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

Abstract

The significance of central noradrenergic, dop-aminergic 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. KeywordsMethylphenidate; Locomotor Activity; 5-Hydroxytryptamine; Tyrosine Hydroxylase Inhibition; Dopamine-β-Hydroxylase Inhibition; p-Chlorophenylalanine; 5,7-Dihydroxytryptamine; 5-Hydroxytryptophan; MAO Inhibitors.Much attention has been directed toward understanding the actions of those stimulant drugs found to be of value in the treatment of hyperkinetic syndrome (MBD) (Snyder and Meyerhoff, 1973). Of these drugs, d-amphetamine has been the most widely studied. From animal experiments, the stimulant effects of d-amphetamine have been suggested to be mediated through the indirect release of catecholamines Hanson, 1966;Fibiger et al., 1973;Von Voigtlander and Moore, 1973;Hollister et al., 1974). Based upon such findings, Snyder and Meyerhoff (1973) have proposed that the therapeutic effectiveness of damphetamine in MBD was related to this action. These workers, however, did not provide an explanation for the paradoxical quieting effects of d-amphetamine in this syndrome. Recently, several studies in animals have provided evidence that the neurochemical effects of d-amphetamine to induce motor activity (Neill et al., 1972;Mabry and Campbell, 1973;Breese et al., 1974b) and to increase rates of responding on a variable-interval schedule of reinforcement (Green and Harvey, 1974) are also influenced by central serotonergic fibers. In these latter studies, reduction of brain serotonin caused a marked enhancement of the stimulant properties of d-amphetamine, suggesting an inhibitory influence of serotonergic pathways. These findings subsequently led to the proposal ...

[3H]Threo‐(±)‐Methylphenidate Binding to 3,4‐Dihydroxyphenylethylamine Uptake Sites in Corpus Striatum: Correlation with the Stimulant Properties of Ritalinic Acid Esters

“…3) localization of [3H]methylphenidate binding, further support the contention that [3H]methylphenidate labels a component of a dopamine transport complex, analogous to the transport complexes described for serotonin and norepinephrine that have been described with [3H]imipramine and desipramine, respectively (see Paul et al, 198417 for review). This hypothesis is consistent with previous studies on the mechanism of action of methylphenidate demonstrating that this compound is effective in releasing and/or blocking the presynaptic uptake of catecholamines (Chiueh and Moore, 1975;Breese et al, 1975) and is further supported by the recent observation that a parallel loss in [3H]dopamine uptake and [3H]methylphenidate binding sites is observed following either electrolytic lesions of the medial forebrain bundle or intracerebroventricular injection of 6-hydroxydopamine (Janowsky et al, 1985).…”

Methylphenidate in 6-Hydroxydopamine-Treated Developing Rat Pups

“…Thus, reduction of serotonin by administration of parachlorphenylalanine produced a signifi¬ cant increase in methylphenidateinduced activity; administration of the serotonin precursor 5-hydroxytryptophan effectively antagonized this potentiation. 27 Although Gauron and Rowley32 had examined the effects of methylpheni¬ date at two different ages (47 and 87 days) in mature animals, no previous investigation has explored the effects of this stimulant in developing rats. Our findings indicate that methyl¬ phenidate produces significantly dif¬ ferent age-related effects on activity in normal developing rat pups.…”

α1 (but not α2)‐Adrenoceptor Agonists in Combination with the Dopamine D2 Agonist Quinpirole Produce Locomotor Stimulation in Dopamine‐Depleted Mice

“…Furthermore, amphetamine-inducd stereotypy is potentiated by DA P-hydroxylase inhibi-*To whom correspondance should be directed. tors such as disulfiram in cats (Ellinwood et al 1974) and diethyldithiocarbamate in mice (Randrup & Scheel-Kriiger 1966), while the DA P-hydroxylase inhibitor U14624 potentiated the stimulant effects of the catecholamine releasing agent methylphenidate in rats (Breese et al 1975). These studies suggested that blockade of NA synthesis removes an inhibitory input thereby potentiating amphetamine and methylphenidate-induced behaviours.…”