Amphetamines and chemically related compounds of the beta-phenylethylamine family are in the pharmacological class of PSYCHOMOTOR STIMULANTS, which also includes methylphenidate and COCAINE. Amphetamine was synthesized in 1887 by Edeleano and introduced commercially first as a bronchial decongestant in 1932 (‘benzedrine’) and later as a treatment for NARCOLEPSY and for weight control. In the war-time years it was used commonly by the military to enhance vigilance and later by the general population for similar purposes. However, in the 1950s and 1960s it became evident that amphetamines were potentially dangerous drugs of abuse with psychotic side-effects. It has recently been claimed that chronic use of high doses of amphetamine can cause permanent neuronal damage in experimental animals. Following observations made in the 1930s, the psychomotor stimulant methylphenidate (‘Ritalin’) is much used in the USA as a medication for ATTENTION-DEFICIT DISORDER and hyperactivity syndromes in children.
Amphetamine exists in two stereoisomeric forms, D and L amphetamine, the former being much more potent. Methamphetamine is more potent still than the D form. It resembles the plant product cathinone in chemical structure. Amphetamines produce their pharmacological effects by a combination of actions as an indirect CATECHOLAMINEAGONIST; it releases DOPAMINE and (probably) NORADRENALINE, as well as blocking the REUPTAKE of both of these neurotransmitters into the presynaptic cell, and probably at higher doses acting as a MONOAMINE OXIDASE inhibitor. Thus, by a combination of these three actions it enhances the concentrations of these catecholamine neurotransmitters in the SYNAPTIC CLEFT. The mechanisms of action of the different psychomotor stimulant drugs differ subtly. Whereas amphe-tamine appears to displace cytoplasmic neurotransmitter via its action on the synaptic VESICULAR TRANSPORTER, both cocaine and methylphenidute work mainly by inhibiting the monoamine (reuptake) transporter on the presynaptic terminal.
In behavioural terms, amphetamine increases central and sympathetic arousal and desynchronizes (see SYNCHRONY/DESYNCHRONY) the ELECTROENCEPHALOGRAM (EEG) in humans, inhibiting SLEEP. It is a mild anorectic (see ANOREXIA) agent but can produce euphoric subjective responses (see EUPHORIA) which contribute to ABUSE POTENTIAL. At high, generally repeated doses, it has been shown to produce symptoms that are difficult to distinguish from those of paranoid SCHIZOPHRENIA, and which can be antagonized by the same NEUROLEPTIC drugs used in the treatment of schizophrenia. For this reason, the behavioural effects of amphetamine have been considered as a model psychosis, the existence of which provides support for a DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA.
Many of the behavioural effects of amphetamine in humans resemble those found in experimental animals. At low doses amphetamine enhances spontaneous locomotor activity in the rat, and at larger doses leads to a syndrome of behavioural STEREOTYPY in which the same response is repeated over and over again at a high rate. In rats, this is often manifested as repeated head movements (including sniffing), but other responses can also become stereotyped. In monkeys, stereotyped GROOMING and even social behaviour are observed. In humans stereotypy can also be observed as grooming: repetitive picking of the skin because of tactile hallucinations of infestation by ants or other insects has been noted. It can however also take a more symbolic form and even be expressed, for example, in the thinking patterns of amphetamine addicts and in their artwork.
In experimental animals, amphetamine may increase responding for food even though it is anorectic, leading to suggestions that it increases the reinforcing or rewarding value of stimuli associated with food (and other rewards)—that is, it enhances the power of the conditioned reinforcer. Amphetamine will also increase responding for, and apparently reduce the rewarding threshold of, ELECTRICAL STIMULATION OF THE BRAIN via implanted electrodes. The clear demonstration of its own rewarding properties is its self-adminstration via intravenous catheters by experimental animals (see INTRAVENOUS SELF-ADMINISTRATION). A good deal is now known about the neural mediation of the behavioural effects of amphetamine, much of which occurs via effects on the mesotelencephalic dopamine system from its origins in the midbrain to innervate structures such as the NUCLEUS ACCUMBENS (or ventral STRIATUM) and the CAUDATE-PUTAMEN or dorsal striatum. Thus, for example, the stereotyped oral behaviour and head movements induced in rats by large doses of the drug are known to depend on the integrity of the NIGROSTRIATAL DOPAMINE SYSTEM that projects to the dorsal striatum, whereas the locomotor hyperactivity is blocked by dopamine depletion from the ventral striatum. Amphetamine has been shown to be reinforcing to rats when it is self-administered directly into the nucleus accumbens, and loss of dopamine there attenuates self-adminstration behaviour. Thus, it appears that the rewarding and potentially addictive effects of amphetamine result from effects on the nucleus accumbens. Much less is known about the neural basis of its effects in man, but recent neuroimaging studies of the effects of cocaine and methylphenidate suggest that subjective effects of the drugs can be correlated with actions in structures such as the striatum and the thalamus.
