Dopamine model validation

Another crucial problem for any neurochemical model is cause and effect. Neuroleptics have a high affinity for dopamine receptors, particularly the D2-subtype. There is also a highly significant positive correlation (r > +0.9) between this receptor binding and their clinical potency (Seeman, 1980). But, this does not necessarily implicate elevated dopamine levels as the cause of schizophrenia. Moreover, blockade of dopamine receptors happens very rapidly, whereas clinical benefits are only seen after chronic treatment. Rose (1973) has criticised the reductionist statement that an abnormal biochemistry causes schizophrenia because it relates cause and effect at different organisational levels (namely, the molecular and behavioural). But, while it can be legitimate to discuss cause and effect at the same level that chlorpromazine blocks dopamine receptors (one molecule altering the response of another), it is not valid to infer that increased dopamine activity causes schizophrenia. Put another way ... 

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]. 

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... 

Maw, H.H. and Hall, L.H., E-state modelling of dopamine transporter binding validation of model for small data set, J. Chem. Inf. Comput. Sci., 40, 1270-1275, 2000. 

It is also clear in retrospect that the reserpine-induced state was a state of dopamine blockade, characterised by sedation and inactivity, rather than a valid model of depression (Mendels Frazer 1974). Whether it commonly caused a true depressive state in humans has also been disputed. One review suggested that it did so in 6% of cases, but mostly in people who had a previous history of depression (Goodwin Bunney, Jr. 1971). The only controlled study of reserpine on mood found no true cases of depression, but several patients were noted to show signs of excessive tranquillisation or pseudodepression (Bernstein Kaufman 1960). 

Rotation provides a very simple measure of the asymmetry in motor activation associated with dopamine lesions. However, PD patients have a more complex range of motor deficits, not just in akinesia and rigidity, but in the initiation of voluntary and purposive movement, and in fine motor control. To develop the validity of the animal models, we need to determine the extent to which dopamine denervation in experimental animals produces comparable impairments in simple motor behaviors not dependent on pharmacological activation, and in more complex behaviors whilst controlling for confounding effects of simple performance deficits. 

With some doubt over the validity of bacteriorhodopsin as a suitable template for GPCRs, a number of models have been constructed without the use of a template. Thus, Dahl et al constructed a model of the dopamine D2 receptor. From the available sequences, hydropathy plots confirmed the presence of seven hydrophobic... 

Mauri, A., Consonrii, V., Pavan, M. andTodeschini, R. (2006) DRAGON software an easy approach to molecular descriptor calculations. MATCH Commun. Math. Comput. Chem., 56, 237—248. Maw, H.H. and HaU, L.H. (2000) f-state modeling of dopamine transporter binding. Validation of the model for a small data set. J. Chem. Inf. Comput. Sci., 40, 1270-1275. 

D-2 dopamine receptor. The statistical models are cross-validated and have been shown to have good predictive utility. In this scheme, two molecules would be similar in three-dimensional properties if they are similar in those three-dimensional properties associated with the biological property of interest. 

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