Tactile-kinesthetic system of rats as an animal model for minimal brain dysfunction

A previous study showed that rats exposed to methylmercury during development exhibit effects similar to those described for children with minimal brain dysfunction (MBD), namely, hyperactivity, altered locomotion structure, and unaltered learning ability, but reduced and more variable attention spans induced by increasing difficulties within an operant learning paradigm. Psychopathological studies suggest that behavioral disturbances of the MBD type may originate directly or indirectly from deficiencies in the tactile-kinesthetic system. This sensory modality is the main mechanism by which an individual organism assimilates reality. Deficiencies in the tactilekinesthetic system impair the action of the equilibration processes (in Piaget's sense) which ensure that the stages of psychological development occur in an orderly sequence. The lack of this control over development may result in the behavioral characteristics of MBD. Problems with the tactile-kinesthetic system may also be the reason for the deficiencies of fine motor control in MBD children. In an atempt to extrapolate this interpretation of human psychopathological mechanisms to experimental animals, an operant paradigm was developed for the assessment of the tactile-kinesthetic system of rats, the schedule of differential reinforcement of force range (DRF). Rats were trained to press in discrete trials a force sensitive lever during at least 1 s between two force thresholds of 60 and 80 g without any feedback other than the rats' own tactilekinesthetic perception. Offspring of rat dams exposed to 1.5 and 5 mg/l methylmercury-chloride in their drinking water from 2 weeks before pairing until weaning, exhibited a clearcut performance deficit (approximately 25% correct responses compared to approximately 50% of the controls). Moreover, they showed a dose-dependent increase in the percentage of responses in which the force excerted exceeded the upper threshold. Using Powers' model of behavior (behavior is the control of perception) the observed effects may be interpreted as a methylmercury-induced deficit in the tactile-kinesthetic sensory system. This result is in accordance both with the earlier interpretation of observed perinatal methylmercury effects on behavior and with the tactile-kinesthetic hypothesis for MBD. The DRF schedule is proposed as a sensitive tool in experimental behavioral teratology for the preclinical assessment of MBD hazard.Dedicated to Professor Dr. Gerhard Zbinden on the occasion of his retirement     

Rate-dependent effects of d-amphetamine on locomotor activity in mice: Possible relationship to paradoxical amphetamine sedation in minimal brain dysfunction

Following a week of habituation to an activity cage, the locomotor activity of mice following a single dose (0, 1.0, 2.5, 5.0, 7.5 or 15.0 mg/kg) of d-amphetamine was measured. At all doses except 0 (saline), the effect of d-amphetamine on activity was inversely correlated with pre-drug baseline activity. These results demonstrate rate-dependent effects of d-amphetamine on locomotor activity and suggest that hyperkinesis per se would predispose to a sedative action of amphetamines in minimal brain dysfunction.     

Drug alterations of punished responding after chlordiazepoxide: possible screen for agents useful in minimal brain dysfunction

In the present study, the effect of various stimulant drugs on the action of chlordiazepoxide to increase punished responding was studied. Drugs such as d-amphetamine, methylphenidate and imipramine that are effective in attentional deficit disorder (MBD) were found to reverse this benzodiazepine-induced increase in responding. Phenobarbital which worsens this condition enhanced the benzodiazepine effect. Since the impairment caused by chlordiazepoxide may be analogous to the lack of impulse control noted in MBD, the bupropion antagonism of this action of chlordiazepoxide suggests that bupropion may be useful in MBD.     

Effects of chronic d-amphetamine on social behavior of the rat: Implications for an animal model of paranoid schizophrenia

Hooded rats in a social colony were given increasing daily doses of d-amphetamine up to 8 mg/kg. Time-lapse 16 mm cinematographically recorded behavior was analyzed for the following: grooming, feeding, sex, sleeping, resting, stereotypy, agonistic behavior, muricidal activity, and the location and movement of each rat. Subordinant rats receiving d-amphetamine actively withdrew from social interactions by retreating to strategically defensible locations in the environment. They remained hypervigilant of other rats and overreacted to their approaches by either fleeing or by defensively rearing and boxing. On the other hand, when the dominant rat received the maximum dose, it seemed totally oblivious to the other rats. The responses to drug treatment in subordinant rats may provide a model for the social behavior of frightened paranoid schizophrenics.NIMH Research Scientist awardee MH 1759     

Simultaneous anhedonia and exaggerated locomotor activation in an animal model of depression

Rationale  Anhedonia, or hyposensitivity to normally pleasurable stimuli, is a cardinal symptom of depression. As such, reward circuitry may comprise a substrate with relevance to this symptom of depression. Objectives  Our aim was to characterize in the rat changes in the rewarding properties of a pharmacological and a natural stimulus following olfactory bulbectomy (OBX), a pre-clinical animal model of depression. Methods  We measured amphetamine enhancement of brain stimulation reward, changes in sucrose intake, as well as striatal cAMP response element binding protein (CREB) activity, a molecular index previously associated with depressant-like behavior. Moreover, since alteration of psychomotor activity is also a common symptom of depression, and psychostimulant reward and locomotion are thought to share common neurobiology, we used the same treatment schedule of amphetamine to probe for changes in locomotion. Results  Our findings show that OBX produces a behavioral phenotype characterized by both anhedonia and exaggerated locomotor activation. Thus, we observed a blunted response to the rewarding properties of amphetamine (1 mg/kg, 21 days post-lesion), a long-lasting reduction in sucrose intake and increased striatal CREB activity. In addition, the same dose of amphetamine, at a coincident time post-lesion, triggered an exaggerated response to its locomotor-stimulant actions. Conclusions  These paradoxical findings are not consistent with the notion that reward and locomotion are mediated by a common substrate; this dissociation may be useful in modeling psychiatric disorders such as mixed depressive states. In addition, our findings suggest that central reward circuitry may constitute a possible target for rationally designed therapeutics for depression.     

Cannabinoids reward sensitivity in a neurodevelopmental animal model of schizophrenia: A brain stimulation reward study

The comorbidity schizophrenia and cannabis has a high prevalence. The consumption of cannabis is ten times higher among schizophrenia patients, suggesting that these patients could be differentially sensitive to its motivational effects. To study this question, we investigated the motivational effects of cannabinoid agonists using the brain stimulation reward paradigm and a neurodevelopmental model of schizophrenia: neonatal ventral hippocampus lesions (NVHL). Using the curve-shift paradigm, we first compared the effect single dose (0.75 mg/kg) of amphetamine in sham and NVHL rats on reward and operant responding. Then, in different groups of NVHL and sham rats, we studied the effect of delta-9-tetrahydrocannabinnol (THC, 0.5 mg/kg, i.p.) and WIN55,212-2 (WIN, 1 and 3 mg/kg, i.p.) Rats were initially trained to self-administer an electrical stimulation to the posterio-medial mesencephalon. Once responding was stable, reward threshold defined as the frequency required to induce a half maximum response rate was measured before and after injection of the drug or the vehicle. Results show that amphetamine enhanced reward in sham and NVHL rats, an effect that was shorter in duration in NVHL rats. THC produced a weak attenuation of reward in sham rats while WIN produced a dose-dependent attenuation in NVHL; the attenuation effect of WIN was blocked by the cannabinoid antagonist, AM251. WIN also produced an attenuation of performance in sham and NVHL rats, and this effect was partially prevented by AM251. These results provide the additional evidence that the motivational effect of cannabinoids is altered in animals with a schizophrenia-like phenotype.     

颅脑冲击伤动物模型的研究进展

冲击波引起机体的损伤称为原发性冲击伤,在伊拉克、阿富汗等战争中78%创伤系冲击伤。为了更好预防治疗此类伤害,本文就冲击伤的实验动物造模,模型建立以及相应的指标检测做了较全面综述,以期为临床防治研究提供参考。     

Criteria for an animal model of alcoholism

A correspondence between the various components of human alcoholism and their animal analogue has not yet been achieved; in some part, this failure resides with experimental attempts which obtain which obtain only surface equivalencies and which lack an underlying motivational structure. Seven criteria for an animal model are proposed including the oral ingestion of alcohol without food deprivation, substantial ingestion of alcohol with competing fluids available, drinking directed to the intoxicating effect of alcohol, the performance of work to obtain alcohol, the maintenance of intoxication over a long period and, finally, the production of physical dependence and, on withdrawal, the abstinence syndrome.     

Intraventricular 6-hydroxydopamine in the newborn rat and locomotor responses to drugs in infancy: No support for the dopamine depletion model of minimal brain dysfunction

Bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) after desmethylimipramine (DMI) in rats 1 and 2 days of age, severely depleted brain dopamine (DA) particularly in the neostriatum, where levels in adulthood were about 7% of control. Compared to vehicle-injected controls these rats were hyperactive only at 15 and 20 days of age, and in adulthood were impaired in a two-way avoidance. Rats with similar 6-OHDA treatment but without DMI pretreatment showed severe depletion of brain norepinephrine (NE) as well as DA, and were behaviorally similar to the DA-depleted only rats. This behavioral syndrome is similar to that reported after intracisternal injection of 6-OHDA in 5-day-old rats, which has been argued as a model for minimal brain dysfunction (MBD). Contrary to expectation from this model, however, challenge doses of either d-amphetamine or methylphenidate did not reduce, but instead increased activity of these rats. The 6-OHDA treatments also did not alter the enhancement of locomotor activity by scopolamine, which was present at 30 days but not at 15 days.     

Neuroleptic-induced vacuous chewing movements as an animal model of tardive dyskinesia: a study in three rat strains

Vacuous chewing movements (VCMs) in three different rat strains developed at considerably different rates after 19 weeks of continual haloperidol treatment at an average daily dose of 1.5 mg/kg. Sprague Dawley (SD) rats displayed relatively high rates of VCMs with low variability, compared to Wistar (W) and Long Evan (LE) rats. Atropine decreased but did not abolish VCMs in two of the three strains (LE>SD). After haloperidol withdrawal, VCMs remitted gradually in all strains, but least rapidly in the SD rats. In a separate group of SD rats, VCMs were rated weekly from the start of haloperidol treatment and showed considerable interindividual variability. Even after 24 weeks of continuous haloperidol, 12 out of 32 treated rats showed no VCMs at all, while 13 out of 32 had intense movements, analogous to the clinical situation in which only some patients treated with neuroleptics develop tardive dyskinesia. These results indicate that there are individual and strain differences in the development of VCMs, and suggest that there may also be genetically determined differences in the development of tardive dyskinesia.     

Toxicity of cuprizone a Cu2+ chelating agent on isolated mouse brain mitochondria: a justification for demyelination and subsequent behavioral dysfunction

Multiple Sclerosis (MS) is a complex disease with an unknown etiology and no effective cure, despite decades of extensive research that led to the development of several partially effective treatments. In this study we aimed to investigate brain mitochondrial dysfunction in demyelination induced by cuprizone in mice. Cuprizone was used for induction of demyelination in mice through a diet containing 0.2% w/w cuprizone for 5 weeks. Behavioral tests for proving of MS was performed and then mitochondria from brain of animals were isolated and afterwards parameters of mitochondrial dysfunction examined. Results of mitochondrial dysfunction parameters such as mitochondrial swelling, production ROS, collapse of the membrane potential showed that isolated mitochondria from cuprizone treated mice have been damaged compared to those of untreated control mice. It is likely that demyelination induced mitochondrial damage led to increased mitochondrial ROS formation and progression of oxidative damages in neurons. It is suggested that cuprizone which is a Cu²⁺?chelating agent causes impairment of electron transport chain (complex IV) and antioxidant system (SOD) in mitochondria leading to decreased ATP production and increased ROS formation.     

Administration of antidepressants,diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these therapeutic effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond therapeutically to antidepressants and not psychomotor stimulants.     

Evaluation of reward processes in an animal model of depression

Rationale Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. Objective Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. Materials and methods The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. Results Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. Conclusions Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence.     

应用脑皮质撞击仪建立颅脑创伤后应激性溃疡动物模型的研究

目的 应用电子脑皮质撞击仪（eCCI）建立颅脑创伤后应激性溃疡的动物模型,为进一步研究颅脑损伤所致应激性溃疡的发生机制及治疗方法奠定基础.方法 选取健康雄性Spraque-Dawley（SD）大鼠20只,按照随机数字表法分为假手术组和颅脑创伤组,每组10只.应用eCCI对颅脑创伤组大鼠顶叶大脑皮质区行精确撞击（打击速率4 m/s,打击时间200 ms,打击深度4 mm）.假手术组仅用牙科钻开骨窗（5 mm ×5 mm）,消毒后缝合头皮但不做打击.伤后48 h应用多普勒血流量计测定2组大鼠脑和胃黏膜表面局部血流量,苏木精-伊红染色观察脑和胃组织病理学改变.结果 致伤48 h后,颅脑创伤组脑组织血流量较假手术组明显下降[（40.2±1.9）ml/（min·100 g）比（107.6±3.4） ml/（min·100 g）]（P ＜0.01）.假手术组和颅脑创伤组胃黏膜表面血流量比较,差异有统计学意义[（32.9±2.0）ml/（min·100 g）比（42.1±1.0）ml/（min·100 g）]（P＜0.01）.致伤48 h后,光镜下假手术组大鼠脑组织正常,结构完整,胞核蓝染,胞质呈粉红色;颅脑创伤组大鼠脑组织损伤灶周围神经元数量明显减少,结构排列紊乱,局部脑组织变性坏死,逐渐形成瘢痕,伴大量红细胞渗出.假手术组大鼠胃组织基本正常,黏膜表层结构完整,黏膜下层未见明显嗜酸性炎细胞渗出;颅脑创伤组大鼠胃组织可见黏膜表层细胞、腺胃细胞变性、脱落,伴红细胞渗出,黏膜下可见嗜酸性炎细胞浸润.结论 大鼠颅脑创伤后存在应激性溃疡,应用脑皮质撞击仪可成功建立颅脑创伤后应激性溃疡的大鼠模型.     

The non-linear pharmacokinetics of prednisone and prednisolone. III. Experiments using the rabbit as an animal model

Intravenous zero order infusions were administered to New Zealand white rabbits. In a pilot study using one rabbit, prednisone and prednisolone clearance values increased with increase in either prednisone or prednisolone infusion rates. In the second study, prednisone was infused until both prednisone and prednisolone achieved steady-state concentrations. In the third study, prednisone was infused until only prednisone achieved steady-state concentrations. The results of the three experiments support the use of a non-linear reversible metabolism model to describe the pharmacokinetic relationship between prednisone and prednisolone.     

An improved model of lead-induced brain dysfunction in the suckling rat

Experimental lead encephalopathy is produced in suckling rats when lead is added to the mother's diet. Lead passes into developing sucklings via maternal milk. Lead-poisoned newborns have been reported to exhibit pronounced retardation of growth and during week 4 of life develop paraplegia and extensive histologic lesions of the cerebellum. Under similar dietary conditions experimental lactating rats eat 30% less food than controls, resulting in: (a) sustained loss in body weight of nursing mothers and (b) offspring who develop paraplegia and cerebellar damage after gaining access to the maternal lead-containing diet.We have found that a lactating mother rat consuming 5% lead acetate (PbAc) in the diet (2.73% Pb) produced milk containing 25 ppm lead. When the diet of the mother is changed on day 16 from 5% PbAc to one containing 25 ppm Pb, and neonates are allowed free access to the same solid diet, the sucklings still have retarded body growth but do not develop paraplegia or grossly apparent vascular damage of the cerebellum. However, during week 4 these animals exhibit hyperactivity, tremors, and stereotype behavior. Pair-fed controls coetaneous to experimental groups do not display such activities. The severe paraplegia and histopathologic lesions reported by others in the older model obscures minimal brain dysfunction. We propose the present procedure as a model for studies of the subtle effects of lead on the central nervous system.     

大鼠脑死亡模型的建立及相关实验研究

目的:应用颅内高压法建立大鼠脑死亡模型,并将爆发式和渐进式颅内高压脑死亡模型进行比较.方法:SD大鼠60只,随机分为对照组(A组)20只、爆发式脑死亡组(B组)20只和渐进式脑死亡组(C组)20只,在呼吸机维持下,生物机能实验系统监测大鼠脑死亡状态6 h,实验过程中监测动脉压及心率的变化,并比较手术成功率.结果:脑死亡组诱导成功32只,诱导后期动脉压及心率骤然升高后,又逐渐下降,其中B组急剧下降,幅度明显,有5只因动脉压过低剔除研究,而C组下降幅度缓慢;与A组比较,脑死亡组谷值和峰值时动脉压及心率的差异均有统计学意义(P＜0.05),手术成功率B组70％(14/20)小于C组90％(18/20).结论:应用颅内高压法能成功建立稳定可靠的大鼠脑死亡模型,其中渐进式颅内高压脑死亡模型有更高的手术成功率.     

脑损伤动物模型实施亚低温的模式概述

摘要：脑损伤是全球死亡和致残的主要原因,给社会和家庭带来沉重的负担。脑损伤动物模型的亚低温实验能够为脑损伤的治疗提供新的干预及治疗措施。在大量的脑损伤动物模型的亚低温治疗实验中,其脑保护的作用已经被证实。然而,目前的脑损伤动物实验的亚低温治疗模式尚不明确,其最佳的治疗模式如低温持续的时间、低温诱导的方法以及最佳的温度等仍然未知。由此,本文对脑损伤动物模型的亚低温实验方法进行概述。     

Antidepressant effects of nicotine in an animal model of depression

Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg SC) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [³H]cytisine binding (selective for the α₄β₂ nicotinic receptor subtype) but not [¹²⁵I]alpha-bungarotoxin binding (selective for the α₇ subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders. Received: 9 June 1998/Final version: 6 August 1998