Amphetamines action

The pharmacology of amphetamine is considerably more complex. It does not only block monoamine reuptake, but also directly inhibits the vesicular monoamine transporter, causing an increase in cytosolic but not vesicular dopamine concentration. This may lead to reverse transport of the amines via the membrane-bound transporters. Further mechanisms of amphetamine action are direct MAO inhibition and indirect release of both dopamine and serotonin in the striatum. 

Jones, S.R., Gainetdinov, R.R., Wightman, R.M., Caron, M.G. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J. Neurosci. 18 1979, 1998. 

Fon EA, Pothos EN, Sun BC, Killeen N, Sulzer D, Edwards RH (1997) Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19 1271-1283. 

Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998) Mechtmisms of amphetamine action reveded in mice lacking the dopamine transporter. J Neurosci 18 1979-1986... 

Experiments in DAT-KO mice (37) clearly illustrated that although the interaction of amphetamine with the DAT is pivotal in its action, an involvement of other critical processes is important as well. Particularly, the role of vesicular storage of DA in amphetamine action has been highlighted in these mice (37). For example, while amphetamine-induced elevation of striatal DA did not occur in mice lacking DAT, the vesicle-depleting action of amphetamine was still observed (37). Furthermore, it has been suggested that amphetamine-triggered reverse transport of DA from cytoplasm to extracellular space does not occur simply due to an elevated cytoplasmic concentration of DA but requires direct action of amphetamine on the DAT (37). 

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

Figure 11.14 Analysis of amphetamines by GC-NPD following HS-SPME exti action from human hair (a) Normal hair (b) normal hair after addition of amphetamine (1.5 ng) and methamphetamine (16.1 ng) (c) hair of an amphetamine abuser. Peak identification is as follows 1, a-phenethylamine (internal standard) 2, amphetamine 3, methamphetamine 4, N-propyl-/3-phenethyamine (internal standard). Reprinted from Journal of Chronatography, B 707,1. Koide et ai, Determination of amphetamine and methamphetamine in human hair by headspace solid-phase microextraction and gas cliromatography with niti ogen-phosphoms detection, pp. 99 -104, copyright 1998, with permission from Elsevier Science.

I. Koide, O. Noguclii, K. Okada, A. Yokoyama, H. Oda, S. Yamamoto and H. Kataoka, Detemination of amphetamine and methamphetamine in human hak by headspace solid-phase microexti action and gas cliromatogi aphy with niti ogen-phosphorus detection , J. Chromatogr. B707 99-104(1998). 

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

The amphetamines, such as amphetamine, dextroamphetamine (Dexedrine), and metliainphetainine (Desoxyn), are sympatiiomimetic (ie, adrenergic) dru that stimulate the CNS (see Chap. 22). Their drug action results in an elevation of blood pressure, wakefulness, and an increase or decrease in pulse rate The ability of these drugs to act as anorexiants and suppress the appetite is thought to be due to their action on the appetite center in the hypothalamus. 

The anorexiants, such as phentennine and phendime-trazine, are nonamphetamine dru pharmacologically similar to the amphetamines. Lake the amphetamines, their ability to suppress the appetite is thought to be due to their action on the appetite center in the hypothalamus. 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

The phenylalkylamine hallucinogens show a close structural resemblance to the catecholamines, noradrenahne and dopamine. The prototype structure is found in mescaline, a naturally occurring substance. Modification of the mescaline molecule has led to synthetic amphetamine derivatives with hallucinogenic action. 

The mode of action of the amphetamine derivatives MDA and MDMA seems to be dissimilar, with MDMA possessing mescaline-like psychoactive properties. MDMA demonstrates greater serotonergic effects than does the more amphetamine-like MDA. 

The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity. Thus DA terminals will not concentrate NA and the DA transporter is blocked by a drug such as nomifensine which has less effect on NA uptake. Despite this selectivity some compounds, e.g. amphetamine and 6-OHDA (but not MPTP), can be taken up by both neurons. The role of blocking DA uptake in the central actions of cocaine and amphetamine is considered later (Chapter 23). 

Most of the motor effects of amphetamine, especially stereotypy, are due to the release of DA as are its psychotic effects such as hallucinations. Its ability to mimic the action of DA in reward and reinforcement behaviour may contribute to its abuse potential (see Chapter 22) but its arousal (stimulant) properties also involve NA release. 

Finally, the actions of the so-called 5-HT releasing agent , if-fenfluramine, which is well known for its anorectic effects, should be mentioned here. This compound inhibits 5-HT uptake but its metabolite, if-norfenfluramine, increases 5-HT release as do high doses of (i-amphetamine. It is important to realise that this 5-HT release is independent of nerve impulses and the action of such compounds rests on their effects on the 5-HT transporters on the storage vesicles and terminal membrane. Once these drugs have been taken up into 5-HT neurons by the transporter, they cause 5-HT to leak out of its storage vesicles and, ultimately, to be extruded from the neuron by retrotransport (see below and Chapter 4 for further details). 

Cocaine, a stimulant, blocks the reuptake of NA (and DA) and so has similar actions to those of the amphetamines which have a number of actions that include the release of NA and DA, and a block of reuptake and metabolism. 

These results show that the MDMA cue is complex and may have some similarity to amphetamine. However, suggestions that the pharmacology of (+)-MDMA is essentially the same as that of amphetamine are clearly not warranted by the data. This partial amphetamine-like action is believed to... 

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). 

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