Effect of metaphit on dopaminergic neurotransmission in rat striatal slices: involvement of the dopamine transporter and voltage-dependent sodium channel.
Metaphit, an isothiocyanate analog of phencyclidine (PCP), increased the basal release of radioactivity (outflow) from perfused rat striatal slices preloaded with [3H]dopamine above levels observed with the dopamine uptake blocker nomifensin. Preperfusing the slices with metaphit, followed by its removal, attenuated the amphetamine- or dopamine-induced outflow. In slices prepared from reserpine-pretreated rats, the metaphit (100 microM)-induced outflow was reduced to that observed with 10 microM nomifensin, suggesting a vesicular releasing effect of metaphit in addition to dopamine uptake blockade. Electrically induced overflow of radioactivity from normal slices was stimulated by nomifensin and PCP, and by metaphit at 3 microM; it was unaffected by metaphit at 10 and 25 microM, and inhibited by higher concentrations of metaphit. Evidence that the latter effect is due to blockade of voltage-dependent sodium channels is as follows. First, metaphit, as did PCP, inhibited the binding of [3H]batrachotoxinin A 20-alpha benzoate to rat striatal synaptoneurosomes by increasing its dissociation rate; the effect of PCP, but not that of metaphit, was reversible by washing. Second, metaphit, as did PCP, inhibited veratridine (5 microM)-induced influx of [14C]guanidinium ion into synaptoneurosomes. Third, metaphit inhibited overflow of radioactivity from [3H]dopamine-preloaded slices induced by 2.5 microM veratridine, as did the sodium channel blocker tetrodotoxin.
Reith
M E
ME
Center for Neurochemistry, N.S. Kline Institute for Psychiatric Research, Ward's Island, New York.
Jacobson
A E
AE
Rice
K C
KC
Benuck
M
M
Zimanyi
I
I
D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000502:physiology*; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins; D019791:Guanidine; D006146:Guanidines / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009627:Nomifensine / Q000494:pharmacology; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium; D014701:Veratridine / Q000494:pharmacology
D001496:Batrachotoxins; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D006146:Guanidines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; D009627:Nomifensine; D013779:Tetrodotoxin; D014701:Veratridine; C031775:batrachotoxinin A 20-alpha-benzoate; C044705:metaphit; D000661:Amphetamine; D010622:Phencyclidine; D019791:Guanidine; D002118:Calcium; D004298:Dopamine