Repeated Administration Of Methamphetamine Research Articles

Effects of methamphetamine administration on brain neurotensin-like immunoreactivity in rats

The effects of methamphetamine (MAP) administration on neurotensin-like immunoreactivity (NTLI) were investigated in the rat brain. A single administration of MAP induced dose-dependent and reversible increases in NTLI in the caudate-putamen, limbic forebrain and midbrain. NTLI in the caudate-putamen, limbic forebrain and midbrain was also enhanced after repeated administration of MAP. It was assumed that MAP enhanced NTLI in the caudate-putamen, limbic forebrain and midbrain through its action upon the nigrostriatal and mesolimbic dopamine systems.

Reduced apomorphine sensitivity of dopamine metabolism in rat striatum after repeated administration of methamphetamine

Rats received daily injections of saline or methamphetamine (MAP; 4 mg/kg/day) for 14 days. Seven days after the completion of this regime, dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured in the striatum following intraperitoneal injections of either saline plus γ-butyrolactone (GBL; 750 mg/kg) or apomorphine (2 mg/kg) plus GBL. The saline plus GBL challenges produced no difference in the DA or DOPAC levels between saline- and MAP-treated rats. By contrast, the apomorphine plus GBL challenges produced higher DOPAC levels in MAP-treated rats than saline-treated rats, although they produced no difference in the DA levels between the two groups. These results indicate that apomorphine depresses the striatal DA metabolism less in MAP-treated rats than in saline-treated control rats. Repeated MAP administration might produce this effect through apomorphine subsensitivity of presynaptic DA autoreceptors.

Alteration of striatal dopaminergic functions implicated in methamphetamine-induced reverse tolerance in rats

Rats were injected repeatedly with methamphetamine (6 mg/kg per day, for 14 days). The effects of the repeated treatment on the change of behaviors and striatal DA metabolism induced by challenge with DA agonists were studied 10 days after the last injection. Repeated methamphetamine administration decreased the sedative effect of low dose apomorphine, and enhanced apomorphine-induced sterotyped behavior but reduced in after pretreatment with tetrabenazine. Striatal DA, HVA and DOPAC contents, and striatal γ-butyrolactone-induced DA or DOPA accumulation were not altered by repeated methamphetamine treatment. The effect of apomorphine to decrease DA metabolite content and DA or DOPA accumulation was not changed either. As evidenced by experiments using α-MT, repeated methamphetamine administration increased DA utilization after methamphetamine or low dose apomorphine challenge, although it did not change DA utilization at the steady state (without drug challenge). These findings suggest that methamphetamine-induced reverse tolerance is accompanied by an increase of DA utilization resulting from the subsensitivity of DA utilization-modulating autoreceptors.

Effects of dopaminergic agents on eye tracking before and after repeated methamphetamine.

The effects of methamphetamine (MA), apomorphine (AP) and haloperidol (HAL) on eye tracking function were tested in rhesus monkeys. Three rhesus monkeys were trained to track with their eyes a disk-shaped projected image that oscillated along a horizontal plane on a screen, using a training procedure in which responses on a lever were reinforced with water only when the center of the disk dimmed for a brief period. Eye movements were recorded by electrooculography (EOG). The effects of intramusuclar administration of MA, APO and HAL on responding were compared before and after a 8-14 day period of repeated MA administration. During this regimen, MA was given in 4 divided doses starting at a total daily dose of 4 mg/kg/day and increasing to 16-40 mg/kg/day. All three drugs disrupted performance during both the initial dose-response determination as well as during the redetermination following the regimen. However, tolerance to MA in 3 monkeys and to APO in 2 monkeys was observed after the regimen, while no marked sensitivity change was observed to haloperidol. Since other data reported elsewhere have shown that dopamine is depleted in the caudate after similar repeated administration regimens, long lasting brain dopaminergic changes are likely present in these monkeys. Therefore, these results suggest that the changes in sensitivity to the drugs that were observed in terms of eye tracking function are related to dopamine depletion in the brain.

Subchronic methamphetamine treatment selectively attenuates apomorphine-induced decrease in 3,4-dihydroxyphenylacetic acid level in mesolimbic dopaminergic regions

To investigate mechanisms of behavioral enhancement produced by repeated doses of amphetamines, the effects of apomorphine on 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels were examined in various brain regions of the rat on the 4th day of withdrawal after repeated administration of saline or methamphetamine (3 mg/kg, s.c.) twice daily for 14 days. Apomorphine (0.1 and 1.0 mg/kg, i.p.) produced a dose-dependent decrease in DOPAC levels and no effect on DA levels in the olfactory tubercle, nucleus accumbens, striatum, frontal and cingulate cortices of saline-treated animals. A decrease in DOPAC levels produced by a low dose of apomorphine was attenuated selectively in the olfactory tubercle and nucleus accumbens of methamphetamine-treated animals. A high dose of apomorphine produced a significant decrease in DOPAC levels in both regions. No such attenuation was obtained in the striatum and the frontal and cingulate cortices. These results suggest that subchronic methamphetamine may induce development of hyposensitivity of presynaptic DA receptors in the mesolimbic regions, which contribute to the behavioral enhancement produced by the drug.

Sensitivity changes to dopaminergic agents in fine moto control of rhesus monkeys after repeated methamphetamine administration

Long-term behavioral and neurochemical effects of repeated methamphetamine (MA) administration were investigated in rhesus monkeys trained to perform a fine motor task requiring control of exerted force for a specific time. Rhesus monkeys were trained to extend their arms into a tube to press a lever with a force between 25 and 40 g for 5 sec in order to receive 1.5 ml of water. The effects of intramuscular administration of MA, apomorphine (APO) and haloperidol (HAL) on responding were compared before and after a 2-week period of repeated MA administration. During this period, MA was given in 4 divided doses starting at a total daily dose of 4 mg/kg/day and increasing to 40 mg/kg/day. Tolerance to MA, increased sensitivity to HAL and no consistent sensitivity change to APO were observed when dose-response functions were redetermined starting 1 month after the repeated MA administration. One month after these determinations were completed, the brains of the monkeys were analyzed for changes in monoamines. Significant depletions of dopamine in the caudate nucleus and serotonin in the frontal cortex were seen. It is hypothesized that the sensitivity changes to the drugs on performance were related to the dopamine depletion.

P2B0106) - The time course of dopamine and serotonin levels in mouse brains after repeated administration of methamphetamine. Second report.

P2B0106) - The time course of dopamine and serotonin levels in mouse brains after repeated administration of methamphetamine. Second report.

Effects of repeated methamphetamine administration on methamphetamine self-administration in rhesus monkeys

The effects of prolonged exposure to high doses of stimulants on stimulant self-administration in rhesus monkeys have not been established. In the present experiment, rates of methamphetamine self-administration as well as the effects of methamphetamine on food-maintained responding were determined before and after a regimen of repeated methamphetamine injections. Increases in self-administration of some doses of methamphetamine as well as tolerance to the rate-decreasing effects of the drug on food-maintained responding were observed following the repeated injection regimen. The results suggest that while tolerance may develop to the rate-decreasing effects of the drug, there may be an increased sensitivity to its reinforcing properties. In addition, since this injection regimen has been shown in previous studies to deplete central monoamines, especially dopamine, the results suggest a role for these monoamines in these behavioral effects of methamphetamine.

P-8) - The time course of dopamine and serotonin levels in mouse brains after repeated administration of methamphetamine

P-8) - The time course of dopamine and serotonin levels in mouse brains after repeated administration of methamphetamine

P-32) - Effects of some drugs on methamphetamine-induced behavioral effects after repeated administration of methamphetamine

P-32) - Effects of some drugs on methamphetamine-induced behavioral effects after repeated administration of methamphetamine

O-25) - Sensitivity changes to dopaminergic agents studied in eye-tracking of rhesus monkeys after repeated methamphetamine administration

O-25) - Sensitivity changes to dopaminergic agents studied in eye-tracking of rhesus monkeys after repeated methamphetamine administration

Methamphetamine-induced behavioral effects and brain catecholamines following repeated administration of methamphetamine

After mice were given methamphetamine (MA) at a dose of 25 mg/kg i.p. twice daily (9:00 a.m. and 5:00 p.m.) for 4 days, the behavioral effects and releases of brain catecholamines induced by MA were investigated. The behavioral effects which were estimated according to the rating system of Peachey et al. were a predominant increase in locomotor activity at 2.5 mg/kg MA, a predominant stereotyped behavior at 10 mg/kg MA and the mixed type at 5 mg/kg MA in the saline control. Following repeated administration of MA, the rating scores of each effect at 2.5 and 5 mg/kg MA were not significantly different from those of the saline control. At 10 mg/kg MA, the behavioral effects were of the mixed type. However, when locomotor activity was measured by Automex II 2SD, significant increases in locomotor activity were observed over 2 hr. Following repeated administration of MA, the brain NE level did not alter, while the brain DA level was significantly decreased. The increased accumulation of brain MHPG-S0i+ induced by MA was not significantly different from the saline control. The accumulation of HVA, however, did not alter at high doses of MA, which caused the increased accumulation of HVA in the saline control.

Decreased in vivo [ 3H]spiroperidol binding in rat brain after repeated methamphetamine administration

The dose of methamphetamine required to produce stereotyped behaviors in rats was reduced 10 days after methamphetamine had been given repeatedly and intermittently (6 mg/kg per day) for 14 days. Decrease of in vivo [ 3H]spiroperidol binding activity was observed in striatum, nucleus accumbens and medial frontal cortex at the same time that the reverse tolerance was confirmed. These two results of repeated methamphetamine treatment suggest that reduction of [ 3H]spiroperidol binding activity may be one of the biological bases of reverse tolerance.

Sex hormones metabolism in the brain: influence of central acting drugs on 5 alpha-reduction in rat diencephalon.

Rats after adrenalectomy-testectomy showed a gradual increase in diencephalon 3-oxo-5 alpha-steroid: (acceptor) delta4-oxidoreductase (5 alpha-reductase) activity for 3 days. The activity then returned near to the normal range on the 4th postoperative day. When rats were given testosterone propionate (TP) 3 days after adrenalectomy-testectomy, diencephalon 5 alpha-reductase activity returned to the preoperative range 2 hr after TP administration. Diencephalon 5 alpha-reductase activity showed a highly significant increase (p less than 0.01) after a single administration of carbamazepine, reserpine, diazepam, phenytoin, phenobarbital or disulfiram. A significant increase (p less than 0.05) was also found after a single administration of methylphenidate, caffeine or methamphetamine. Plasma testosterone decreased concurrently after administration of all these agents, except diazepam. Diencephalon enzyme activity decreased significantly after repeated disulfiram administrations (p less than 0.01) but increased significantly after methamphetamine administrations (p less than 0.05). Plasma testosterone showed a tendency to decrease after repeated methamphetamine administrations but tended to increase after repeated disulfiram administrations.