John E. Thornburg

The relative importance of dopaminergic and noradrenergic neuronal systems for the stimulation of locomotor activity induced by amphetamine and other drugs.

When administered in the diets of mice, α-methyltyrosine reduced the brain contents of endogenous dopamine and norepinephrine and inhibited the formation of 14C-dopamine and 14C-norepinephrine from 14C-tyrosine. α-Methyltyrosine also blocked the locomotor stimulant actions of (+)-amphetamine and phenmetrazine but not of methyl-phenidate or pipradrol. Administration in the diet of U-14,624 or FLA-63, inhibitors of dopamine-β-hydroxylase, reduced brain contents of endogenous and 14C-norepinephrine but failed to alter the locomotor stimulant actions of any of the drugs tested. These results suggest that (+)-amphetamine and phenmetrazine exert locomotor stimulant effects through a dopaminergic mechanism.

Brain cholinergic, behavioral, and morphological development in rats exposed in utero to methylparathion☆

The purpose of this study was to determine the effects of subchronic administration of the organophosphate methylparathion (MPTH) during gestation on behavior and development of brain cholinergic neurons in the offspring. Pregnant rats received daily po doses of MPTH from Day 6 through Day 20 of gestation at doses causing no (1.0 mg/kg) or minimal (1.5 mg/kg) visible signs of maternal toxicity. Acetylcholinesterase (AChE) and choline acetyltransferase (CAT) activities, and [3H]quinuclidinyl benzilate (QNB) binding to muscarinic receptors, were determined in several brain regions at 1, 7, 14, 21, and 28 days postnatal age and in maternal brain at Day 19 of gestation. Prenatal exposure to 1.5 mg MPTH/kg reduced AChE and increased CAT activity in all brain regions at each developmental period and in maternal brain. Similar exposure to 1.0 mg MPTH/kg caused a significant but smaller and less persistent reduction in AChE activity but no change in brain CAT activity of the offspring. Both doses of MPTH decreased the Bmax of 3H-QNB binding in maternal frontal cortex but did not alter the postnatal pattern of 3H-QNB binding. In parallel studies, prenatal exposure to MPTH did not affect a variety of behaviors. However, cage emergence, accommodated locomotor activity, and operant behavior in a mixed paradigm were impaired in rats exposed to 1.0 but not to 1.5 mg/kg MPTH. No morphological changes were observed in hippocampal or cerebellar tissue. Thus, subchronic prenatal exposure to MPTH altered postnatal development of cholinergic neurons and caused subtle alterations in selected behaviors of the offspring.

A comparison of effects of apomorphine and ET495 on locomotor activity and circling behaviour in mice

Abstract In mice with 6-hydroxydopamine-induced left striatal lesions, apomorphine and ET495 produced dose-related contralateral circling behaviour. Apomorphine was 30 times more potent than ET495 with respect to the dose required to elicit the half-maximal rate of circling. ET495, however, had a markedly longer duration of action. In normal mice apomorphine stimulated locomotor activity, whereas ET495 depressed activity. Pretreatment with SKF-525A did not prevent ET495-induced depression. In contrast to its effects in mice, ET495 stimulated locomotor activity in rats.

A comparison of the locomotor stimulant properties of amantadine and l- and d-amphetamine in mice ☆

Abstract Amantadine, administered intraperitoneally at doses of 20, 40, 80 and 160 mg kg , increased locomotor activity in mice with peak stimulation at 1 hr; maximal stimulation produced by this drug was only one-tenth of that caused by l - or d -amphetamine. A 4 hr diet containing 0.4% dl -α-methyltyrosine, an inhibitor of catecholamine synthesis, did not alter amantadine-stimulated motor activity but completely blocked the stimulant effects of l - and d -amphetamine. Pretreatment with a monoamine oxidase inhibitor (pheniprazine) did not alter amantadine-stimulated motor activity, and amantadine pretreatment did not influence d -amphetamine-stimulated locomotor activity. Thus, amantadine, in contrast to the amphetamines, produces a very weak stimulation of locomotor activity which is not dependent upon brain catecholamine synthesis.

Effect of subchronic administration of methyl parathion on in vivo protein synthesis in pregnant rats and their conceptuses

Pregnant rats received daily po doses of the organophosphate methyl parathion (MPTH) from Day 6 through Day 15 or 19 of gestation at doses causing no (1.0 mg/kg) or minimal (1.5 mg/kg) signs of maternal toxicity. Following the dose of MPTH on Day 15 or 19, in vivo protein synthesis was measured 0.5, 1.0, and 2.0 hr after sc injection of L-[1-14C]valine at a dose of 5 microCi/mmol/100 g body wt. The specific activity of [14C]valine in the free amino acid pool and protein bound pool was significantly reduced in various regions of maternal brain and in maternal viscera, placenta, and whole embryos (Day 15), and in fetal brain and viscera (Day 19). The inhibitory effect of MPTH on net protein synthesis was dose dependent, greater on Day 19 than 15 of gestation and more pronounced in fetal than in maternal tissues.

Differential actions of dopamine agonists and antagonists on the γ-butyrolactone-induced increase in mouse brain dopamine

Abstractγ-Butyrolactone (GBL) increased the dopamine concentration in the forebrain of the mouse. Apomorphine dose-dependently antagonized the GBL effect, while piribedil was less effective. Haloperidol prevented the antagonism of GBL by apomorphine but pimozide was ineffective in blocking apomorphine. After chronic treatment with haloperidol or pimozide, there was no alteration of the maximum GBL-induced increase in dopamine nor was there any significant change in the antagonism by apomorphine, although a trend toward increased sensitivity to apomorphine was noted in the group withdrawn from haloperidol. These results suggest that in the mouse, haloperidol is a more effective antagonist of presynaptic dopamine autoreceptors than pimozide, while apomorphine is a better presynaptic agonist than piribedil.

Inhibition of anticholinergic drug-induced locomotor stimulation in mice by α-methyltyrosine

Abstract α-Methyltyrosine, administered in the diet to mice, inhibited locomotor stimulation induced by benztropine, scopolamine and atropine. FLA-63, administered in the same manner, did not alter any of the drug-stimulated activities. These results suggest that a dopaminergic system is involved in the pathway mediating anticholinergic drug-induced locomotor stimulation.

Blockade of α-methyltyrosine-induced supersensitivity to apomorphine by chronic administration of L-DOPA

Abstract The locomotor stimulating effect of apomorphine was enhanced in mice maintained for 2 weeks on a diet containing α-methyltyrosine suggesting that chronic blockade of catecholamine synthesis increases the sensitivity of central dopaminergic receptors. Cuncurrent administration of L-DOPA with α-methyl-tyrosine effectively restored the α-methyltyrosine-depleted brain catecholamine stores and prevented the enhancement of the response to apomorphine. These data support the concept that the development of α-methyltyrosine-induced supersensitive dopaminergic receptors in the brain results from a chronic deficiency of dopamine at these receptors.

Effect of chloramphenicol pretreatment on malathion‐induced acute toxicity in the rat

Pretreatment of rats with chloramphenicol (CAP) (100 mg/kg, ip) 30 min prior to a single oral LD50 dose of malathion (MTH) at 340 mg/kg completely protected against MTH-induced signs of cholinergic toxicity. Pretreatment with CAP also decreased the extent and duration of MTH-induced inhibition of cholinesterase (ChE). It was previously established that CAP inhibits (1) the cytochrome-P-450-catalyzed oxidative desulfuration of methylparathion to the much more toxic oxygen analog methylparaoxon (MOX) and (2) the carboxyesterase in rat liver. Since carboxyesterases account for 60% or more of the catabolism of MTH in the rat, the present results were surprising. Thus it appears that the inhibition of MTH toxicity by CAP pretreatment is attributable to inhibition by CAP of the metabolic activation of MTH to MOX.

Importance of brain dopamine for the stimulant actions of amphetamine

Publisher Summary This chapter describes the importance of brain dopamine for the stimulant actions of amphetamine. The antiamphetamine actions of α-methyltyrosine (αMT), an inhibitor of tyrosine hydroxylase, are well documented. It has been reported that DBH inhibitors produce behavioral depression and block the central stimulation produced by amphetamines and related drugs. The behavioral depressant and NE depleting actions of these inhibitors do not appear to be casually related. Intra-peritoneal administration of various DBH inhibitors reduces locomotor activity in rodents and markedly elevates plasma corticosterone and blood glucose concentrations. It is found that blockade of DBH with U-14, 624 did not influence amphetamine-induced stimulation of activity. It is found that because disruption of both NE and D synthesis by αMT blocks d -amphetamine-stimulated activity while disruption of only NE synthesis does not, it appears that the stimulation produced by amphetamine is primarily dependent upon a dopaminergic mechanism. This conclusion, however, is based upon the premise that antiamphetamine properties of αMT are related to the ability of this drug to inhibit tyrosine hydroxylase.