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

Abstract

Abstract. 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-cc-methyl-tyrosine (a-MPT), 6-hydroxydopamine (6-OHDA), or the dopamine-fl-hydroxylase inhibitor 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624). In animals pretreated with reserpine, amphetamine-stimulated locomotor activity was blocked by ~-MPT but not by U-14,624 when amphetamine was given 1 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 norepinepbrine 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.

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

“…Since blockade of norepinephrine synthesis with U-14,624 in the reserpinized rats did not decrease methylphenidate-induced motor activity, it would appear that the locomotor stimulation induced by methylphenidate is dependent upon an intact dopaminergic mechanism. Although a similar conclusion has been reached concerning d-amphetamine-induced locomotor activity (Thornburg and Moore, 1973;Hollister et al, 1974), the mechanism of action of methylphenidate would appear to differ from that of d-amphetamine in that methylphenidate stimulation is not antagonized by α-methyltyrosine unless reserpine is present (see Thornburg and Moore, 1973;Franklin and Herberg, 1974).This study also provides evidence for an involvement of serotonergic fibers in the action of methylphenidate. Similar to reports that reduction of serotonin in brain will enhance locomotor activity induced by d-amphetamine (Neill et al, 1972;Mabry and Campbell, 1973; Breese et al., 1974a, b), methylphenidate hyperactivity was found to be potentiated following reduction of brain serotonin with PCPA or 5,7-DHT.…”

“…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.…”

SCH-23390 antagonism of a D-2 dopamine agonist depends upon catecholaminergic neurons

“…However, like LY-171555, behavior mediated by these compounds are also potentiated by 6-OHDA treatment (Hollister et al, 1979;Kilts et al, 1979). Thus these dopamine agonists are unlike d-amphetamine which has its locomotor stimulant action blocked by 6-OHDA-treatment (Hollister et al, 1974), suggesting a different underlying neural mechanism from that induced by d-amphetamine. Whether the pharmacological profile of LY-171555 is in some way linked to the pharmacology of SCH-23390 is at present unknown.…”

“…Since binding of [ 3 H]-flupentixol and [ 3 H]SCH-23390 is not altered in striatum of 6-OHDA-treated rats (Breese et al, 1985; unpublished data), it does not appear that removal of D-1 receptor sites is responsible for the loss of action of SCH-23390 against a D-2 agonist in 6-OHDA-treated rats (Breese et al, 1985;unpublished data). For this reason, an additional experiment was undertaken to determine whether disruption of catecholamine-containing neural function with reserpine and α-methyltyrosine would have an effect similar to 6-OHDA-treatment Hollister et al, 1974). In this study, the response to LY-171555 was not antagonized by SCH-23390 in the rats treated with reserpine, as was accomplished by haloperidol administration.…”

“…Locomotor activity was measured in circular activity monitors with six sensors about the periphery of the doughnut shaped units (Hollister et al, 1974). Rats were habituated to the chambers for 1 h before receiving dopamine agonists.…”