Comparison of responses by striatonigral substance P and neurokinin A systems to methamphetamine treatment.

Multiple administrations of high doses of methamphetamine (METH) previously have been shown to significantly elevate the concentrations of substance P-like immunoreactivity in CNS regions associated with the basal ganglia. Recently, another tachykinin, neurokinin A (NKA), has been found to be closely associated with substance P (SP). While both neuropeptides exert comparable effects when locally injected, there are significant differences in their potencies apparently based on the relative concentrations of their unique receptors. Due to the controversy which has arisen as to their respective roles within the basal ganglia, we have evaluated and compared the responses of the striatal and nigral SP and NKA systems to METH treatment. We observed that multiple high doses of this stimulant increased the nigral and striatal concentrations of both neuropeptides in an identical fashion. Our observation that METH treatment did not alter the relative concentrations of SP and NKA suggests that responses of both transmitter systems, associated with the basal ganglia, parallel each other and are sensitive to the same regulatory mechanisms.

Characterization of dopaminergic influence on striatal-nigral neurotensin systems.

Dopamine depletion by treatment with alpha-methyl-p-tyrosine had no effect on methamphetamine-mediated increases in striatal neurotensin (NT) concentrations but significantly attenuated nigral increases; the attenuation in the nigral response was reversed by L-DOPA. Blockade of D2-receptors, with sulpiride, by itself increased striatal NT levels, while having no effect on the nigral NT system or its response to methamphetamine. In contrast, D1 blockade with SCH 23390 had no effect of its own on NT levels but significantly blocked the methamphetamine-induced actions in both the striatal and nigral NT systems.

Characterization of methamphetamine effects on the striatal-nigral dynorphin system.

Multiple high doses of methamphetamine (METH) induced 200-300% increases in the concentration of striatal and nigral dynorphin-like immunoreactivity (DLI). Increases in striatal and nigral DLI levels also were seen within 6 h following a single administration. The changes in the striatal-nigral dynorphin system had subsided 48 h after either acute or multiple treatments with METH. Selective lesioning of the nigral-striatal dopamine pathway blocked the effects; thus, the METH-induced changes appeared to be mediated by dopamine released from the nigral-striatal dopamine projection. Administration of the METH analog, 3,4-methylenedioxymethamphetamine, appeared to alter striatal and nigral DLI concentrations in a manner similar to that of METH.

Changes in the limbic neurotensin systems induced by dopaminergic drugs.

Single or multiple high doses of the dopamine-releasing drug, methamphetamine, induced 100-150% increases in the content of neurotensin-like immunoreactivity (NTLI) in the nucleus accumbens, but was without effect on the NTLI level in the ventral tegmental area. The increases in NTLI content in the nucleus accumbens were selectively blocked by the dopamine D-1 receptor antagonist, SCH 23390, which failed to exert any significant effect of its own in the same area. In contrast, haloperidol or the selective dopamine D-2 antagonist, sulpiride, when administered alone, significantly raised the NTLI level in the nucleus accumbens and when given concomitantly with methamphetamine, their effects on the amount of NTLI appeared to be additive. Very different patterns of response were observed in neurotensin systems associated with the mesocortical dopaminergic terminal fields of the frontal cortex and olfactory bulbs. Changes in NTLI contents occurred following only multiple doses of methamphetamine and consisted of decreases in levels of this peptide. However, like the nucleus accumbens, these methamphetamine-induced alterations were blocked completely by D-1 antagonism, while D-2 blockade appeared to be additive with the effects of methamphetamine.

Effects of amphetamine analogs on neurotensin concentrations in rat brain.

The present study investigates the effects of amphetamine-like analogs on neurotensin systems and compares the same to those of methamphetamine. Like methamphetamine, multiple high doses of each of the analogs examined significantly increased the concentrations of neurotensin-like immunoreactivity in the striatum, substantia nigra and nucleus accumbens; these effects were reversible and specific. The changes in the neurotensin systems developed rapidly and were evident within 6 h following a single administration of two of the analogs studied.

Effect of methamphetamine on neurotensin concentrations in rat brain regions.

High doses of methamphetamine (METH) induced 200 to 300% increases in the neurotensin-like immunoreactivity (NTLI) concentrations of the substantia nigra and striatum in rats after a single or multiple drug doses; smaller but significant increases of 30 to 50% were observed in the hypothalamus and hippocampus after multiple, but not single, METH administrations whereas no measurable changes were detected in the NTLI levels of the periaqueductal gray area or the amygdala. These METH-induced increases in NTLI concentrations were attenuated by coadministration of haloperidol in the substantia nigra, hypothalamus and hippocampus, indicating a possible involvement of dopamine receptors in these tissues. In the striatum haloperidol alone produced significant increases in NTLI levels; these increases were additive with those induced by METH treatment demonstrating that the neurotensin pathways associated with the striatum are regulated differently from that of the other brain areas examined. The implications of these findings to the relationship between dopamine and neurotensin transmitter systems are discussed.

Role of the 5-HT2 receptor in the methamphetamine-induced neurochemical alterations.

The possibility that serotonin (5-HT) modulates dopamine (DA) synthesis by acting at 5-HT2 receptor sites during methamphetamine (METH) treatment was investigated. The neostriatal accumulation of 3,4-dihydroxyphenylalanine was not altered by ritanserin (1 mg/kg i.p.), a 5-HT2/1c receptor antagonist, or by METH (15 or 25 mg/kg s.c.), which indicates that METH-induced DA and 5-HT release did not invoke increased DA synthesis. Interestingly, the combined treatment of METH with ritanserin reduced 3,4-dihydroxyphenylalanine formation. We also examined the possibility that 5-HT2 receptors participate in the mechanism by which METH alters central tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities as well as the concentration of neurotensin-like and substance P-like immunoreactivity. Five administrations of METH given at 6-hr intervals reduced neostriatal TH and TPH activity to 27 and 13% of control, respectively, 18 to 20 hr after the last drug administration; ritanserin failed to alter these decreases significantly. Ritanserin also failed to alter the METH-induced increase in neostriatal neurotensin-like immunoreactivity or in nigral neurotensin-like immunoreactivity and substance P-like immunoreactivity. Finally, the administration of ICS 205-930, a 5-HT3/4 receptor antagonist, also failed to prevent the METH-induced decrease in TH and TPH activities at doses below 200 micrograms/kg, whereas a dose of 500 micrograms/kg potentiated the effect of METH. These results suggest that 5-HT2 does not modulate DA synthesis nor does it mediate the changes in central TH and TPH activity, or neurotensin-like immunoreactivity and substance P-like immunoreactivity content induced by METH. Because 3,4-methylenedioxymethamphetamine is reported to stimulate DA synthesis by a 5-HT2 receptor-dependent mechanism, these observations suggest that METH and 3,4-methylenedioxymethamphetamine regulate the central dopaminergic system in a different manner.

Effects of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine isomers on central serotonergic, dopaminergic and nigral neurotensin systems of the rat.

This study demonstrates that the isomers of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) are different in their ability to induce changes in serotonergic parameters and nigral concentrations of neurotensin-like immunoreactivity. With five successive doses (3.5 mg/kg) the d-MDA isomer was more potent than the l-MDA in its ability to decrease the concentrations of serotonin in the frontal cortex and hippocampus. The same difference occurred in the ability to decrease the hippocampal activity of tryptophan hydroxylase as well as the hippocampal and neostriatal 5-hydroxyindoleacetic acid concentrations. However, both isomers of MDMA were equipotent in their ability to decrease serotonergic parameters in the brain areas examined. When the doses were increased to 5 and 10 mg/kg, both isomers of MDA were equipotent in their effects on the serotonin system, whereas the l-MDMA was significantly less potent than its d isomeric counterpart in causing a decrease in serotonergic parameters of the different brain areas. In contrast, treatments with any of the isomers appeared to have a minimal impact on neostriatal dopaminergic parameters. However, treatment with MDA or MDMA caused increases in the nigral concentrations of neurotensin, with the d isomer of both compounds having substantially greater effects on this neuropeptide system. These increases are suspected to result from drug-released dopamine. This study demonstrates that at selected doses, the d isomers of MDA and MDMA are more potent than their l forms in affecting neurochemical systems, whereas high doses of either isomer of MDA share a common ability to induce changes in the serotonergic system that are likely associated with neuronal damage.