Abstract / Conclusions of my Doctoral Thesis (
Deutsche Version)
Functional characterization of presynaptic dopamine receptors in rat striatumusing locally administration of typical and atypical neuroleptics and receptor-specific CCK-agonists
The aim of this work was to clarify the dopamine and cholecystokinine receptor interactions in the striatum of rats using in-vivo microdialysis and HPLC.
The dose- and subreceptor affinity differences between haloperidol and clozapine to achieve a similar striatal dopamine release were compared and it was found that the D2-receptor acts as main target of presynaptic dopamine action. The D4-receptor subtype could play a regulatory role in adjustment of D2-receptor sensitivity and therefore represent an example of receptor-receptor interaction. Post-synaptic feedback mechanisms and interactions between different neurotransmitter systems (like CCK and serotonine) could be part of a complicated regulatory network.
The observed reduction of extra cellular concentration of dopamine-metabolites following local administration of haloperidol directly into the striatum opposes the well-known effects of systemic use of this substance.
A possible reason for this contradiction is an inhibitory effect of haloperidol on dopamine re-uptake.
Direct blocking of dopamine autoreceptors, as well as by interactions involving other transmitters, for example acetylcholine or cholecystokinine are other explanations.
Concerning functional characteristics of presynaptic cholecystokinine (CCK) receptors in rat striatum, only the CCK-B receptor subtype seems to possess regulatory function on dopaminergic systems. Presynaptic CCK-dopamine interactions probably lead to a reduction of dopamine release.
It was concluded that presynaptic CCK-B receptors initiate an amplification of a dopamine-autoreceptor-mediated blockade of dopamine release and could change dopamine receptor sensitivity.
Neuroleptic-like effects of CCK, as suspected by several authors, could not be confirmed.
Methodological aspects of microdialysis were discussed
The thesis was submitted in May 1995 and successfully disputed in August 1996.
The dose- and subreceptor affinity differences between haloperidol and clozapine to achieve a similar striatal dopamine release were compared and it was found that the D2-receptor acts as main target of presynaptic dopamine action. The D4-receptor subtype could play a regulatory role in adjustment of D2-receptor sensitivity and therefore represent an example of receptor-receptor interaction. Post-synaptic feedback mechanisms and interactions between different neurotransmitter systems (like CCK and serotonine) could be part of a complicated regulatory network.
The observed reduction of extra cellular concentration of dopamine-metabolites following local administration of haloperidol directly into the striatum opposes the well-known effects of systemic use of this substance.
A possible reason for this contradiction is an inhibitory effect of haloperidol on dopamine re-uptake.
Direct blocking of dopamine autoreceptors, as well as by interactions involving other transmitters, for example acetylcholine or cholecystokinine are other explanations.
Concerning functional characteristics of presynaptic cholecystokinine (CCK) receptors in rat striatum, only the CCK-B receptor subtype seems to possess regulatory function on dopaminergic systems. Presynaptic CCK-dopamine interactions probably lead to a reduction of dopamine release.
It was concluded that presynaptic CCK-B receptors initiate an amplification of a dopamine-autoreceptor-mediated blockade of dopamine release and could change dopamine receptor sensitivity.
Neuroleptic-like effects of CCK, as suspected by several authors, could not be confirmed.
Methodological aspects of microdialysis were discussed
The thesis was submitted in May 1995 and successfully disputed in August 1996.
