Toxicity Of D-amphetamine Research Articles

D-Amphetamine Toxicity in Freshly Isolated Rat Hepatocytes: A Possible Role of CYP3A

The aim of this study was to trace D-amphetamine toxicity in isolated rat hepatocytes and to elucidate a possible involvement of CYP3A in the mechanisms of its toxicity. To this end, male Wistar rats were treated with nifedipine (5 mg kg(-1) i.p., 5 days), a substrate and inducer of CYP3A. Hepatocytes isolated from nifedipine-treated and control rats were incubated with D-amphetamine at a concentration of 100 micromol L(-1), which was determined to be an average toxic concentration (TC50) for the compound. To evaluate the possible toxic effects of D-amphetamine on freshly isolated rat hepatocytes, we assessed the following parameters: cell viability, lactate dehydrogenase (LDH) activity, and glutathione (GSH).The results showed that nifedipine potentiated amphetamine cytotoxicity in vitro, as follows: cell viability dropped by 65% (p>0.001), GSH by 80% (p>0.001), and LDH activity increased by 190% (p>0.001). To clarify the role of nifedipine in amphetamine cytotoxicity, we used amiodarone, a substrate and an inhibitor of CYP3A. Pre-incubation of nifedipine-treated hepatocytes with amiodarone (14 micromol L(-1)) significantly lowered amphetamine cytotoxicity. Our results confirmed the toxicity of D-amphetamine in isolated rat hepatocytes and the involvement of CYP3A in its metabolism and hepatotoxicity.

In vitro toxicity of d-amphetamine and cocaine in hepatocytes, isolated from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NTR)

In vitro toxicity of d-amphetamine and cocaine in hepatocytes, isolated from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NTR)

Potentiation of cocaine and d-amphetamine toxicity with caffeine.

The effect of caffeine when combined with cocaine or amphetamine was studied in rats. Animals were pretreated with intraperitoneal vehicle (normal saline [NS]) or caffeine 100 mg/kg, then challenged with intraperitoneal cocaine (0, 35, 50, 70, or 90 mg/kg) or intraperitoneal d-amphetamine (0, 15, 25, 35, or 42 mg/kg). Animal behavior, time to, and incidences of seizures and death were recorded. This dose of caffeine alone did not cause seizures or death. Caffeine pretreatment significantly increased the incidence of overt seizures induced by either cocaine or amphetamine. Caffeine increased the incidence of cocaine-induced death from 10% to 90% at the 70 mg/kg cocaine dose (P less than .01). Caffeine increased amphetamine-induced death from 0% to 80% at 15 mg/kg (P less than or equal to .01), 10% to 70% at 25 mg/kg (P less than or equal to .01), and 30% to 80% at 35 mg/kg (P less than or equal to .01). To investigate mechanisms, additional animals were pretreated with the adenosine agonist, 2-chloroadenosine (2.5 and 10 mg/kg), before being challenged with NS, 90 mg/kg cocaine, or 42 mg/kg amphetamine. Pretreatment with 2-chloroadenosine had no affect in reducing cocaine or amphetamine toxicity. Combination pretreatment with caffeine and 2-chloroadenosine potentiated cocaine toxicity. The phosphodiesterase inhibitor, pentoxifylline, did not potentiate cocaine toxicity. The authors conclude that caffeine potentiates the acute toxicity of both cocaine and amphetamine, and that the failure of 2-chloroadenosine to alter this suggests that the toxicity of the stimulants cocaine and amphetamine may be modulated by nonspecific rather than specific adenosine- or phosphodiesterase-induced mechanisms.

Super-reactivity to amphetamine toxicity induced by schedule of reinforcement

The chronic exposure of rats to a schedule of operant water reinforcement coupled with chronically restricted access to water sensitized the animals to intermittent d-amphetamine injections (0.31-2.5 mg/kg with intervals of 12-23 days between any two injections) in such a way that this drug came to produce catastrophic losses of body weight (32.4% of control levels). In the sessions when d-amphetamine was administered, the rats were also given a total of 12 brief electric shocks. Loss of body weight was unaccompanied by parallel changes in operant behavior performance, or in food or water intake. Remarkably, in other studies with the same interventions (sham schedule sessions, water deprivation, and foot shocks), with the exception that reinforcers were never delivered, d-amphetamine did not produce catastrophic falls in body weight. This super-reactivity to d-amphetamine toxicity may be mediated by a possible stressor action of the schedule of reinforcement. Its mechanism might be analogous to the known sensitization produced by classical experimental stressor stimuli to the repeated administration of d-amphetamine.

Protection against d-amphetamine toxicity

The efficacy of diazepam, haloperidol, propranolol, and yohimbine in antagonizing the toxic manifestations of d-amphetamine were studied in rats. In the control group of animals given 75 mg/kg intraperitoneal (ip) d-amphetamine, 95% developed seizures, and 100% died in mean times of 12.6 +/- 1.0 and 50.1 +/- 5.9 minutes, respectively. Significant protection against d-amphetamine-induced death was afforded by pretreatment with haloperidol (1.0 to 20.0 mg/kg) or propranolol (20.0 to 30.0 mg/kg). Diazepam (5.0 to 10.0 mg/kg) significantly reduced the incidence of clinically overt seizures but offered no protection against death. Yohimbine (2.5 to 10.0 mg/kg) was ineffective in preventing either seizures or death. When haloperidol (1.0 mg/kg) was administered in combination with diazepam (2.0 mg/kg), the incidence of death was no different than if haloperidol were given alone. In combination, haloperidol (1.0 mg/kg) and propranolol (10.0 mg/kg) reduced death more than either agent alone. These data support a protective role of haloperidol or propranolol in the treatment of d-amphetamine intoxication and show no protection with diazepam or yohimbine.

Interactions between ethanol and amphetamine in mice and rats

1. 1. Interactions between ethanol and amphetamine were studied on four different psychopharmacological tests. 2. 2. Toxicity of d-amphetamine in aggregated mice was reduced or eliminated by ethanol. 3. 3. Hyperthermia and hypermotility produced by d-amphetamine in mice were partly suppressed by ethanol. 4. 4. Stereotyped behaviour produced by d-amphetamine in rats was unchanged after ethanol administration. 5. 5. These effects were observed in about 2 g·kg −1 acute dose of ethanol given orally.

The lethal effects of Δ 1-tetrahydrocannabinol in aggregated and isolated mice following single dose administration

The lethal activity of i.p. administered Δ 1-THC in a single injection was significantly enhanced in mice housed in isolation. Conversely, the toxicity of d-amphetamine was greater in aggregated mice. The mortality rate of the central nervous system depressants, chlorpromazine and phenobarbital, was unaffected by housing conditions.

Effect of fenfluramine on the d-amphetamine toxicity in mice

The toxicity of d-amphetamine in grouped mice is antagonized by theanorexic drug fenfluramine but not by its derivative S 992. The protection of the d-amphetamine toxicity in grouped mice correlates with a decrease in the hyperthermic effect of d-amphetamine. Fenfluramine does not antagonize the action of amphetamine in decreasing brain noradrenaline.

Different sensitivity to amphetamine of three strains of mice

The typical symptomatology induced by amphetamine in laboratory animals is dependent not only on the species but also on the strain of the animals employed in the experiments. In different strains of mice the hyperthermic response and the lethality to amphetamine showed extreme variations, from more sensitive strains (Albino Swiss) to more resistant strains (C 57 B1/6 and C 3H). d-Amphetamine toxicity Brain and liver amphetamine Different mice strains

Effect of hallucinogenic anticholinergic agents on d-amphetamine toxicity for aggregated mice

Members of a series of anticholinergic N-alkyl-3-piperidyl benzilates and one closely related N-alkyl-3-piperidyl phenylcyclopentyl glycolate have been shown to extend the excitatory lethality produced by d-amphetamine in aggregated mice. This effect of these compounds was exerted by the members of the series having tertiary nitrogen configuration but not by those with quaternary nitrogen. Protection against the extension of the excitatory lethality of d-amphetamine produced by of the active compounds in crowded mice was afforded either by change of state from aggregation to solitary, uncrowded confinement or by the prior administration of the phenothiazine tranquilizer perphenazine.

Effects of d-amphetamine on plasma and tissue electrolyte concentrations of aggregated and of hyperthyroid mice.

SummaryThe enhanced toxicity of damphetamine in aggregated and in hyperthyroid mice is accompanied by similar changes in tissue electrolyte concentrations. These changes include an increase in the sodium and a decrease in the potassium contents of liver and kidney and a decrease in the sodium and an increase in the potassium concentrations in the plasma.

Amphetamine toxicity in hyperthyroid mice: Effects on endogenous catecholamines

The actions of d-amphetamine were studied in mice made hyperthyroid by daily injections of triiodothyronine. The LD 50 of d-amphetamine in hyperthyroid mice was approximately one twentieth of that in euthyroid animals. d-Amphetamine induced a dose-dependent reduction of norepinephrine stores in the brain, heart, and spleen of euthyroid mice. The d-amphetamine-induced depletion of norepinephrine was significantly greater in the brain and spleen of hyperthyroid mice. d-Amphetamine had no effect on the catecholamine content of adrenal gland of hyperthyroid mice. Chlorpromazine, phenoxybenzamine, and propranolol pretreatment reduced the lethality of d-amphetamine in hyperthyroid mice while α-methyl- m-tyrosine, α-methyl- p-tyrosine, and reserpine pretreatment did not. The toxicity of α-methyl- m-tyrosine was enhanced in hyperthyroid mice. The role of endogenous catecholamines in the enhanced toxicity of d-amphetamine and α-methyl- m-tyrosine in hyperthyroid animals is discussed in the light of these findings.