DOPAMINE RELEASE INDUCED BY 4-METHYLAMINOREX

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The novel stimulant drug 4-methylaminorex (4-MAX;2-amino-4-methyl-5- phenyloxazoline; street name "U4Euh" has recently gained attention as a drug of abuse. Drug users have described the subjective effects of 4- MAX to be like those of amphetamine and cocaine, and 4-MAX is self- administered by monkeys in a manner similar to cocaine. IN fact, on the clandestine market, 4-MAX is often misrepresented by drug dealers as cocaine or amphetamine. Illegally manufactured 4-MAX has been confiscated by authorities in Florida, California and pennsylvania. Due to the high potential for abuse of this substance, the cis isomer of 4- MAX was assigned to the schedule 1 drug category of the Controlled Substances Act in October, 1987. Authorities fear that the ease of synthesis of this compound and the accessibility of precursors will lead to more widespread abuse of 4-MAX. Nonetheless, very little is known about its pharmacological actions on the central nervous system. The limited data available suggest that 4-MAX has stimulant, anorectic and sympathomimetic properties similar to those of the well characterized stimulant amphetamine. Amphetamine primarily exerts its effects via its action on brain dopamine and norepinephrine systems. The scant existing biochemical and behavioral data available on 4-MAX are also consistent with the hypothesis that 4-MAX produces its effects by interacting with brain dopamine systems. 4 Max exists in four isomeric forms which vary in potency. The overall goal of this proposal is to examine the ability of the our isomers of 4-MAX to induce the release of the neurotransmitter dopamine from selected forebrain structures in the awake freely moving rat. The samples will be collected by microdialysis technique, and dopamine content in the samples will be quantitatively analyzed by high performance liquid chromatography (HPLC). Midbrain dopamine neurons in the ventral tegmental area (A10) have different biochemical and physiological characteristics than dopamine neurons found in the adjacent substantia nigra region (A9). Hence, dopamine release will be examined in several different forebrain areas which are selectively innervated by only one of these two populations of dopamine neurons. This is important since, unlike amphetamine, preliminary data indicate that 4-MAX has a differential effect on the electrical discharge activity of these two populations of dopamine neurons. In selected experiments observations of stimulant-induced behavioral changes will be correlated with simultaneous measures of dopamine release. In addition, the mechanism by which 4-MAX induces the release of dopamine will be examined. In all of the proposed studies the effects of 4-MAX will be compared to the effects of the prototypical stimulant amphetamine. Our approach should yield important data about the action of the isomers of 4-MAX on dopamine-containing neurons in the brain, which will help us to understand the mode of action of 4-MAX.