Hyperactivity model

Describe how the dopamine hyperactivity model for schizophrenia has changed and evolved over time. 

Recently a hyperactivity model induced by a combination of D-amphetamine and chlordiazepoxide was studied. Lamotrig-ine, valproate, and carbamazepine, all used to treat bipolar disorder, were all found to decrease this hyperactivity (Arban et al., 2005). Interestingly, while most mania models assume an increase in dopamine, an early model used dopamine depletion with in tracerebr oven trie ular injection of 6-hydroxydopa-mine, which induces hyper-reactivity to environmental stimuli, but not hyperactivity per se (Petty and Sherman, 1981). This model was responsive to chronic lithium and to chronic electroconvulsive shock, and also to acute chloiq romazine, while imipramine w orsened the behavior. 

Somoza EC, Winhusen TM, Bridge TP, et al An open-label pilot study of methylpheni-date in the treatment of cocaine-dependent patients with adult attention deficit/ hyperactivity disorder. J Addict Dis 23 77—92, 2004 Sora 1, Wichems C, Takahashi N, et al Cocaine reward models conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95 7699-7704, 1998 Soral, Hall FS, Andrews AM, etal Molecular mechanisms of cocaine reward combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Nad Acad Sci U S A 98 5300-5305, 2001 Spear J, Alderton D Psychosis associated with prescribed dexamphetamine use 0etter). 

The close resemblance between schizophrenia and PCP-induced psychosis suggests that the behavioral effects produced by PCP might be useful as a model of psychosis. On this basis, most animal studies have examined the ability of various agents to modify PCP-induced hyperactivity and stereotypy. While some studies suggest that neuroleptics such as haloperidol (Castellani and Adams 1981 Garey et al. 1980), chlorpromazine, or clozapine (Freed et al. 

Other knockout models that could be used to validate candidate genes include mice that lack monoamine oxidase A (MAO-A), which have demonstrated altered behavior and alcohol tolerance [54]. Transgenic mice in which the dopamine transporter gene has been deleted show striking hyperactivity via enhanced persistence of dopamine which is not altered by cocaine or amphetamine administration [55]. Knockouts of the serotonin IB receptor are also available and are best used as models of vulnerability to drug abuse [56]. 

Recent in vitro hybridization studies in the rat have demonstrated that t)rpical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the s)mthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid s)mthesis inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRT) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. 

ANIMAL MODELS OF ATTENTION-DEFICIT HYPERACTIVITY DISORDER... 

The mechanism of deprenyl s action is unclear. In addition to enhancing dopaminergic activity in the brain by inhibiting dopamine degradation, deprenyl is metabolized into various stimulant metabolites. In spontaneously hyperactive rats used in an animal model of ADHD, chronic deprenyl administration improved im-pulsivity (but not hyperactivity or attention) along with altering levels of noradrenaline, dopamine, and serotonin and their metabolites (Boix et ah, 1998). 

The hyperactivity of, for example, lipases at low w -values (shown in Fig. 5) is explained by the water-shell-model [2]. The activity of the enzyme at w -values higher than 5 corresponds to its activity in bulk aqueous solutions. There exist two aqueous regions within a reverse micelle, schematically shown in Fig. 6. One is located in the inner part of the reverse micelle and has the same physical properties as bulk water the other is attached to the polar head groups of the surfactant and differs in its physical properties strongly from bulk water. 

Repeated ECS enhances apomorphine and other dopamine agonist-induced hyperactivity and stereotypy [Grahame-Smith et al. 1978 A. R. Green 1984 Modigh 1989]. Although apomorphine-stimulated behavior is not a face valid model for depression, ECS sensitizes apomorphine-stimulated behavior very... 

McCracken JT A two-part model of stimulant action on attention-deficit hyperactivity disorder in children. J Neuropsychiatry Clin Neurosci 3 201-208, 1991... 

Russell V, de Villiers A, Sagvolden T, et al Differences between electrically, Ritalin-, and D-amphetamine-stimulated release of pH]dopamine from brain slices suggest impaired vesicular storage of dopamine in an animal model of attention-deficit hyperactivity disorder. Behav Brain Res 94 163-171, 1998... 

The utility of this model was further evaluated by establishing the procognitive effects of established attention deficit hyperactivity disorder (ADHD) agents in the juvenile rat pups.82-83 Methylphenidate (Ritalin ) was tested in the juvenile pup model to assess its effects on acquisition in the PAR. Methylphenidate (3 mg/kg, ip) was chosen as an intermediate dose, which in adult rats provided dear evidence of psychostimulant activity. Pretreatment (20 min) of the pups with methylphenidate produced a significant, improvement in the acquisition of the PAR (Fig. 6). 

Hartley P, Neill D, Hagler M, Kors D, Vogel G. Procedure- and age-dependent hyperactivity in a new animal model of endogenous depression. Neurosci Biobehav Res 1990 14 69-72. 

Prathiba J, Kumar KB, Karanth KS. Hyperactivity of hypothalamic pituitary axis in neonatal clomipramine model of depression. J Neural Trans (Bud) 1998 105 1335-1339. 

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