Patricia K. Sonsalla

Methamphetamine‐Induced Depression of Monoamine Synthesis in the Rat: Development of Tolerance

Abstract: Animals treated with high doses of amphetamines have been used as a model of schizophrenia due to the similarities between the psychosis associated with this mental disorder and that induced by chronic amphetamine abuse. When administered to naive rats in high doses, the amphetamine‐like CNS stimulant methamphet‐amine produces drastic alterations in the neurochemical parameters of the neostriatal monoaminergic systems. These alterations are characterized by a decrease in the activities of the rate‐limiting enzymes for dopamine and serotonin synthesis, as well as a decrease in the concentrations of both neurotransmitters and their metabolites. However, tolerance develops to these neurochemical effects when drug administration occurs in a pattern similar to that encountered during chronic amphetamine abuse. The results indicate that the neurochemical alterations produced by amphetamines in naive and tolerant animals differ widely. This suggests that the administration of high doses of amphetamine‐like central stimulants to naive rats may not be an appropriate model for studying the neurochemical changes associated with psychosis and amphetamine abuse.

Studies on the mechanism of tolerance to methamphetamine

We have reported that the ability of high doses of methamphetamine to impair dopamine and serotonin synthesis in the rat brain is attenuated when animals are pretreated with gradually increasing doses of methamphetamine. To examine the mechanism of this tolerance phenomenon, the effect of methamphetamine on several neurochemical parameters was determined in naive and methamphetamine-pretreated rats. The elevation of nigral substance P concentrations by methamphetamine was attenuated in pretreated compared to naive rats. The methamphetamine-induced reduction in [3H]sulpiride binding in the rat neostriatum and nucleus accumbens was similarly attenuated in animals pretreated with methamphetamine. Determination of brain concentrations of methamphetamine and amphetamine revealed significantly lower concentrations of both compounds in the brains of pretreated compared to naive animals. The results indicate a reduction in the ability of methamphetamine to increase dopamine transmission in the brains of methamphetamine-pretreated rats. Furthermore, this effect appears to be due, at least in part, to a change in the disposition of methamphetamine in pretreated animals.

Nigrostriatal dopamine actions on the D2 receptors mediate methamphetamine effects on the striatonigral substance P system.

Multiple administrations of methamphetamine to rats produced elevated concentrations of substance P-like immunoreactivity within the substantia nigra, an effect which is believed to be mediated by increases in dopaminergic activity induced by methamphetamine. The results reported here demonstrate that the effect of methamphetamine is mediated specifically by the dopamine pathway in the nigrostriatum. Thus, extensive destruction of dopamine neurons in the nigrostriatum by lesions induced by 6-hydroxydopamine or blockade of synthesis of dopamine with alpha-methyl-p-tyrosine prevented the increases in substance P-like immunoreactivity in the nigra, induced by methamphetamine. Similarly, the concurrent administration of the D2 receptor antagonist, sulpiride, also prevented the effects of methamphetamine on substance P-like immunoreactivity in a dose-dependent way. In addition, multiple administrations of the D2 agonist, RU24926, elevated, whereas the DI agonist, SKF38393, decreased the content of substance P-like immunoreactivity in the nigra. The effects of methamphetamine were not altered in rats with lesions induced by 5,7-dihydroxytryptamine. Thus, these findings suggest that the effect of methamphetamine on the striatonigral substance P pathway is mediated by nigrostriatal dopaminergic actions on D2 receptors.

An Evaluation of the EMIT®st Assay for the Detection of Tricyclic Antidepressant Drugs in Plasma or Serum

The EMIT st assay for tricyclic antidepressant drugs (TADs) was evaluated for use as a screening technique in the detection of these drugs in serum or plasma. The qualitative assay was found to be rapid, easy to perform, requires no sample or reagent preparations, and reliably detected the TADs in patient samples at concentrations greater than or equal to 200 ng/mL. The technique also detected seventeen of nineteen patient samples with TAD concentrations ranging from 150-199 ng/mL and ten of forty-three samples with concentrations less than 150 ng/mL. The EMIT st assay was found to be a reliable technique for detecting high concentrations of TADs and is well-suited for use in emergency drug screening situations.