Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates.
The pharmacologic treatment of many neuropsychiatric disorders (Alzheimer's disease, schizophrenia, depressive illness) has been targeted at the central hypothesis that defects in a single neurotransmitter system underlie the pathophysiology of the disease state. With the recognition that such treatments have not been efficacious consistently, recent drug development has been directed at altering other functionally linked neurotransmitters involved in these diseases. Using positron emission tomography, we have noninvasively investigated the effects of two noncholinergic drugs on the release of acetylcholine. By examining the effects of gamma-vinyl gamma-aminobutyric acid (GABA) (a GABA transaminase inhibitor) or altanserin (a serotonergic antagonist) on the regional binding of 11C-benztropine in the primate brain (Papio anubis), we demonstrated that drugs acting upon either GABAergic or serotonergic neurons produce profound regional changes in acetylcholine release. These findings indicate that the mechanisms of action and the subsequent therapeutic efficacy of these centrally acting drugs may be linked to their multitransmitter effects. This application of positron emission tomography represents an extremely promising experimental approach that can be directed towards elucidating abnormalities in neurotransmitter modulation relevant to disease progression and pharmacologic treatment.
Dewey
S L
SL
Department of Chemistry, Brookhaven National Laboratory, Upton, New York 11973.
Smith
G S
GS
Logan
J
J
Brodie
J D
JD
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000614:Aminocaproates / Q000494:pharmacology; D000818:Animals; D001590:Benztropine / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D005260:Female; D007650:Ketanserin / Q000031:analogs & derivatives / Q000494:pharmacology; D010215:Papio; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology*; D014055:Tomography, Emission-Computed; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000614:Aminocaproates; D002250:Carbon Radioisotopes; D011950:Receptors, Cholinergic; D001590:Benztropine; D012701:Serotonin; C071983:altanserin; D005680:gamma-Aminobutyric Acid; D007650:Ketanserin; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin