MK-801 at doses < 100 μg/kg given orally induced an ipsilaterally directed directed rotational response in rats with a unilateral nigrostriatal lesion produced by 6-hydroxydopamine. (+)-Amphetamine, amfonelic acid, and methylphenidate also evoked ipsilateral turning with their dose-response lines lying considerably to the right of that for MK-801. Rotations caused by a standard test dose of 50 μg/kg of MK-801 were reduced by pretreatment with haloperidol (ED50 = 0.068 mg/kg IP), clozapine (ED50 = 3.35 mg/kg IP), or prazosin (ED50 = 0.15 mg/kg SC). MK-801-induced turning was also inhibited by pretreatment with α-methyl-p-tyrosine (α-MPT) and blocked by reserpine.



Locomotor activity in mice was increased by MK-801, amfonelic acid, (+)-amphetamine, and methylphenidate. Following administration p.o., MK-801 was the most potent in this regard and methylphenidate the least. Stimulation of locomotor activity by equivalent doses of the four compounds was differentially affected by pretreatment with α-MPT or reserpine, Reserpinization abolished the increase in activity usually produced by MK-801, amfonelic acid and methylphenidate, whereas (+)-amphetamine was only partially (36%) inhibited. Locomotor stimulation by (+)-amphetamine was, on the other hand, markedly reduced in α-MPT-pretreated mice, while the actions of the other three compounds were not singnificantly altered. The ability of all four compounds to increase motor activity was significantly antagonized by haloperidol, but prazosin at the dose (3 mg/kg SC) examined was an effective antagonist of only MK-801 and (+)-amphetamine.



MK-801 has effects in rodents resembling indirect-acting central sympathomimetic substances such as amfonelic acid, (+)-amphetamine, and methylphenidate. The central sympathomimetic actions of MK-801 are mediated via catecholamine-dependent processes. Results from the drug-interaction studies in mice (locomotor activity) indicate that the precise mechanism of action of MK-801 differs from that of the other three compounds.

Central sympathomimetic activity of (+)-5-methyl-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine(MK-801), a substance with potent anticonvulsant, central sympathomimetic and apparent anxiolytic properties

Microvoltammetric electrodes were used to monitor dopamine released in the caudate nucleus of the rat after electrical stimulation of the medial forebrain bundle. The time resolution of the technique is sufficient to determine in vivo concentration changes on a time scale of seconds. Direct evidence identifying the substance released as dopamine was obtained both voltammetrically and pharmacologically. Administration of alpha-methyl-p-tyrosine terminates the release of dopamine, although tissue stores of dopamine are still present. Thus there appears to be a compartment for dopamine storage that is not available for immediate release. This compartment appears to be mobilized by amfonelic acid, since administration of this agent after alpha-methyl-p-tyrosine returns the concentration of dopamine released by electrical stimulation to 75 percent of the original amount.

http://science.sciencemag.org/content/sci/221/4606/169.full.pdf

Direct in vivo monitoring of dopamine released from two striatal compartments in the rat

Central α1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals

polyphoretin PPP, a PG antagonist, also enhanced the responses about 15 to 30% and did not show any antagonistic effects. The doses of indomethacin and PPP used here markedly inhibited the relaxation induced by 10 pg ml-l ATP in the presence of histamine, 10 p ~ , as described in our previous paper. From these results, it is apparent that the non-adrenergic inhibitory response to field stimulation and the response to ATP of guinea-pig tracheal muscle are different with respect to their pharmacological characteristics. We conclude that the transmitter substance of non-adrenergic inhibitory neurons is neither ATP nor PGs. The enhancement of the inhibitory response by indomethacin and PPP may be caused by inhibition of the PG-mediated negative feedback control of adrenergic neurotransmission (Hedqvist, 1973). We wish to thank Dr B. Fredholm, AB Leo, Helsingborg, for supplying PPP. March 11, 1976

Actions of amfonelic acid and other non-amphetamine stimulants on the dopamine neuron.

Amphetamine has well-established actions on pre-synaptic dopamine signaling, such as inhibiting uptake and degradation, activating synthesis, depleting vesicular stores, and promoting dopamine-transporter reversal and non-exocytotic release. Recent in vivo studies have identified an additional mechanism: augmenting vesicular release. In this study, we investigated how amphetamine elicits this effect. Our hypothesis was that amphetamine enhances vesicular dopamine release in dorsal and ventral striata by differentially targeting dopamine synthesis and degradation. In urethane-anesthetized rats, we employed voltammetry to monitor dopamine, electrical stimulation to deplete stores or assess vesicular release and uptake, and pharmacology to isolate degradation and synthesis. While amphetamine increased electrically evoked dopamine levels, inhibited uptake, and up-regulated vesicular release in both striatal sub-regions in controls, this psychostimulant elicited region-specific effects on evoked levels and vesicular release but not uptake in drug treatments. Evoked levels better correlated with vesicular release compared with uptake, supporting enhanced vesicular release as an important amphetamine mechanism. Taken together, these results suggested that amphetamine enhances vesicular release in the dorsal striatum by activating dopamine synthesis and inhibiting dopamine degradation, but targeting an alternative mechanism in the ventral striatum. Region-distinct activation of vesicular dopamine release highlights complex cellular actions of amphetamine and may have implications for its behavioral effects.

/pdf/amphetamine-augments-vesicular-dopamine-release-in-the-265km71q0h.pdf

Martin R

Papers

Pharmacologic properties and mechanism of action of amfonelic acid.