Faculty Bibliography

Amiloride, an inhibitor of the Na+/Ca2+ exchanger, blocked the hydrolysis of inositol phospholipids in mouse cerebrocortical slices induced by the sodium channel activator veratridine, by KCl, or by the sodium ionophore monensin; there was no inhibition by A 23187, a Ca2+ ionophore, or by serotonin. It is concluded that agents that increase intracellular Na2+ stimulate inositide hydrolysis by an indirect effect via Na+/Ca2+ exchange

Norcocaine (NC) and N-hydroxynorcocaine (NHNC), products of the oxidative metabolism of cocaine, were examined in plasma, brain, and liver of mice injected intraperitoneally with cocaine. Plasma levels of NHNC were altered in vivo by inhibiting esterase activity with diazinon and chloral hydrate or activating esterase activity with phenobarbital, and activating the microsomal P-450 system with phenobarbital. Changes in plasma concentrations of NHNC resulted in similar changes in brain, which were often different from those in liver. After intracisternal administration of cocaine to mice, no appreciable amount of NC or NHNC could be detected in brain; the same results were obtained upon intracisternal and intraventricular administration to rats. Microsomal preparations from mouse brain were found to be considerably less active than those from liver in converting NC to NHNC. We conclude that the cerebral oxidative metabolism of cocaine is not appreciable and that most of the NC and NHNC found in the brain after systemic cocaine administration is derived from plasma rather than formed centrally by brain microsomal enzymes

[3H]Mazindol was used to label the dopamine uptake complex in mouse striatum in vitro in the presence and absence of metaphit, an isothiocyanate derivative of phencyclidine. In some experiments, metaphit was present in the incubation fluid throughout the procedure; in other experiments it was eliminated by several washings and centrifugations. It was found that after removal of the metaphit by washing and centrifugation, the mazindol binding was not restored. Membranes that were pretreated with metaphit and washed had a lower density of mazindol binding sites than control membranes; the remaining mazindol sites had the same afinity for [3H]mazindol. These findings are in agreement with the previous studies on [3H]cocaine and [3H]methylphenidate binding. The following observations support that metaphit is irreversibly acting and not slowly dissociating from the mazindol recognition sites of the dopamine uptake carrier complex: 1) Metaphit did not change the off-rate of [3H]mazindol binding, arguing against an allosteric action at a distinct site. 2) The presence of cocaine protected the mazindol binding sites from the action of metaphit, supporting binding of metaphit and mazindol to the same site. 3) Nine hours after metaphit pretreatment and removal, the degree of inhibition of mazindol binding was the same as immediately after pretreatment, consonant with an irreversible effect of metaphit. 4) The potency of metaphit in inhibiting mazindol binding was greater under slightly alkaline conditions, consistent with acylation of the mazindol sites. Furthermore, it was found that intracerebroventricular application of metaphit did not result in a decrease in the binding of [3H]mazindol 5 hr after the administration

Electrophysiological and biochemical evidence suggests that the voltage-dependent sodium channel is the site of local anesthetic action, and that there is pharmacological similarity between alpha-adrenoceptors and Na+-channels. Yohimbine, a non-selective alpha 2-adrenoceptor antagonist, with a structure similar to that of cocaine affects the sodium channel by a mechanism different from that of other local anesthetics including cocaine. Some structural analogues of yohimbine -berbane compounds- were found to be potent and selective alpha 2-adrenoceptor antagonists. In this work the local anesthetic properties of two berbane compounds (6c and 6d (CH-38083) from the paper of Vizi, Toth, Somogyi, Szabo, Harsing and Szantay, 1987) were examined and compared to those of yohimbine in vitro on scorpion venom-enhanced specific binding of [3H]batrachotoxinin A 20-alpha-benzoate [( 3H]BTX-B) to the voltage-sensitive sodium channel and on the veratridine-induced depolarization measured by the uptake of [3H]trimethylphenylphosphonium ion [( 3H]TPMP+) in mouse brain cortex. Both of the compounds inhibited the [3H]BTX-B binding with an IC50 of (approximately) 150 microM, which is more than four orders of magnitude higher than the concentration required for antagonism of a presynaptic alpha 2-adrenoceptor (7 nM). They are 15 times less potent in inhibiting [3H]BTX-B binding and 2.5 times less potent in inhibiting veratridine-induced depolarization than yohimbine