The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep-waking cycle

Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood–brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines—amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.

Toxicity of amphetamines: an update

( ± )3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that has been proposed to be useful as an adjunct to psychotherapy. This study assessed the neurotoxic potential of MDMA in nonhuman primates. Monkeys were repeatedly administered doses (2.50, 3.75, and 5.00 mg/kg) of MDMA subcutaneously and analyzed for regional brain content of serotonin and 5-hydroxyindoleacetic acid two weeks later. In all regions of the monkey brain examined, MDMA produced a selective dose-related depletion of serotonin and 5-hydroxyindoleacetic acid. These neurochemical deficits were associated with evidence of structural damage to serotonergic nerve fibers. In addition, MDMA produced pathological changes in nerve cell bodies in the dorsal, but not median, raphe nucleus. These results indicate that MDMA is a selective serotonergic neurotoxin in nonhuman primates and that humans using this drug may be at risk for incurring central serotonergic neuronal damage. ( JAMA 1988;260:51-55)

(+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates.

Central monoamines and convulsive thresholds in mice and rats

Long-term effects of p-chloroamphetamine on tryptophan hydroxylase activity and on the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in brain.

The present investigations were undertaken to study the mechanism by which p -chloramphetamine decreases both serotonin (5-HT) and 5-hydroxyindole acetic acid in the brains of rats. 1) Doses of p -chloroamphetamine, which markedly reduced the level of endogenous 5-HT in brain, failed to decrease labeled 5-HT derived from either intraventricularly administered 5-HT-H 3 or 5-hydroxytryptophan-C 14 . Under similar conditions, reserpine and RO 4-1284 caused a striking reduction of both the endogenous and the labeled 5-HT. 2) p -Chloroamphetamine partially blocked the increase of endogenous brain 5-HT but not that of brain norepinephrine, after monoamine oxidase inhibition by pargyline. 3) The increase in brain 5-hydroxyindole acetic acid resulting from the administration of probenecid was almost completely blocked in animals treated 48 and 24 hours previously with p -chloroamphetamine. This blockade was not evident when p -chloroamphetamine was administered 10 minutes prior to probenecid. 4) Like p -chlorophenylaline, p -chloroamphetamine caused a decrease in the amount of 5-HT-C 14 in brain formed from intraventricularly administered tryptophan-C 14 ; however, it did not change the amount of 5-HT-C 14 derived from intraventricular 5-hydroxytryptophan-C 14 5) p -Chloroamphetamine did not alter the level of either endogenous tryptophan or tryptophan-C 14 taken up into the brain from the ventricular system. On the basis of these experimental data, it is concluded that p -chloroamphetamine impairs the synthesis of cerebral 5-HT. Moreover, the results of these studies in vivo implicate an inhibition of cerebral tryptophan hydroxylase in the simultaneous lowering of cerebral 5-HT and 5-hydroxyindole acetic acid by p -chloroamphetamine.

F Sulser

Papers

P-chloroamphetamine: in vivo investigations on the mechanism of action of the selective depletion of cerebral serotonin.