C. D. Kilts

Simultaneous quantification of dopamine, 5-hydroxytryptaine and four metabolically related compounds by means of reversed-phase high-performance liquid chromatography with electrochemical detection

A method for simultaneously quantifying dopamine, 5-hydroxytryptamine (5-HT) and four metabolically related compounds has been developed, permitting more efficient neurochemical examination of these often interrelated biogenic amine systems. The method uses high-performance liquid chromatographic separation of these compounds on a C18 reversed-phase column with a buffered mobile phase containing methanol as an organic modifier and heptanesulfonate as an ion-pair reagent. Using 5-hydroxy-N-methyltryptamine as an internal standard and electrochemical detection, chromatography time is less than 12 min. Sample preparation simply involves the addition of internal standard, homogenization in the mobile phase, centrifugation and injection of the supernatant into the chromatograph. The method is sensitive to a tissue content of these compounds of less than 1 ng. The utility of this method for neuropharmacological--neurochemical studies is illustrated with studies using inhibitors of monoamine oxidase (pargyline) and aromatic amino acid decarboxylase (RO 4-4602).

Behavioral and biochemical studies of the scopolamine-induced reversal of neuroleptic activity.

Scopolamine reversed the reduction in avoidance responding caused by spiperone and antagonized the inhibitory effects of spiperone on the behavioral actions of d-amphetamine or apomorphine. Scopolamine-induced locomotor activity was greater in 6-hydroxydopamine (6-OHDA)-treated animals than in controls. This increase was prevented by administration of α-methyltyrosine, but not by inhibition of dopamine-β-hydroxylase, indicating that this action of scopolamine was associated with presynaptic dopaminergic fibers. Therefore, the possibility that pre-synaptic dopaminergic function was the locus of the antagonism of spiperone by scopolamine was examined using drug interaction studies in 6-OHDA-treated rats. However, when 6-OHDA-treated rats were given α-methyltyrosine, scopolamine still reversed the spiperone blockade of apomorphine-induced locomotion. Although these data provided evidence for a post-synaptic action for this cholinergic blocking agent, scopolamine affected neither dopamine-stimulated adenylate cyclase activity nor 3H-spiperone binding in vitro. Furthermore, scopolamine did not alter the level of specific 3H-spiperone binding found in brain after in vivo administration. This suggests that the postsynaptic mechanism affected by scopolamine is different from the site affected by spiperone. Thus, it is concluded that scopolamine can affect both pre- or post-synaptic events associated with dopaminergic function and that both may contribute to the reversal of the actions of spiperone.

Animal models related to developmental disorders: Theoretical and pharmacological analyses

Abstract One consequence of rapid advances in the neurosciences has been the use of animal models of developmental disorders. Three general approaches to the establishment of such models were discussed with particular reference to hyperkinesis. We concluded that, despite the employment of sophisticated physiological techniques, animal models suffer from a number of conceptual and empirical weaknesses, and have yet to offer major pragmatic gains. Careful intercalation of complementary preclinical studies and carefully controlled clinical investigations would seem the most promising approach.