Dopamine-b-hydroxylase (DbH) gene, and increased expression of the dopaminetransporter (DAT) gene, both correlating with the positive symptoms in schizophrenia. Decreased expression of DbH results in reduced enzymatic degradation of dopamine (DA) in the synaptic cleft.
Dopamine-b-hydroxylase (DbH) gene, and increased expression of the dopaminetransporter (DAT) gene, both correlating with the positive symptoms in schizophrenia. Decreased expression of DbH results in reduced enzymatic degradation of dopamine (DA) in the synaptic cleft.
Dopamine-b-hydroxylase (DbH) gene, and increased expression of the dopaminetransporter (DAT) gene, both correlating with the positive symptoms in schizophrenia. Decreased expression of DbH results in reduced enzymatic degradation of dopamine (DA) in the synaptic cleft.
TREATMENT OF SCHIZOPHRENIA D.St. Stojanov Military Medical Academy, Department of Neurology, Psychiatry and Neurosurgery, Sofia, Bulgaria
dopamine-β-hydroxylase (DβH) gene, and
increased expression of the dopamine- transporter (DAT) gene, both correlating with the positive symptoms (verbal halluci- nations, for instance) in the significant number of clinically diagnosed patients. From a pharmacogenetical view, these results are a premise for a pharmacody- namic hypothesis for the resistance of the positive symptoms in schizophrenia to neuroleptic (dopamine receptor antago- nists) treatment. The decreased expression of DβH results in reduced enzymatic de- gradation of dopamine (DA) in the synaptic cleft. The persisting increased [DA] con- centration stimulates the postsynaptic D2 receptors, then they respond adaptively, by down-regulation. The feed-back mecha- nism must decrease the DA synthesis, by It is accepted at present the neo-bleulerian inhibiting directly the tyrosine-hydroxylase theory, adapted to the organodynamic con- (the pace-making, speed-limiting, reaction cept of Henri Ey (1). It explains the nega- of the process), and by increasing the de- tive symptoms, consisting the primary defi- struction of DA by DβH. Even if the first cit in schizophrenia with the dissolution of mechanism is intact, the second is insuffi- the higher neurobiological functions, dem- cent. The available DA, meanwhile is onstrated with hypoactivity of the prefron- transported to the synaptic terminal by tal cortex. DAT at a rate, that obstructs the effective- This leads to hyperdopaminergic desin- ness of the monoaminooxydase (MAO) hibition (derepression) of older in evolution catabolism in the vesicles. So the excess of structures of the mesencephalo-limbic DA is directed to exocytosis and neuro- tractus, as well as the temporal polar cor- transmission without being destroyed. If tex, acting in the determination of the posi- there is a defect in the TH or in its cofac- tive symptoms in schizophrenia (such as tors, so to that supraphysiological (DA) delusions and hallucinations). there are joining the de novo produced DA According to the D. Toncheva’s re- molecules, in the synaptic space ,so that sults(3), there is a reduced expression of the postsynaptic neuron reacts with tonic
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excessive postsynaptic potentials and re- therapeutic diapason (2)). Therefore the mains in a permanent state of excitation, absolute DA concentration must decrease that is irregular, due to the disturbed feed- to physiological values, during their back with the presynaptic neuron. The re- occupation. This does not occur, because duced DβH, as well as the non-specific of the described phenomenon, and most catechol-o-methyl –transferase ( C-O-MT ) probably the excessive amount of the pro- can not eliminate the abnormal amount of toligand (the native DA), competes with DA because of the hyperactivity of the au- the neuroleptic molecules for the D2 bind- toregulatory transporter (DAT). During the ing sites, and because of the higher affinity rapid recycling of DA the intracellular , removes them.At the background of 80% MAO, can not remove the excessive DA, expression, there appears a compensatory also. The absolute number of the postsy- up – regulation of the receptors, and re- naptic D2 receptors is decreasing (down- gardless to the therapeutic saturation, DA regulation), due to the continuous stimula- proceeds binding to the unoccupied sites, tion, signalling to the regulatory mecha- and thus realises its pathobiochemical ef- nisms to catabolise the excessive DA. So, fects. because of their insufficiency and the rapid reuptake, realised by DAT, DA proceeds REFERENCES turning over in the “hurricane” or a vicious 1. Ey Henry (1962) Am. J. of Psychiatry, 673-682. circle. 2. Milanov K., Milanova V. (2003) Biological Psy- This phenomenon may explain some chiatry, vol. 1, Sofia. 3. Toncheva D.I. (2005) Genetic factors in the cases of resistance to antipsychotic treat- pathogenesis of some common diseases. A thesis for ment. receiving the D.Sc. degree, Medical University of Neuroleptics (DA receptor antagonist), Sofia. must block 65-85% of the expressed re- ceptor proteins in order to induce remission On the 105-th anniversary of the birth of French psy- (verified with positron-emission tomography chiatrist Henri Ey (10.08.1900-8.11.1977)