that stimulus properties of drugs vary in a quantitative way and that the calculated ED₅₀ values are mainly determined by the training dose used. It was found that the higher the training dose used the higher was the corresponding ED₅₀ value. Hashish smoke can maintain drug responding among THC-trained rats. A lowered content of brain catecholamines and/or serotonin, induced by AMPT (150 mg/kg) and PCPA (310–350 mg/kg), did not lessen ⁹-THC (2.5 mg/kg) discrimination.Portions of the results were presented at the Fourth Scandinavian Meeting on Physiology and Behavior, Oslo May 22–24, 1975.     

Mnemonic deficits in animals depend upon the degree of cholinergic deficit and task complexity

The role of cholinergic basal forebrain (CBF) neurons in mnemonic behaviors was investigated using the immunotoxin 192IgG-saporin. We assessed two routes of immunotoxin administration: intracerebroventricular (ICV) and intraparenchymal (INTRA). INTRA lesions of the medial septum (MS) and/or the nucleus basalis magnocellularis (NBM) were compared with ICV-lesions, INTRA-phosphate-buffered saline injected, and naive controls. The INTRA-NBM/MS and ICV NBM/MS lesions produced a similar depletion of choline acetyltransferase activity of 80% across all CBF projections. Water maze performance was similarly impaired for ICV- and INTRA-NBM/MS animals during various phases of testing, whereas animals with individual lesions of the NBM or MS performed at the level of controls. In contrast to the allocentric demands of water maze performance, the egocentric-based T-maze task revealed a vast group difference between the ICV- and the INTRA-NBM/MS animals. INTRA-NBM/MS animals showed a severe deficit in the non-match- and match-to-position version, whereas again, animals with single lesions were unimpaired. In addition, a dichotomy between animals with complete cholinergic deafferentation was observed in the inhibitory avoidance task. ICV-NBM/MS showed a diminished retention for the aversive stimulus while the INTRA-NBM/MS animals remembered well. During plus maze testing, only the INTRA-NBM/MS animals had a reduced level of anxiety. Although non-CBF regions may have been differently affected by the two routes of immunotoxin administration, global measures of arousal, motivation, and motor initiation did not reveal a different behavioral pattern. Our findings suggest that a dynamic interplay exists between the degree of cholinergic deficit and task demands revealing different types of mnemonic impairments.     

Effects of the selective angiotensin II receptor antagonists losartan and PD123177 in animal models of anxiety and memory

There is increasing interest in the potential functional role of the octapeptide angiotensin II (AII) in psychiatric and cognitive disorders. The novel angiotensin II (AII) receptor antagonists, losartan and PD123177, selective for the AT₁ and AT₂ receptor subtypes respectively, constitute important pharmacological tools for the assessment of the behavioural consequences of modulation of AII function. The present series of studies investigated the effects of each compound in two animal models of anxiety, the rat elevated zero-maze and mouse light/dark box, and two models of working memory in the rat, the operant delayed matching to position (DMTP) task and the spatial reinforced alternation test in the T-maze. Our data indicate that both compounds (0.01–10 mg/kg SC) were without significant effect in any of the behavioural assays. Using the present methods and strains of laboratory rodents, these findings provide no support for the involvement of AII receptor function in the mediation of anxiety or working memory.     

Impulsive choice in hippocampal but not orbitofrontal cortex-lesioned rats on a nonspatial decision-making maze task

Orbitofrontal cortical (OFC) and hippocampal (HPC) lesions in primates and rodents have been associated with impulsive behaviour. We showed previously that OFC- or HPC-lesioned rats chose the immediate low-reward (LR) option in preference to the delayed high-reward (HR) option, where LR and HR were associated with different spatial responses in a uniform grey T-maze. We now report that on a novel nonspatial T-maze task in which the HR and LR options are associated with patterned goal arms (black-and-white stripes vs. gray), OFC-lesioned rats did not show impulsive behaviour, choosing the delayed HR option, and were indistinguishable from controls. In contrast, HPC-lesioned rats exhibited impulsive choice in the nonspatial decision-making task, although they chose the HR option on the majority of trials when there was a 10-s delay associated with both goal arms. The previously reported impairment in OFC-lesioned rats on the spatial version of the intertemporal choice task is unlikely to reflect a general problem with spatial learning, because OFC lesions were without effect on acquisition of the standard reference memory water-maze task and spatial working memory performance (nonmatching-to-place) on the T-maze. The differential effect of OFC lesions on the two versions of the intertemporal choice task may be explained instead in terms of the putative role of OFC in using associative information to represent expected outcomes and generate predictions. The impulsivity in HPC-lesioned rats may reflect impaired temporal information processing, and emphasizes a role for the hippocampus beyond the spatial domain.     

Methylphenidate reduces impulsive behaviour in juvenile Wistar rats, but not in adult Wistar, SHR and WKY rats

Rationale Impulsivity is a core symptom of attention deficit/hyperactivity disorder (ADHD). The spontaneously hypertensive rats (SHR) is a strain commonly used as an animal model of ADHD. However, there is no clear evidence that psychostimulants, which are used for treatment of ADHD, reduce impulsivity in SHR. Because ADHD mainly affects children, it may be relevant to study psychostimulants on juvenile animals. Objectives Using tolerance to delay of reward as index of impulsivity, the effects of methylphenidate were assessed in adult SHR, Wistar Kyoto (WKY) and Wistar rats and in juvenile Wistar rats. Materials and methods Animals were trained in a T-maze to choose between a small-but-immediate and a large-but-delayed reward. Adult SHR, WKY and Wistar rats were compared for their ability to tolerate a 15-s delay. The effect of methylphenidate on the tolerance to a 30-s delay was studied in adult rats of the three strains and in juvenile (4.5 to 6.5-week-old) Wistar rats. Results In adult rats, the waiting ability was lower in SHR than in control strains. Waiting ability was improved by methylphenidate (3 and 5 mg/kg) in juveniles, but not by methylphenidate (3 mg/kg) in adults. Conclusions These data support the idea that SHR are more impulsive than control strains. However, at the dose studied, methylphenidate fails to improve tolerance to delay in adult rats whatever the strain used. The reduction of impulsivity induced by methylphenidate in juvenile Wistar rats indicates that juvenile animals may be suitable for testing the therapeutic potential of drugs intended to the treatment of ADHD in children.     

Postnatal Protein Malnutrition Affects Inhibitory Avoidance and Risk Assessment Behaviors in Two Models of Anxiety in Rats

Abstract

Protein malnutrition induces structural, neurochemical and functional alterations in the central nervous system, leading to alterations in behavioral function. In order to study the effects of early protein malnutrition on inhibitory avoidance and escape behaviors we used the elevated T-maze (ETM), while the risk assessment behaviors were evaluated by the canopy stretched attend posture (SAP) test. Rat pups were fed by lactating females receiving 16% (control) or 6% (malnourished) protein diets during the lactation period. After weaning the animals received the same diets until 49 days of age, when all animals started receiving a lab chow diet. Behavioral tests were started at 70 days of age. ETM results showed lower inhibitory avoidance in malnourished animals, without differences in escape behavior. SAP test results showed higher exploration and lower risk assessment behaviors in malnourished animals compared to control. These results suggest that malnourished animals are less anxious and/or more impulsive as measured by these two animal models and that malnutrition seems to affect differently behavioral strategies underlying fear and anxiety responses.     

Behavioural studies on the effects of d-amphetamine and estradiol benzoate alone and in combination

The effects of d-amphetamine sulphate on grooming, rearing, and ambulatory behaviour in the T-maze was studied in rats. Low doses (0.25–2.0 mg/kg) produced a dose-dependent change in behaviour; ambulatory behaviour was increased while grooming and rearing behaviour was decreased. The results suggest that the behavioural changes are a direct effect of amphetamine rather than a secondary consequence of a competition between different types of behaviour.The effects of d-amphetamine sulphate and/or estradiol benzoate on grooming, rearing, and ambulatory behaviours in the T-maze and open field were also studied. Rats chronically treated with estradiol or oil were injected with amphetamine or saline just prior to evaluation in the maze or open field. Amphetamine treatment, irrespective of environment or hormone treatment, stimulated ambulatory behaviour while inhibiting grooming behaviour. Estradiol specifically antagonized the amphetamine induced reduction of grooming in the maze only. The results suggest that amphetamine has an independent action on T-maze behaviour whereas estradiol has an effect that depends on the environment for its manifestation.     

Behavioral correlates of denervation and reinnervation of the hippocampal formation of the rat: open field activity and cue utilization following bilateral entorhinal cortex lesions

Bilateral lesions of the entorhinal cortex (E.C.) of the rat result in persistent deficits in both spontaneous and reinforced alternation. The present study analyzes the nature of this impairment. To determine if changes in exploratory activity accompanied the deficits in alternation, open field activity was measured daily from 2–22 days following bilateral E.C. lesions. Such lesions resulted in a pronounced transient increase in open field activity which peaked between 5 and 7 days postlesion, but subsequently decreased to near preoperative levels at approximately 11 days postlesion. Alternation performance was also analyzed, to determine which cues are utilized to make the alternation, and whether cue utilization is affected by bilateral E.C. lesions. Utilizing a plus (+) maze, animals readily learned to alternate goal arms, but even with extensive training, failed to learn to alternate turns (left and right). However, the ability to identify the two goal arms in a nonalternation situation (which does not require short term recall of the preceding trial) was not permanently impaired by bilateral E.C. lesions. Since bilateral E.C. lesions do not result in persistent deficits in the ability to identify the two goal arms, but do disrupt alternation performance, we hypothesize that the deficit in alternation might reflect an inability to recall which arm was chosen on preceding trials. The implications of these results for an understanding of the behavioral consequences of postlesion reorganization of neuronal circuitry are discussed.     

Panicolytic-like effect induced by the stimulation of GABAA and GABAB receptors in the dorsal periaqueductal grey of rats

Activation of GABA(A) and benzodiazepine receptors within the dorsal periaqueductal grey inhibits the escape behaviour evoked by the electrical stimulation of this midbrain area, a defensive reaction that has been related to panic. Nevertheless, there is no evidence indicating whether the same antiaversive effect is also observed in escape responses evoked by species-specific threatening stimuli. In the present study, male Wistar rats were injected intra-dorsal periaqueductal grey with the benzodiazepine receptor agonist midazolam (10, 20 and 40 nmol), the GABA(A) receptor agonist muscimol (2, 4 and 8 nmol), the GABA(B) receptor agonist baclofen (2, 4 and 8 nmol), or with the benzodiazepine inverse agonist FG 7142 (20, 40 and 80 pmol) and tested in an ethologically-based animal model of anxiety, the elevated T-maze. Besides escape, this test also allows the measurement of inhibitory avoidance which has been related to generalised anxiety disorder. Midazolam, muscimol and baclofen impaired escape, a panicolytic-like effect, without altering inhibitory avoidance. FG 7142, on the other hand, facilitated both avoidance and escape reactions, suggesting an anxiogenic and panicogenic-like effect, respectively. The data suggest that GABA(A)/benzodiazepine and GABA(B) receptors within the dorsal periaqueductal grey are involved in the control of escape behaviour and that a failure in this regulatory mechanism may be of importance in panic disorder.