Amphetamines dependence mechanisms

The development of effective pharmacotherapy has lagged behind progress in understanding the reward mechanisms and chronic impairments underlying stimulant abuse. Pharmacological and behavioral treatment approaches that have been used for cocaine abuse have not been as widely tested for the treatment of amphetamine abuse, limiting what can be offered for treatment of this disorder. No treatment agents are approved by the FDA for treatment of cocaine or amphetamine dependence. 

There are no proven pharmacotherapies for treatment of cocaine or amphetamine dependence. Disulfiram, however, shows some promise in randomized controlled trials for treating cocaine dependence at doses of 250 mg daily, especially in combination with CBT.45 Its mechanism of action for treating cocaine dependence is not known, but may be due to its inhibition of the dopamine P-hydroxylase enzyme that converts DA to NE in the brain. The resulting increase in DA levels may counter the DA-deficient state that is believed to underlie cocaine withdrawal and craving. 

Similarly, self-administration of MDMA in monkeys trained to self-administer amphetamine (Kamien et al. 1986) or in monkeys or baboons trained to self-administer cocaine (Beardsley et al. 1986 Lamb and Griffiths 1987) probably reflects a dopaminergic component to the pharmacology of MDMA. This would be consistent with current theories of dopamine involvement in the mechanism of action of drugs with dependence liability (Wise and Bozarth 1987). 

The actions of amphetamine are widespread throughout the brain. Amphetamine s immediate effect is to alter the release of monoamines in a dose-dependent manner that is specific for each monoamine transmitter neuronal system. The net effect of amphetamine on monoamine release is complex, with some mechanisms tending to increase monoamine release (e.g., blockade of reuptake and nonimpulsedependent release), and several mechanisms tending to diminish release (e.g., activation of somatodendritic and terminal autoreceptors). 

Dopamine is removed from the synapse via two mechanisms. First, COMT degrades intrasynaptic DA. Second, the dopamine transporter (DAT) [see (4) in Fig. 2.9], a Na /CD-dependent neurotransmitter transporter, transports DA in either direction, depending on the concentration gradient. The DAT is blocked selectively by drugs such as cocaine, amphetamine, bupropion, and nomifensine. 

Unlike many other abused drugs, amphetamines are neurotoxic. The exact mechanism is not known, but neurotoxicity depends on the NMDA receptor and affects mainly serotonin and dopamine neurons. 

Cross-tolerance occurs between all opiates that act primarily via the mu receptors. This is the basis of the methadone substitution therapy which is commonly used to withdraw people who are dependent on heroin or morphine methadone is used because of its relatively long half-life (about 12 hours) and its ease of administration in an oral form. Cross-tolerance does not occur between the opiates and other classes of dependence-producing drugs such as the barbiturates, alcohol or the amphetamines, which act through different mechanisms. 

Mechanism of action As with cocaine, the effects of amphetamine on the CNS and peripheral nervous system are indirect that is, they depend upon an elevation of the level of catecholamine transmitters in synaptic spaces. Amphetamine, however, achieves this effect by releasing intracellular stores of catecholamines (Figure 10.7). Since amphetamine also blocks monoamine oxidase (MAO), high levels of catecholamines are readily released into synaptic spaces. Despite different mechanisms of action, the behavioral effects of amphetamine are similar to those of cocaine. 

In other studies, volunteers previously dependent on amphetamines were dosed to a level at which amfetamine psychosis was produced, in order to examine the mechanism of action and pharmacokinetics of amfetamine and its possible relation to schizophrenia (64,65). Psychosis was induced by moderately high doses of amfetamine and the psychotic symptoms were often a replication of the chronic amfetamine psychosis, raising the question of whether the establishment of chronic stimulant psychosis leaves residual vulnerability to psychosis precipitated by stimulants. The mechanism might be similar to that which operates in the reverse tolerance that has been seen in experimental animals (66). In some cases an underlying psychosis can be precipitated an increase in schizophrenic symptoms (SED-8, 12) was observed in 17 actively ill schizophrenic patients after a single injection of amfetamine. 

Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, et al. 2000. Amphetamine-induced loss of human dopamine transporter activity an internalization-dependent and cocaine-sensitive mechanism. Proc. Natl. Acad. Sci. USA 97 6850-55... 

The mechanism of the central action of amphetamine continues to be explored and the prevailing evidence points to multiple mechanisms involving catecholamine release, inhibition of catecholamine uptake, MAO inhibition and a direct intrinsic action73-75. Dependence on amphetamine and other stimulant drugs, its clinical manifestations and treatment are the subject of two excellent reviews76,77. 

I. Mechanism of toxicity. All these agents stimulate the adrenergic system, with variable effects on alpha- and beta-adrenergic receptors depending on the compound. Generally, these agents stimulate the central nenrous system much less than other phenylethylamines (see amphetamines, p 72). 

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