Outflow and overflow of picogram levels of endogenous dopamine and DOPAC from rat striatal slices: improved methodology for studies of stimulus-evoked release and metabolism.

An improved method for the rapid and sensitive determination of endogenous dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in superfusates of single rat striatal slices, using high-performance liquid chromatography (HPLC) coupled with 'coulometric' electrochemical detection (EC), is described. Superfusates are directly injected into an HPLC-EC system following addition of a small aliquot of solubilized ascorbate-oxidase. DA and DOPAC are both separated and quantitated in 3-5 min.

Evidence for antiserotonergic properties of yohimbine.

Yohimbine (YOH) is a widely used pharmacological tool employed to produce a selective blockade of alpha 2-adrenergic receptors. In the present study operant behavior was used as a biobehavioral assay to determine the activity of YOH at serotonergic receptors, as indicated by its ability to antagonize the behavioral effects of a serotonergic agonist, lysergic acid diethylamide (LSD). Rats were trained to respond on a Fixed Ratio 15 schedule for food reinforcement.

Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide.

Groups of rats administered cocaine-HC1 (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose.

Sensitization to cocaine in the nigrostriatal dopamine system.

Behavioral sensitization involving the nigrostriatal dopaminergic tract is manifested after treatment with only a single dose of cocaine and is augmented following repeated treatment. One neurochemical change observed that is consistent with behavioral sensitization is the increase in amphetamine-induced 3H-DA release from striatal slices seen after one injection of cocaine. One day after repeated administration of cocaine, however, the increase is no longer evident.

Biphasic modulation of evoked [3H]D-aspartate release by D-2 dopamine receptors in rat striatal slices.

It has been hypothesized that dopamine (DA) inhibits glutamate release from corticostriatal fibers via presynaptically located D-2 DA receptors although the evidence presented in the literature has not been conclusive. In the present experiments, the effect of D-2 receptor ligands on K+-stimulated tritium release from rat striatal slices preloaded with the nonmetabolizable glutamate analog [3H]D-aspartate ([3H]ASP was measured. The D-2 receptor antagonist S-sulpiride increased stimulated [3H]ASP release by 75% (EC50 value = 240 nM) and the biologically less-active isomer R-sulpiride, although equally effective, was tenfold less potent.

Robust modulation of [3H]dopamine release from rat striatal slices by D-2 dopamine receptors.

Conflicting results have been reported for D-2 dopamine (DA) receptor modulation of DA release from rat striatal slices. After systematic examination of the assay conditions used to evoke release of [3H]DA, we report robust modulation of calcium-dependent stimulation-evoked 3H-overflow by D-2 receptors in rat striatal slices preloaded with [3H]DA. In the presence of the DA uptake inhibitor, nomifensine, the amount of 3H-overflow evoked by low numbers (15-30) of pulses was not dependent on the frequency of stimulation (0.

Studies on the specificity of neurochemical and behavioral effects of LSD-25.

Brain perfusion experiments of conscious rats engaged in operant behavior and administered fluoxetine or LSD, with or without prior injection of 5-HTP, indicate there is probably more than one functional pool of 5-HT in the CNS. Furthermore, the fact that prior loading with the precursor is necessary before unmasking an effect of LSD suggests the LSD-sensitive pool is newly synthesized and represents only a small fraction of total CNS serotonin. Separating the effects of LSD's behavioral action into pausing (disruption) and depressed responding rate, with or without pausing, enabled us to demonstrate blockade of the disruption by methysergide without blockade of the decreased responding rate.

Pharmacological evidence for the existence of multiple functional pools of brain serotonin: analysis of brain perfusate from conscious rats.

The serotonin reuptake inhibitor fluoxetine significantly reduced levels of endogenous 5-hydroxyindoleacetic acid (5-HIAA) in brain perfusate of rats implanted with push-pull cannulas. This occurred in conjunction with its suppressant effect upon fixed-ratio operant behavior. Behavior suppressed with the serotonin agonist lysergic acid diethylamide (LSD) occurred in conjunction with a reduction of 5-HIAA only after 5-HIAA was elevated, shortly before, by 5 mg/kg of the serotonin precursor 5-hydroxytryptophan.

Yohimbine exacerbates and clonidine attenuates acute morphine withdrawal in rats.

The involvement of alpha 2-noradrenergic receptors in the expression of opiate withdrawal was studied using an operant behavioral model of acute morphine dependence. Clonidine, an alpha 2-agonist, attenuated and yohimbine, an alpha 2-antagonist, exacerbated the naloxone-induced suppression of fixed ratio 15 responding in rats pretreated several hours earlier with a single, moderate dose of morphine. These data indicate that the alpha 2-agonist action of clonidine is responsible for its amelioration of withdrawal symptoms.

Behaviorally inactive doses of mianserin antagonize the suppressant effect of lysergic acid diethylamide on a fixed-ratio operant.

Male Sprague-Dawley rats were trained to respond for food reinforcement on a fixed-ratio 15 schedule. Low, behaviorally inactive, doses of mianserin (0.1-1.

Synthesis and turnover of 3H-5-hydroxytryptamine in the later cerebroventricle.

The lateral cerebroventricle was perfused using two different labelling procedures in three separate experiments on 5-hydroxytryptamine metabolism. The sensitivity of 5-hydroxytryptamine metabolism to various drugs was subsequently determined. The results demonstrate that two serotonin reuptake blockers, imipramine and fluoxetine, increase the efflux of 3h-5-hydroxytryptamine into the ventricle without affecting the efflux of 3H-5-hydroxyindoleacetic acid.