Cocaine is a naturally occurring substance that is extracted from the leaves of the coca plant (Erythroxylon
The articles on ► neurotransmitters and ► transporters reveal that amine neurotransmitters (► dopamine, ► serotonin, and ► norepinephrine) are removed from the synapse by ► transport or reuptake into the synaptic terminal that released them (see Fig. 2). As noted in those articles, this uptake mechanism (the ► neurotrans-mitter transporter) is very important for turning off the signal created by the neurotransmitters interacting with
Cocaine. Fig. 1. Chemical structures of cocaine and related compounds. WIN 35,428, RTI-55, and RTI-336 are very similar to cocaine, but have somewhat different pharmacological properties. While cocaine is equipotent in inhibiting the uptake of norepinephrine, dopamine, and serotonin, WIN 35,428 and RTI 55 are more selective for the serotonin and DATs; and RTI-336 is more selective for DAT alone. Both WIN 35,428 and RTI-55, in their radiolabeled forms, are important tools for studying and imaging the DAT. RTI-336 is currently being tested as a medication for cocaine abusers. Benzoylecgonine, which lacks the methyl ester found in cocaine, is a longer half-life metabolite of cocaine and is the target of urine tests for cocaine ingestion. The figure was supplied by Dr Ivy Carroll with permission.
Cocaine. Fig. 2. The dopamine hypothesis of cocaine reinforcement. A variety of binding, behavioral, and neurochemical studies indicate that inhibition of DAT, rather than the norepinephrine or serotonin transporters, is responsible for the reinforcing (addicting) properties of cocaine. Thus, DAT is the initial molecular site of action of cocaine in regard to its addicting properties. (Reproduced from Kuhar et al. 1991.)
their receptors. Being able to turn off the signal is just as important as being able to turn it on; otherwise, there is no discrete signal, just a constant background. These transporters are the initial molecular sites of action of cocaine. The rewarding properties of the drug are due to cocaine's blockade of the ► dopamine transporter (DAT) (Kuhar et al. 1991), and not the serotonin or norepinephrine transporters.
The blockade of the transporters by cocaine results in a buildup of the neurotransmitter in the synaptic cleft and an increased signaling of the neurotransmitter at its receptors. This increased signaling is how cocaine imparts its actions. The brain has evolved hand in hand with neurotransmitters and has developed mechanisms to handle them. For example, dopamine is discretely released by action potentials at nerve terminals onto receptors, and then removed from receptors by reuptake. This occurs at a rapid time scale and, in a sense, in an orderly fashion. However, the brain is not equipped to "handle" cocaine in
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