Michel Johnson

A comparison of the neurotoxic potential of methylenedioxyamphetamine (MDA) and its N-methylated and N-ethylated derivatives

Three psychoactive amphetamine congeners were evaluated for their ability to cause long-term changes in several neurochemical parameters indicative of central serotonergic function. Two weeks after multiple doses (10 mg/kg) of 3,4-methylenedioxyamphetamine (MDA) or its N-methylated derivative, 3,4-methylenedioxymethamphetamine (MDMA), selective and dramatic decreases were observed in regional brain tryptophan hydroxylase (TPH) activities, and in corresponding concentrations of 5-hydroxytryptamine (5-HT) and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA). However, the N-ethylated derivative of MDA, N-ethyl-3,4-methylenedioxyamphetamine (MDE), was much less potent in its ability to lower brain hydroxyindoles, and in most regions examined did not significantly affect TPH activity. The neurotoxic implications of these results are discussed.

Effect of MK-801 on the decrease in tryptophan hydroxylase induced by methamphetamine and its methylenedioxy analog

The role of N-methyl-D-aspartate (NMDA) receptors in the decrease in neostriatal tryptophan hydroxylase (TPH) activity induced by repeated high doses of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received 4 injections of methamphetamine (15 mg/kg) or MDMA (10 mg/kg) at 6 h intervals, and were killed 18-20 h after the last administration. These treatments with methamphetamine or MDMA reduced neostriatal TPH activity to 26 and 34% of control, respectively. Coadministration of MK-801 (2.5 mg/kg) significantly attenuated the methamphetamine-induced decrease in TPH activity (66% of control), but did not alter the effect of MDMA. This study suggests that excitatory amino acids may participate in the methamphetamine-induced decline in central TPH activity, and that the mechanism by which MDMA and methamphetamine decreases TPH activity may differ.

Response by the neurotensin systems of the basal ganglia to cocaine treatment

Multiple administrations of high doses of cocaine had profound effects on the neurotensin (NT) systems of the basal ganglia. Approximately 200-300% increases in striatal content of neurotensin-like immunoreactivity (NTLI) were observed 1-8 h following five doses of 30 mg/kg per dose of cocaine. The effect subsided by 48 h after treatment. Significant changes in striatal NTLI levels were not observed after a single dose of this stimulant. The nigral NT systems appeared to be even more sensitive to cocaine administration. Compared to striatal changes, increases in nigral NTLI content were greater (as much as 455% of control), required lower cocaine doses (20 mg/kg per dose), lasted longer (still elevated to 200% of control after 48 h) and were significant following a single cocaine exposure. The response of the striatal NT systems to cocaine appeared to be mediated principally by dopamine D-1 receptors, while both D-1 and D-2 receptors contributed to the response by the nigral NT projections. Specific dopamine, but not serotonin, uptake blockers caused increases in striatal and nigral NTLI concentrations similar to that seen with cocaine treatments, suggesting that interference with the dopamine uptake carrier complex by cocaine was responsible for its actions on extrapyramidal NT systems.

Role of the dopaminergic nigrostriatal pathway in methamphetamine-induced depression of the neostriatal serotonergic system

The prevention of the decrease in neostriatal tryptophan hydroxylase (TPH) activity with a single dose of methamphetamine (MA) was attempted by lesioning the nigrostriatal dopaminergic projections with bilateral nigral injections of 6-hydroxydopamine (6-OHDA). The rats were injected with MA (10 mg/kg) 11 days later, and killed 3 h after the injection. The 6-OHDA lesions prevented the decrease of TPH activity in the neostriatum, while the decrease of enzyme activity was slightly attenuated in the hippocampus and unaffected in the frontal cortex. This study demonstrates: that the attenuation of TPH activity can be prevented in a selected brain area by destroying its dopaminergic afferents, and implicates central dopamine (DA), or its metabolite, in the decrease in central TPH activity observed after a single injection of MA.

The role of NMDA receptor systems in neuropeptide responses to stimulants of abuse

High doses of stimulants of abuse, such as methamphetamine and cocaine, cause significant increases in the content of neurotension- and dynorphin-like immunoreactivity in the striatum and nucleus accumbens (approximately 200-600% of control) in the rat. These changes in neuropeptide content are caused by stimulation of dopamine D1 receptors and prevented by the glutamate NMDA receptor antagonist, MK 801. Stimulation of the NMDA receptor with N-methyl-D-aspartate results in increases in the neuropeptide levels like that caused by methamphetamine and cocaine. These findings demonstrate that stimulants of abuse profoundly influence neurotensin and dynorphin pathways associated with extrapyramidal and limbic structures by an interaction of activated dopamine D1 and glutamate NMDA receptors.

Body temperature effect on methylenedioxymethamphetamine-induced acute decrease in tryptophan hydroxylase activity.

Brain tryptophan hydroxylase activity decreases within 15 min after a single administration of 3,4-methylenedioxymethamphetamine. In the present study, the effect of body temperature on this acute decrease of tryptophan hydroxylase activity was examined. 2 h after a single dose of 3,4-methylenedioxymethamphetamine (20 mg/kg, s.c.), rats exhibited hyperthermia (38.7 degrees C) or hypothermia (35.8 degrees C) when maintained at 25 degrees C or 6 degrees C, respectively. The rectal temperature of control animals maintained at 6 degrees C was not altered. Tryptophan hydroxylase activity measured in the hippocampus, striatum and frontal cortex of hyperthermic rats treated with 3,4-methylenedioxymethamphetamine was decreased to 61%, 65%, and 71% of control levels, respectively, 2 h after drug treatment. However, in hypothermic rats, 3,4-methylenedioxymethamphetamine had no effect on tryptophan hydroxylase activity in the hippocampus, striatum or frontal cortex. Non-drug-induced hyperthermia or hypothermia did not affect tryptophan hydroxylase activity. Since hypothermia may prevent the 3,4-methylenedioxymethamphetamine-induced decrease in tryptophan hydroxylase activity by reducing the formation of free radicals, the effect of a free radical scavenging agent, N-tert-butyl-alpha-phenylnitrone, was examined. N-tert-butyl-alpha-phenylnitrone (200 mg/kg, i.p.) alone caused hypothermia but had no direct effect on tryptophan hydroxylase activity. Preadministration of N-tert-butyl-alpha-phenylnitrone prevented 3,4-methylenedioxymethamphetamine from raising the temperature above normal and attenuated the drug-induced decrease in tryptophan hydroxylase activity in hippocampus, striatum and frontal cortex. However, when the rats treated with a combination of N-tert-butyl-alpha-phenylnitrone and 3,4-methylenedioxymethamphetamine were maintained at hyperthermic conditions, N-tert-butyl-alpha-phenylnitrone had no protective effect. These results suggest that body temperature plays a prominent role in the 3,4-methylenedioxymethamphetamine-induced acute decrease in tryptophan hydroxylase activity.

EFFECT OF NEONATAL HYPOXIA-ISCHEMIA ON NIGRO-STRIATAL DOPAMINE RECEPTORS AND ON STRIATAL NEUROPEPTIDE Y, DYNORPHIN A AND SUBSTANCE P CONCENTRATIONS IN RATS

Perinatal hypoxic-ischemic brain injury was induced in 7- to 8-day-old rats by ligating the left carotid artery with subsequent exposure to 9% oxygen atmosphere for 2.5 h. The animals were killed 7 days later and grouped according to the degree of brain injury sustained after hypoxia-ischemia. Total protein content measured in striatum ipsilateral to the ligation, and dissected from brains showing extensive damage, was reduced to 64% of contralateral tissue. The protein content was not altered in other groups including control animals exposed to air and in sham-operated animals exposed to hypoxic conditions. The concentration of (pg/mg protein) and total (pg/striatum) striatal dynorphin A-like immunoreactivity (DLI) from brains with extensive damage were increased to 481% and 285% of the contralateral side, respectively. Hypoxia-ischemia increased striatal neuropeptide Y-like immunoreactivity (NPYLI) concentration from brains with extensive damage to 157% of contralateral side, but when the results were expressed as total NPYLI content per striatum, NPYLI content in striatum with extensive damage remained unaltered. Substance P-like immunoreactivity (SPLI) concentration and total content per striatum from brains with extensive damage were reduced to 66% and 43% of the contralateral side, respectively. D1 and D2 receptor density in animals killed 10 days after injury was reduced by 24% and 22% of control, respectively, in striatum from brains with extensive damage. These results indicate complex changes in brain neuropeptides following neonatal hypoxia-ischemia. Damage in the substance P system could have functional effects on dopaminergic transmission while the increase in NPYLI and in DLI concentrations may respectively reflect the relative preservation from neuronal damage and possibly an increase in neuropeptide synthesis or decrease in release. The decrease in SPLI concentration and the increase DLI concentration induced by hypoxia-ischemia suggests that these peptides may be present in separate neurons.

Glucocorticoids and 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity.

The present study was carried out in order to explore the role of glucocorticoids in 3,4-methylenedio-xymethamphetamine (MDMA)-induced neurotoxicity of the central serotonergic system. The activity of tryptophan hydroxylase (TPH) was used as an index of this drug-induced neuronal degeneration. One week after a single high dose of MDMA (20 mg/kg), a significant decrease in the enzyme activity was measured in both the frontal cortex and hippocampus. Adrenalectomy (ADX) attenuated or blocked this decrease in TPH activity in the hippocampus but not in the frontal cortex. This protective effect of ADX on hippocampal serotonergic neurons disappeared with concurrent administration of corticosterone (CORT) and MDMA administration. The long-term MDMA-induced decreases in hippocampal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were similarly affected by CORT replacement. However, ADX did not alter the short-term decline in hippocampal TPH activity and 5-HT concentrations measured 3 h after a single dose of MDMA (10 mg/kg s.c.). This study suggests that CORT play a role in the development of neurotoxicity induced by MDMA in the hippocampal serotonergic system, but may be less important in other brain structures.

Responses of limbic and extrapyramidal neurotensin systems to stimulants of abuse. Involvement of dopaminergic mechanisms

In summary, we have observed that drugs of abuse, which can cause schizophrenia-like paranoia, alter striatal and accumbens NT systems in a similar, dramatic fashion. The NT responses to these drugs, in particular METH, are mediated by activation of DA D1 receptors. We have observed that NMDA-type glutamate receptors are essential for the D1-NT interaction. NMDA receptors are selective, since they do not contribute to the antagonistic effects of DA D2 receptors on NT activity. This observation suggests that NT responses to D1 and D2 regulation are mediated through separate and distinct mechanisms. Finally, we found that the presence of METH dramatically reduces striatal NT release, which most likely leads to NT accumulation in nerve terminals and the observed increase in NT tissue level. The blockade of NT release by a psychotogenic drug, such as METH, is consistent with the hypothesis that NT has antipsychotic activity and a decrease in its release may contribute to some forms of schizophrenia similar to that caused by intense use of the stimulants of abuse.

Blockade of the 3,4-methylenedioxymethamphetamine-induced changes in neurotensin and dynorphin A systems

The levels of neurotensin-like immunoreactivity (NTLI) and dynorphin-like immunoreactivity (DLI) in the neostriatum, nucleus accumbens and substantia nigra were increased 18 h after a single administration of MDMA (3,4-methylenedioxymethamphetamine, 10 mg/kg). Coadministration of SCH 23390, a dopamine D1 receptor antagonist, or MK-801, a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptor complex, prevented the MDMA-induced increase of NTLI and DLI in all three brain structures while the administration of sulpiride, a dopamine D2 receptor antagonist, failed to alter the MDMA effects. These findings suggest that MDMA-induced changes in neurotensin and dynorphin involve both the dopaminergic and the glutamatergic systems.