Dopamine models

Over the last 40 years, the dopamine model has been the leading neurochemical hypothesis of schizophrenia. This model has proved heuristically valuable, with all current medications for schizophrenia... 

Fig. 2. Molecular modeling of dopamine D2 receptor agonists used to define the molecular conformation needed for selective high affinity binding.

Of special importance is the complex problem of nitrogen addition as related to the dmg dopamine, where even model compounds lead to extremely complex chemistry and difficult analytical problems (65). 

Figure 3 The chemical structures of the ligands used in the molecular modeling study of the Di dopamine receptor. The ligands were divided into two groups (active and inactive) based on their pharmacological properties. The hypothesized pharmacophoric elements are shown in bold.

DMF, see Dimethylformamide DM SO, see Dimethyl sulfoxide DMT (dimethoxytrilyl ether), DNA synthesis and, 1114 DNA, see Deoxyribonucleic acid DNA fingerprinting, 1118-1119 reliability of, 1119 STR loci and, 1118 Dopamine, molecular model of. 930 Double bond, electronic structure of, 16... 

Molar absorptivity. 502 Molecular ion (M+), 410 Molecular mechanics. 130 Molecular model, dopamine, 930 acetaminophen, 29 acetylene, 18 adenine, 67 adrenaline, 323 alanine, 28, 1016 alanylserine, 1028 rr helix, 1039 p-aminobenzoic acid, 25 anti periplanar geometry, 387 a recoline, 79 aspartame, 29 aspirin. 17 ball-and-stick, 61 /3-pleated sheet, 1039 p-bromoacetophenone, 449 bromocyclohexane, 121 butane, 80... 

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

Grace AA, Bunney BS, Moore H, Todd CL (1997) Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. TINS 20 31-37... 

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). 

Fuxe K, Andersson K, Nilsen OG, et al Toluene and telencephalic dopamine selective reduction of amine mrnover in discrete DA nerve terminal systems of the anterior caudate nucleus by low concentrations of toluene. Toxicol Lett 12 115—123,1982 Cause EM, Mendez V, Geller I Exploratory smdies of a rodent model for inhalant abuse. Neurobehav Toxicol Teratol 7 143—148, 1985 Gentry JR, Hill C, Malcolm R New anticonvulsants a review of applications for the management of substance abuse disorders. Ann Clin Psychiatry 14 233—245, 2002 Gerasimov MR, Ferrieri RA, Schiffer WK, et al Smdy of brain uptake and biodistribution of [llCjtoluene in non-human primates and mice. Life Sci 70 2811 — 2828, 2002... 

Varady J, Wu X, Fang X, Min J, Hu Z, Levant B, Wang S. Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor discovery of novel and potent D3 ligands through a hybrid pharmacophore-and structure-based database searching approach. / Med Chem 2003 46 4377-92. 

Samanta, S., Debnath, B., Gayen, S., Ghosh, B Basu, A., Srikanth, K., Jha, T. QSAR modeling on dopamine D2 receptor binding affinity of 5-methoxy benzamides. Farmaco 2005, 60, 818-825. 

We are routinely screening compounds for ability to displace 1-125 DOI from frontal cortex homogenates. As far as the CNS stimulant effects, differentiating from psychostimulants, the present model we are using is substitution in amphetamine-trained rats, in drug discrimination. We have used synaptosomes and looked at their effect on dopamine release and reuptake. But basically they are correlative models. 

COMMENT The main point that 1 wanted to make is that it is very important to attempt to develop models where one is looking at least at some sort of in vivo integrated preparation. We look at serotonin depletion. We look at dopamine depletion. We have a variety of different mechanisms. Again we really do not know what, at this point in time, the serotonin depletion is doing. I think 1 know what it means if you deplete dopamine beyond a certain level. But even there, it is difficult to put an exact degree of impairment on the levels of dopamine depletion that we see in most of these models. 

COMMENT I would like to know why you thought the amphetamine model of dopamine neurotoxicity might be more suitable or more revealing for the study of Parkinson s disease than the MPTP model. 

COMMENT I think another matter to take into account is that, at least from the experienee of dopamine systems, in order to get overt behavioral dysfunetion you really need a pretty whopping lesion. In the primate, to get the kind of Parkinsonism that people talk about in animal models, that animal model actually turns out to be very difficult to produce in chronic Parkinsonism. The problem is developing an animal that has 90 to 95 percent depletion of dopamine on a chronic basis. As you know, it is a very narrow window, and it is very difficult to produce that kind of animal preparation. So I think you have to consider the possibility that lack of symptoms after serotonergic lesions could, perhaps, be related to the fact that we are dealing with preparations where there is a 50, 60, 70 percent depletion where we don t have enough of a lesion to produce an overt behavioral disturbance. 

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