Faculty Bibliography

Selective binding of [3H]bremazocine and [3H]-ethylketocyclazocine to kappa-opioid receptor sites in frog (Rana esculenta) brain membranes is irreversibly inactivated by the sulfhydryl group alkylating agent N-ethylmaleimide (NEM). Pretreatment of the membranes with kappa-selective compounds [ethylketocyclazocine (EKC), dynorphin (1-13), or U-50,488H] but not with [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO; mu specific ligand) or [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DADLE; delta specific ligand) strongly protects the binding of the radioligands against NEM inactivation. These results provide more evidence for the existence of kappa-opioid receptors in frog brain. The relatively high concentrations of NEM that are needed to decrease the specific binding of [3H]bremazocine together with the observation of an almost complete protection of its binding sites by NaCl suggest that bremazocine may act as an opioid antagonist in frog brain

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

Although epidemiological studies have suggested a lower incidence of Parkinson's disease in cigarette smokers, repeated exposure to cigarette smoke or nicotine does not protect against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since there is some evidence that nicotinic antagonists, nicotine, and neurotransmitters may have tropic effects on neurite outgrowth, the present study examined the effects of chronic nicotine administration for 16 weeks (in drinking water; 5 mg/kg consumed per day) on the rate of terminal recovery after striatal lesioning with MPTP (2 x 30 mg/kg, s.c.). Terminal recovery, as measured by the rate of recovery in the level of striatal dopamine, was not affected by nicotine. Monoamine oxidase-B activity was not reduced by MPTP, nor did nicotine affect its activity in striatal homogenates

Sex and strain differences in tyrosine hydroxylase activity (TH) of brain dopamine systems have been reported for mice. To investigate if there might be a causal relationship between perinatal androgen secretion and regional mesotelencephalic TH activity, BALB/cJ and C57BL/6ByJ male mice were treated perinatally with cyproterone, a steroidal anti-androgen (or vehicle), and orchiectomized at 1 month of age. Two-way analysis of variance indicated significant treatment and strain effects in the mesencephalon and tuber olfactorium: perinatal cyproterone treatment lowered TH activity, and BALB/cJ had higher regional TH activities than those of C57BL/6ByJ. The most prominent behavioral effects of cyproterone treatment were found in the expression of scratching, which was considerably increased in both strains. Possible implications of these results are discussed

This study examined the effects of nicotine on locomotor activity and on the level of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and olfactory tubercle of mice that had been treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP significantly lowered the spontaneous locomotor activity 1-2 weeks and 2 months after 2 injections of MPTP (30 mg/kg SC, 24 hr apart) in young adult (3 months) and old mice (22-24 months old). The effect of nicotine on locomotion was biphasic; an initial stimulation of locomotor (0-5 min after nicotine) followed by a depressant period lasting from 5 to 20 min after injection. Tolerance to the depressant effect of nicotine developed after the 5th day of daily injections of nicotine (0.4 mg/kg SC, twice daily). Tolerance did not occur by day 8 to the initial stimulatory effect of nicotine. A similar effect of nicotine on locomotor activity was seen in mice treated with MPTP. The levels of DOPAC and HVA in the striatum were reduced by about 20% in the chronic nicotine-treated animals. The levels of DOPAC, DA, and HVA were reduced in the MPTP-treated mice; however, acute and chronic nicotine did not cause an additional change in the amine levels. The results suggest that nicotine has an influence on locomotor activity in MPTP-treated mice and that this effect is not due to changes in DA receptor activity in the striatum caused by chronic nicotine