Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior

doi:10.1016/0006-2952(86)90148-6

Biochemical Pharmacology

Volume 35, Issue 7, 1 April 1986, Pages 1123-1129

https://doi.org/10.1016/0006-2952(86)90148-6 Get rights and content

Abstract

We report here saturation analysis of [³H]cocaine binding in various mouse brain regions, and the necessary structure-activity relationships for cocaine congeners to inhibit Na⁺-dependent [³h]-cocaine binding and [³H]dopamine uptake in the mouse striatum, and to inhibit [³H]cocaine binding that cannot be stimulated by Na⁺ and [³H]serotonin uptake in the mouse cerebral cortex. Generally similar structure-activity relationships were noted for all these processes. The ester linkage between the tropane and phenyl rings was not required for activity, in contrast to the configuration of the groups on C₂, and to a lesser extent C₃, in the tropane ring. Stereospecificity was evident from the differences between cocaine and (+)-pseudococaine, and between WIN 35,065-2 and WIN 35,065-3. There were remarkable differences between the above structure-activity relationships and those for local anesthetic activity of cocaine congeners, indicating that sodium channels were not labeled to a measurable extent with [³H]-cocaine under the present conditions. Preliminary data indicated a significant correlation between the potencies of cocaine congeners in inhibiting the Na⁺-dependent binding of [³H]cocaine and their potencies in inducing stereotyped sniffing upon intraventricular administration.

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Citation Excerpt :
According to this biochemical effect and in agreement with our findings, an increase of DA tissue levels was demonstrated in NAcc after acute injection of cocaine with a concomitant decrease either in DA metabolites or in DA turnover. DOPAC decrease is likely a direct result of the DA reuptake blockage by cocaine (Reith et al., 1986) since DAT blockage would limit the access of DA to monoamine oxidase located primarily in presynaptic terminals (Kalivas et al., 1988). Moreover, DA can also be reuptaken by glial cells.
Coca-paste (CP), an illicit drug of abuse, has been frequently associated with aggressive and impulsive behaviors in humans. However, preclinical studies have not been carried out in order to characterize CP effects on aggression. The acute effect of CP, cocaine and caffeine (the main adulterant present in seized samples) on aggression was assessed using the isolation-induced aggression paradigm in male rats. The dopaminergic (DA) neurotransmission in the nucleus accumbens (NAcc) and serotonergic (5-HT) activity in the frontal cortex were explored.
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Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior

Abstract

Life Sci.

Eur. J. Pharmac.

Eur. J. Pharmac.

Neuropharmacology

Analyt. Biochem.

J. Neurosci. Meth.

Brain Res. Rev.

Neuropharmacology

Life Sci.

Life Sci.

Biochem. Pharmac.

Brain Res.