| description: |
1st generation classic (conventional or typical) antipsychotics (neuroleptics) act predominantly as dopamine D2 receptor blockers. The latter effect causes beside the antipsychotic effect alsopronounced motor disturbances, acting on in the extrapyramidal system. The 2nd generation antipsychotics (the atypical antipsychotics) act preferentially as the serotonin 5-HT receptor antagonists (the subtypes of 5-HT2 and the 5-HT4 receptors) and only in higher dosages they block D2 receptors as well. These drugs do not elicit dopamine blockade-mediated adverse effects that are typical for the 1st generation antipsychotics and they even enhance cognitive functions. In addition, the 2nd generation antipsychotocs relief negative symptoms of psychosis. These compounds have found to elicit some dopamine-and histamine-positive profile. However, the molecular mechanism of action of the 2nd generation antipsychotics is still not known. The objective of the present work is to elucidate the effects of the 2nd generation antipsychotics on the serotonin- and glutamatergic neurotransmission in terms of the involvement of distinct receptor subtypes, and thereby to clarify indirectly the influence of other neuromediator systems (incl. peptidergic neurotransmission). The in vivo microdialysis technique, in vivo and post mortem measurement of monoamine and amino acid contents as well as validated behavioural models of anxiety, psychotic behaviour, aggressiveness etc. will be used in laboratory rodents. The pharmacokinetic studies of novel compounds are also planned in order to find out dose-response relations. For the elucidation of the pharmacodynamical profile of the 2nd generation antipsychotics neurotoxins will be used to impair specific neurotransmitter systems. This project will be co-operated with the Department of Pharmacy of the Helsinki University in Finland and Department of Pharmacology of Karolinska Institute in Sweden. |