title: In vitro studies on the possible effects of 1-aminoadamantanes on the serotonergic system in M. Parkinson.
abstract: Synaptosomes, synaptic vesicles, and membranes were isolated from rat brain homogenates by differential and density gradient centrifugation in sucrose. Synaptosomes incorporated serotonin (5-HT) with two different uptake mechanisms, high affinity: Kt1 = 47 nM and low affinity: Kt2 = 660 nM. Both uptake mechanisms are non-competitively inhibited by the potential antiparkinson drugs 1-aminoadamantane (amantadine, D 1: Ki1 = 57 microM, Ki2 = 96 microM) and 1-amino-3,5-dimethyladamantane (memantine, D 145: Ki1 = 97 microM, Ki2 = 150 microM). The incorporated 5-HT is released from synaptosomes on incubation with high concentrations (0.5--5 mM) of the drugs or on electrical stimulation with rectangular pulses of alternating polarity. Subthreshold concentrations of these drugs (5--50 microM) which are too low to liberate 5-HT increase the electrically stimulated release of 5-HT.--The effect of D 1, D 145, and electrical stimulation on DA release parallels the results observed with 5-HT. The uptake of 5-HT into isolated synaptic vesicles and the binding to isolated nerve ending membranes is non-competitively inhibited by 1-aminoadamantanes. D 145 inhibits the binding of 5-HT to membranes more effectively (Ki = 0.95 mM) than its uptake into vesicles (Ki = 1.2 mM) contrasting with D 1 which is a weaker inhibitor affecting vesicular uptake (Ki = 2.5 mM) slightly more than membrane binding (Ki = 3.1 mM). The results obtained suggest that, in addition to other mechanisms like receptor stimulation, 1-aminoadamantanes may act in parkinsonian patients by enriching the transmitter content in the synaptic cleft.
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology*; D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004558:Electric Stimulation; D007700:Kinetics; D008297:Male; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D001952:Bridged-Ring Compounds; D012701:Serotonin; D000547:Amantadine; D000218:Adamantane