Alan S. Hollister

Comparison of tyrosine hydroxylase and dopamine-Β-hydroxylase inhibition with the effects of various 6-hydroxydopamine treatments on d-amphetamine induced motor activity

The significance of central noradrenergic and dopaminergic neural systems for the locomotor stimulant effects of d-amphetamine were investigated in rats with depletions of norepinephrine, dopamine, or both catecholamines produced by treatment with either reserpine, L-α-methyl-tyrosine (α-MPT), 6-hydroxydopamine (6-OHDA), or the dopamine-Β-hydroxylase inhibitor 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624). In animals pretreated with reserpine, amphetamine-stimulated locomotor activity was blocked by Β-MPT but not by U-14,624 when amphetamine was given l h after these catecholamine synthesis inhibitors. In rats with chronic depletions of brain norepinephrine, dopamine, or both catecholamines produced by different 6-OHDA treatments, both amphetamine-stimulated motor activity and stereotyped behavior were antagonized by treatments reducing dopamine or both catecholamines but not in animals in which brain norepinephrine was reduced. Results are consistent with the view that the locomotor stimulation and stereotyped behaviors produced by d-amphetamine are dependent upon functional dopaminergic neural systems in brain.

The roles of monoamine neural systems in the anorexia induced by (+)-amphetamine and related compounds

Abstract The anorectic effects of ( + )-amphetamine, mephentermine, methylphenidate, amantα-dine, or fenfluramine were examined in animals pretreated intracisternally with either 6-hydroxydopamine or 5,7-dihydroxytryptamine. Destruction of brain dopamine systems antagonized the anorectic effect of ( +)-amphetamine and mephentermine, but did not block the anorectic effects of fenfluramine. Neither destruction of brain norepinephrine systems nor depletion of norepinephrine with the dopamine-β-hydroxylase inhibitor, U-14,624, antagonized the anorectic response to ( + )-amphetamine. While destruction of brain serotonin-containing systems did not alter the anorectic response to ( + )-amphetamine, it significantly enhanced the anorectic potency of fenfluramine.

Involvement of brain monoamines in the stimulant and paradoxical inhibitory effects of methylphenidate

The significance of central noradrenergic, dopaminergic and serotonergic neural systems for the locomotor stimulant effects of methylphenidate was investigated in the rat. In order to study the role of brain catecholamines, rats were pretreated with reserpine (2.5 mg/kg) followed 24 hrs later by treatment with α-methyltyrosine (25 mg/kg) or U-14,624 (75 mg/kg), a dopamine-Β-hydroxylase inhibitor. In these experiments, methylphenidate stimulated motor activity was antagonized by α-methyltyrosine and enhanced after treatment with U-14,624, suggesting that release of newly synthesized dopamine is important to a locomotor stimulant action of methylphenidate. Evidence implicating brain serotonin in the actions of methylphenidate was obtained in rats pretreated with pargyline or p-chlorophenylalanine (PCPA). Administration of pargyline 1 hr prior to methylphenidate was found to reduce the locomotor activity induced by methylphenidate and this was antagonized by pretreatment with low doses of PCPA. Higher doses of PCPA caused a significant elevation of methylphenidate induced activity which could be reduced by 5-hydroxytryptophan. Destruction of serotonergic neurons with 5,7-dihydroxytryptamine also potentiated methylphenidate induced locomotion. These latter findings suggest that serotonergic fibers have an inhibitory function in brain. These results are discussed in relation to the possible mechanism by which methylphenidate may act in hyperkinesis.

RELATIONSHIP OF BIOGENIC AMINES TO BEHAVIOR

Abstract Present data support the proposal that dopaminergic fibers play an important role in the maintenance of intracranial self-stimulation. In addition, amphetamine-induced motor activity as well as the sterotypies produced by this drug were also found to be dependent upon intact dopaminergic fibers. Evidence was also presented that serotonin fibers may modulate the behavioral actions of amphetamine by acting as an inhibitory transmitter.

Role of Monoamine Neural Pathways in d-Amphetamine- and Methylphenidate-Induced Locomotor Activity

Extensive efforts have been made during the past few years to correlate the pharmacological actions of d-amphetamine and other centrally-acting stimulants with neurochemical changes in brain. Initial work was directed toward the role of brain catecholamine systems in the complex actions of such centrally-acting stimulants. Studies showing that tyrosine hydroxylase inhibitors antagonized the behavioral actions of d-amphetamine led to the proposal that d-amphetamine is an indirectly acting amine and that an uninterrupted synthesis of catecholamines is required for its central actions (Weissman, Koe, and Tenen, 1966; Hanson, 1967). From experiments that utilized a dopamine-β-hydroxylase inhibitor, Randrup and Scheel-Kruger (1966) suggested that noradrenergic fibers were responsible for amphetamine-induced locomotor activity and that dopaminergic pathways were necessary for the stereotypies that occur after amphetamine administration. However, even though subsequent studies supported the view that dopamine was involved in the stereotypic behavior induced by d-amphetamine (Simpson and Iversen, 1971; Fibiger, Fibiger, and Zis, 1973), several investigators provided evidence that dopamine rather than norepinephrine release was essential for amphetamine-induced locomotor activity (Costa, Groppetti, and Naimzada, 1972; Carlsson, 1970; Breese, Cooper, and Smith, 1973; Hollister, Breese, and Cooper, 1974).