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PubMedDate not supplied

Disposition kinetics of d- and l-amphetamine following intravenous administration of racemic amphetamine to rats.

Amphetamine (AP), a chiral drug, displays stereoselective differences in biological action. The effect of stereochemistry on the disposition kinetics of the enantiomers has not been thoroughly studied. We examined the disposition kinetics of AP in rats using a sensitive precolumn derivatization HPLC method that can separate the enantiomers of AP and its metabolites. Male Sprague-Dawley rats were given a short intravenous infusion of racemic AP (15 mg/kg). The systemic and renal clearances, steady-state volume of distribution, and terminal half-life for l-AP were (mean +/- SD), respectively: 65.6 +/- 9.25 ml/min.kg; 15.4 +/- 2.55 ml/min.kg; 4.33 +/- 0.71 liters/kg; and 0.96 +/- 0.13 hr. The corresponding values for d-AP were: 50.8 +/- 6.88 ml/min.kg; 12.5 +/- 2.02 ml/min.kg; 3.84 +/- 0.55 liters/kg; and 1.12 +/- 0.09 hr. There are statistically significant differences between the enantiomers in all pharmacokinetic parameters except half-life. About 40% of the l-AP dose was excreted in urine as l-p-hydroxyamphetamine and 24% as intact drug. The corresponding values for d-AP were 32% and 26%, respectively. p-Hydroxyamphetamine was primarily excreted into urine as the conjugated form. These data indicate stereoselective differences in the pharmacokinetics of the enantiomers of AP after administration of racemic drug in the rat.

Amphetamine↗
PubMed1982

Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences.

Amphetamine (AMPH)-induced rotational behavior in non-lesioned rats and AMPH-stimulated dopamine (DA) release from striatal tissue fragments in vitro were used to study the long-term effects of a single injection of AMPH on activity in the mesostriatal DA system. A single injection of a low dose of AMPH (1.25 mg/kg) greatly enhanced the rotational behavior produced by a second injection of AMPH given 3-4 weeks later in intact female, ovariectomized female and castrated male rats. The effect of AMPH pretreatment in intact males differed from that in the other groups. When only 7-8 days separated the two test sessions both intact male and female rats showed sensitization of rotational behavior, but the magnitude of the change was greater in females. In addition, a single injection of 1.25 mg/kg of AMPH in vivo produced a long-lasting (3-5 weeks) enhancement of AMPH-stimulated DA release from striatal tissue in vitro. It is suggested that: (1) repeated injections of AMPH are not necessary to produce a long-lasting facilitation of behaviors mediated by the mesostriatal DA system; (2) gender and/or hormonal state influences the development of long-term changes in the mesostriatal DA system; and (3) changes in DA release from presynaptic terminals may contribute to the behavioral sensitization produced by stimulant drugs. The phenomena reported here may provide complementary in vitro and in vivo models for studying neuroplasticity in brain DA systems.

Animals↗
PubMed1987

Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion.

The repeated intermittent administration of relatively low doses of amphetamine (AMPH) produces an enduring hypersensitivity to the motor stimulant effects of AMPH (behavioral sensitization), and this is accompanied by enhanced mesotelencephalic dopamine (DA) utilization/release. In contrast, chronic treatment with very high doses of AMPH does not produce sensitization, but is neurotoxic, resulting in the depletion of brain DA (and often other monoamines). However, gradually escalating doses of AMPH provide protection against the neurotoxic effects of higher doses given later. Therefore, the purpose of the present experiment was to determine if a regimen of gradually escalating doses of AMPH, culminating in much higher doses than usually used to study sensitization, would produce neural and behavioral changes associated with AMPH neurotoxicity (DA depletion) or behavioral sensitization (increased DA utilization). Female rats were given 60 injections (2/day) of increasing (1 to 10 mg/kg) doses of d-AMPH, culminating in rats receiving 20 mg/kg/day for four consecutive days. This treatment did not deplete brain DA or serotonin, but did produce a long-lasting enhancement (at least 12 days) in striatal and nucleus accumbens DOPAC concentrations, and DOPAC/DA ratios. These neurochemical changes were accompanied by an enduring hypersensitivity to the stereotypy-producing effects of a subsequent AMPH 'challenge.' In contrast to this enhanced response to a challenge, AMPH-pretreated rats showed a marked reduction in spontaneous nocturnal motor activity. It is concluded that rats can be given escalating doses of AMPH, which mimic to some extent the AMPH 'runs' common in addicts and that this produces neural and behavioral changes consistent with the development of sensitization; not neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Behavioral changes and [123I]IBZM equilibrium SPECT measurement of amphetamine-induced dopamine release in rhesus monkeys exposed to subchronic amphetamine.

Previously we have shown that twelve weeks of repeated low-dose d-amphetamine (AMPH) exposure in rhesus monkeys induces a long-lasting enhancement of behavioral responses to acute low-dose challenge. The present study was designed to investigate the behavioral and neurochemical consequences of a six-week regimen of low-dose AMPH exposure (0.1-1.0 mg/kg, i.m., b.i.d.) in rhesus monkeys. SPECT imaging of AMPH's (0.4 mg/kg) ability to displace [123I]IBZM bound to D2 dopamine receptors in the striatum of saline control and AMPH-treated animals prior to and following chronic treatment was accomplished using a bolus/constant infusion paradigm. Following chronic AMPH treatment, all monkeys showed an enhanced behavioral response to acute AMPH challenge and a significant decrease in the percent of AMPH-induced displacement of [123I]IBZM in striatum compared to their pretreatment scans. These findings suggest that relatively small changes in presynaptic dopamine function may be reflected in significant alterations in the behavioral response to acute AMPH challenge.

Animals↗