Physiology And Pharmacology

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4.1 Where and How These Drugs Work

Neurons in the central nervous system communicate by chemical transmission. Of relevance to the present discussion are monoamine neurons that release dopamine, norepinephrine, or serotonin as one of their transmitters in response to an action potential. Reuptake transporter proteins embedded in the neuronal plasma membrane then clear the synapse of monoamines, typically taking up 70-80% of the released transmitter. This is thought to be the major termination mechanism for the monoamine chemical signaling process.

All psychostimulants appear to elevate synaptic levels of dopamine and norepinephrine. In addition, cocaine and, to a lesser extent, some of the other agents also raise synaptic levels of serotonin. It is the current consensus that elevated dopamine levels lead to CNS stimulation and are responsible for the reinforcing properties of stimulants (72-78). Nevertheless, recent studies have begun to focus attention on glutamate systems as potential key components of the actions of psychostimulants. For example, Swanson et al. (79) have shown that repeated cocaine administration leads to long-term attenuation of group I metabotropic glutamate receptor function in the nucleus accumbens. In particular, this functional reduction was related to significantly reduced mGluRS immunoreactivity in the medial nucleus accumbens. Even more exciting is the recent report that mGluR5 knockout mice do not display the reinforcing and locomotor effects of cocaine, in spite of the fact that cocaine administration increases extracellular dopamine in the nucleus accumbens of these mice to levels that do not differ from those of wild-type animals (80). In the near future, the role of glutamate systems in the actions of psychostimulants will no doubt be more fully elucidated, resulting in new approaches to the treatment of conditions that now respond to classical stimulants.

There are two principal mechanisms for increasing synaptic monoamine levels. One is to block the reuptake of neurotransmitter after its excitation-coupled release from the neuronal terminal. Thus, blocking the action of the uptake carrier protein prevents clearance of the neurotransmitter from the synapse, leaving high concentrations in the synaptic cleft that can continue to exert a signaling effect. This mechanism is the one invoked to explain the action of cocaine, a potent inhibitor of monoamine reuptake at the dopamine, serotonin, and norepinephrine transporters, and of methylphenidate, which is a reuptake inhibitor at the dopamine and norepinephrine transporters (81)1 t should be noted, however, that methylphenidate also has the ability to induce the release of catecholamines stored in neuronal vesicles (82, 83).

Figure 4.1. Amphetamine interacts with the dopamine transporter protein (l)and is transported inside. Na+ and CI" are cotransported, and K+ is countertransported in the process. After being transported inside the terminal, high concentrations of amphetamine can displace dopamine from vesicular storage sites (2), leading to elevated cytoplasmic levels of dopamine (3). After amphetamine dissociates on the intraneuronalsurface, dopamine binds to the carrier (4). The carrier then transports dopamine to the extracellular face (5), driven by the favorable concentration gradient, where the dopamine dissociates and leaves the carrier available for another cycle.

Figure 4.1. Amphetamine interacts with the dopamine transporter protein (l)and is transported inside. Na+ and CI" are cotransported, and K+ is countertransported in the process. After being transported inside the terminal, high concentrations of amphetamine can displace dopamine from vesicular storage sites (2), leading to elevated cytoplasmic levels of dopamine (3). After amphetamine dissociates on the intraneuronalsurface, dopamine binds to the carrier (4). The carrier then transports dopamine to the extracellular face (5), driven by the favorable concentration gradient, where the dopamine dissociates and leaves the carrier available for another cycle.

The second mechanism is the one more relevant to the action of amphetamine and related agents. This mechanism is illustrated in Fig. 4.1. Amphetamine, and other small molecular weight compounds with similar structures, are substrates at the monoamine uptake carriers and are transported into the neuron. The uptake carrier has an extracellular and intracellular face, and after transporting a substrate (amphetamine, etc.) into the neuron, the intracellular carrier face can bind to dopamine and transport it back to the extracellular face. This exchange diffusion mechanism is calcium independent, and is capable of robustly increasing synaptic transmitter levels. This process is often described as a "reversal" of the normal uptake carrier process.

Whereas the CNS stimulant effects of these molecules depend on an action in the brain, uptake inhibitors and substrates at peripheral monoamine carrier sites can obviously exert other physiological effects. Cocaine is an excellent local anesthetic agent. Furthermore, its potent inhibition of norepinephrine reuptake leads to stimulation of a-adrenergic receptors, causing local vasoconstriction that delays the diffusion of the anesthetic agent out of the tissue. Similarly, users who chronically insufflate cocaine into their nasal passages often develop necrotic lesions as a result of the local vasoconstricting effect of cocaine, again arising from the blockade of norepinephrine re uptake. Not surprisingly, cocaine and amphetamines have effects on the cardiovascular system, by virtue of their ability to enhance indirect adrenergic transmission at peripheral sites. Knowledge of the physiology of the sympathetic nervous system and the functions of peripheral adrenergic nerve terminals allows a relatively straightforward prediction of the types of drug effects possessed by monoamine uptake inhibitors or releasing agents.

4.2 Biochemical Pharmacology: Receptor Types and Actions

The monoamine reuptake carrier proteins (targets of the psychostimulants) are members of a larger Na+/Cl~ transporter family that includes a number of other proteins, including the GABA transporters, amino acid transporters, and orphan transporters (84). The primary amino acid sequence of the monoamine transporters is highly conserved, with several regions of these proteins having high homology. It is presently believed that all of the members of this family possess a membrane-spanning 12 a-helix motif, with a single large loop containing glycosylation sites on the external face of the membrane (Fig. 4.2). Members of this family of proteins have been identified not only in mammalian species, but also in eubacteria and archaebacteria, indicating their very early emergence in the evolution of life.

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