George C. Wagner

Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine.

Repeated administration of high doses of methamphetamine produced long-term decreases in dopamine (DA) levels and in the number of DA uptake sites in the rat striatum. These two effects were dose-related and did not appear to be due to the continued presence of drug in striatal tissue. Long-lasting depletions induced by methamphetamine were selective for striatal DA neurons since norepinephrine (NE) levels in all of the rat brain regions examined were not changed on a long-term basis by methamphetamine treatments. Supersensitivity of DA receptors did not accompany the loss of striatal DA and its uptake sites.

Methamphetamine-induced changes in brain catecholamines in rats and guinea pigs

Repeated administration of methamphetamine was found to cause long-term changes in caudate dopamine levels in the rat and guinea pig. Methamphetamine was administered twice a day for thirty days. Two weeks following the last injection, the animals were killed and brains assayed for catecholamine content. These long-term depletions of dopamine, when combined with similar observations previously reported in rhesus monkeys, indicate a species generality of the effects of methamphetamine on caudate dopamine levels.

Alpha-methyltyrosine attenuates and reserpine increases methamphetamine-induced neuronal changes

The repeated administration of methamphetamine to rats has been shown to cause a long-lasting depletion of dopamine in various brain regions. In the first study, the effects of pretreatment with alphamethyltyrosine (AMT) or reserpine on the long-lasting methamphetamine-induced dopamine depletion were examined. In the second study, the effects of AMT and reserpine on central dopamine levels were measured in rats previously treated with methamphetamine. Pretreatment with AMT attenuated the long-lasting dopamine depletion induced by methamphetamine, whereas, pretreatment with reserpine increased the depletion. The acute effects of AMT and reserpine on brain dopamine were not altered when administered two weeks after the last methamphetamine injection.

Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain

Previous studies indicate that the repeated administration of D-methylamphetamine (MA) produces a long-lasting depletion of dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) in various brain regions of a number of species. The objectives of the present study were: (1) to establish a short, subcutaneous injection regimen which would reliably produce the neuronal alterations; (2) to evaluate MA-induced NE depletions produced by this new regimen; and (3) to determine whether central MA-induced neuronal changes are reflected in changes in cerebrospinal fluid monoamine metabolite concentrations. It was observed that high doses of MA administered (s.c.) over a 2-week period to rhesus monkeys produced decreases in DA and 5-HT, but not NE levels, in various brain regions. The decrease in caudate DA levels was accompanied by a decrease in the number of DA uptake sites, a decrease in the level of homovanillic acid (HVA) and an increase in DA turnover. This decrease in brain DA was also accompanied by a decrease in the cerebrospinal fluid concentration of HVA.

Neurochemical similarities between d,l-cathinone and d-amphetamine.

Cathinone, the principal alkaloid of Khat, was compared to the psychomotor stimulant d-amphetamine on a number of neurochemical measures. Like d-amphetamine, d,l-cathinone released and blocked the uptake of tritiated dopamine (DA) in synaptosomal preparations. In addition, repeated high doses of d,l-cathinone produced long-lasting DA depletions in various rat brain regions and decreased the number of synaptosomal DA uptake sites in a manner similar to that seen after repeated d-amphetamine administration. Importantly, this DA neurotoxic effect of d,l-cathinone, like that of d-amphetamine, is selective since regional brain levels of norepinephrine (NE) or serotonin (5-HT) are not altered on a long-term basis by repeated administration of d,l-cathinone. These findings are discussed with reference to the current practice of Khat leaf chewing by people in north-eastern Africa.

Effects of a high-dose treatment of methamphetamine on caudate dopamine and anorexia in rats

Dose-effect curves of d-methamphetamine (MA) on intake of sweetened condensed milk by rats were obtained before and after twice a day treatment for four days with either saline (control) or a high (50 mg/kg) dose of MA previously shown to decrease the dopamine levels of the caudate. The animals that were more sensitive to MAs anorexic effect during the before-treatment determination were found to be more sensitive to the lethal effects of the high-dose treatment. This treatment produced a six month decrease in brain dopamine but no change in the anorexic effect on milk intake or in the stereotypic behavior elicited by the drug. Subsequently, the daily administration of 2.5 mg/kg of MA, 15 min before presentation of the milk, to both control and treatment groups produced tolerance to the drugs anorexic effect. After 4 to 5 weeks of repeated administration of this dose there was a significant difference between the control groups intake of milk and treatment groups intake as well as body weight. These differences indicate an effect on the treatment upon the formation of tolerance to the anorexic effects of MA.

Dopamine depletion by 6-hydroxydopamine prevents conditioned taste aversion induced by methylamphetamine but not lithium chloride☆

Specific lesions of the central dopaminergic system produced by intraventricular injections of 6-hydroxydopamine with pargyline and desmethylimipramine pretreatment significantly attenuated conditioned taste aversions to a sweetened-condensed milk solution induced by methylamphetamine. Identically treated rats formed an aversion to the milk solution when lithium chloride was utilized. These results suggest that the methylamphetamine-induced aversion is dependent upon intact dopaminergic neurons.

The effects of dopaminergic agents on the locomotor activity of rats after high doses of methylamphetamine

Treatment of rats with 100 mg/kg/day of methylamphetamine for four days produced long lasting (16 week) depletions of central nervous system levels of dopamine but not of norepinephrine. This methylamphetamine treatment also attenuated the ability of methylamphetamine and apomorphine to produce increases in locomotor activity without shifting the dose-response curve to the right or left. These rats underwent significant decreases in activity after lower doses of haloperidol while the response to L-Dopa was virtually unchanged.

Decreased sensitivity of rat pups to long-lasting dopamine and serotonin depletions produced by methylamphetamine

Abstract Neonatal rats were administered 6-hydroxydopamine or high doses of methylamphetamine and the long-lasting effect on monoamine levels were examined. The neonatal rats were very sensitive to dopamine depletions produced by 6-hydroxydopamine. In contrast, the neonatal rats demonstrated little sensitivity to dopamine and serotonin depletions produced by methylamphetamine. Comparison of the depletions produced by these neonatal treatments with the depletions reported for adult treatments revealed that the neonatal rats were more sensitive to the 6-hydroxydopamine-induced depletions and less sensitive to the methylamphetamine-induced depletions.

Neurochemical consequences following administration of CNS stimulants to the neonatal rat

The possible induction of long-lasting catecholamine depletions in discrete brain regions by psychomotor stimulant drugs was examined in neonatal rats. Three agents, methylamphetamine, d-amphetamine, and methylphenidate were administered to groups of rat pups from days 10 to 40 of life. Pups were killed 2 weeks beyond the last drug administration. Catecholamine levels of various brain regions from groups of rats receiving 12.5, 25 or 50 mg/kg/day of each drug were compared with levels of vehicle treated pups. Both methylamphetamine and d-amphetamine at the higher doses induced long-lasting dopamine depletions in the caudate of rat pups. Methylphenidate had no long-term effect on dopamine while norepinephrine levels were not altered by any treatment.