Cocaine catecholamine transport

Because guanadrel is actively transported to its site of action, drugs that block or compete for the catecholamine transporter on the presynaptic membrane will inhibit the effect of guanadrel. Such drugs include the tricyclic antidepressants, cocaine, chlorpromazine, ephedrine, phenylpropanolamine, and amphetamine. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

The linkage of uptake to the Na+ gradient may be of physiological significance since transport temporarily ceases at the time of depolarization-induced release of catecholamines. The transport of catecholamines can be inhibited selectively by such drugs as tricyclic antidepressants and cocaine. In addition, a variety of phenylethyl-amines, such as amphetamine, are substrates for carrier thus, they can be concentrated within catecholamine-containing neurons and can compete with the catecholamines for transport. 

Studies of sudden death in novice as well as experienced drug abusers found that cocaine causes vasoconstriction of the coronary arteries which seems to result from an enhancement of Ca2+ influx across myocardial membranes. However, remember that this class of drug affects other neurotransmitter systems. Cocaine inhbiits reuptake of NE and 5-HT as well as binds to the DA transporter. It increases catecholamine receptor sensitivity but does not seem to directly influence enkephalinergic receptors. In addition it also affects neurotransmission the H, Ach and phenylethylamine pathways. Activation of DA, NE or 5-HT neurons independently does not produce the euphoria associated with cocaine misuse. Euphoria seems to be related to simultaneous inteeraction between catecholamine and serotoninergic systems. 

Although cocaine can function as a local anesthetic, most of its actions relate to a second mechanism. Cocaine increases synaptic concentrations of catecholamines (i.e., dopamine and norepinephrine) in the brain by blocking their reuptake mechanisms. Normally, when these transmitters are released from nerve terminals, they are rapidly removed from the synaptic cleft by specific energy-dependent transporter proteins that carry them back into the terminal. By blocking these transporter systems, cocaine prolongs the time the catecholamines remain in the synapse and intensifies their actions. This increase in dopamine concentration in the CNS appears to be the basis for the various euphoric and related changes that occur in people who use cocaine. A similar mechanism has been suggested for methamphetamine. 

The effect of released norepinephrine wanes quickly, because -90% is transported back into the axoplasm by a specific transport mechanism (norepinephrine transporter, NAT) and then into storage vesicles by the vesicular transporter (neuronal reuptake). The NAT can be inhibited by tricyclic antidepressants and cocaine. Moreover, norepinephrine is taken up by transporters into the effector cells (extraneuronal monoamine transporter, EMT). Part of the norepinephrine undergoing reuptake is enzymatically inactivated to normetanephrine via catecholamine O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells) and to dihydroxymandelic acid via monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells). 

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)It should be noted, however, that methylphenidate also has the ability to induce the release of catecholamines stored in neuronal vesicles (82, 83). 

S5mthesized via tyramine (Fig. 30-26), apparently functions in place of noradrenaline. Note fhe precursor-product relationship between dopamine, noradrenaline, and adrenaline. The synthetic pathways to these neurotransmitters involve decarboxylation and hydroxylahon, types of reacfion imporfanf in formation of other transmitters as well. The most important process for ferminafing fhe acfion of released catecholamine transmitters is reuptake by the neurons. High-affinity uptake systems transport the catecholamine molecules back into the neurons and then into the synaptic vesicles. The uptake is specifically blocked by the drug reserpine (Fig. 25-12).7 The dopamine transporter is a major binding site for cocaine (see Fig. 30-28).7 7-7Si Catecholamine trans-miffers are catabolized by two enzymes. One is the... 

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