Reuptake, dopamine/norepinephrine action terminated

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

How precisely does cocaine achieve these effects in the brain As described in Chapter i, once a neurotransmitter is released from its neuronal terminal, its actions within the synapse are ended principally by reuptake into the presynaptic terminal. Cocaine primarily blocks the reuptake of dopamine but also acts similarly on norepinephrine and serotonin reuptake. If your neuronal terminals can be seen as acting like little vacuum cleaners, then cocaine essentially clogs the vacuum nozzle. As a consequence of this blockade, the concentrations of dopamine, norepinephrine, and serotonin within the synaptic cleft between two neurons increases dramatically. Withinmillions of synapses in the brain, these neurotransmitters are now free to continue to stimulate their receptors over and over, again and again. There are neuronal terminals for dopamine, norepinephrine, and serotonin scattered throughout the entire brain, and thus the consequences of cocaine on brain function are also widespread. 

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 reuptake is thought to be the major termination mechanism for the monoamine chemical signaling process. 

Cocaine is a potent CNS stimulant that elicits a state of increased alertness and euphoria with its actions similar to those of amphetamine but of shorter duration. These CNS effects are thought to be largely associated with the ability of cocaine to block dopamine reuptake at nerve synapses and thereby prolong the action of dopamine in the CNS. It is this response that leads to recreational abuse of cocaine. Cocaine also blocks the reuptake of norepinephrine at presynaptic nerve terminals this produces a sympathomimetic response (including an increase in blood pressure, heart rate, and body temperature). Cocaine is effective as a local anesthetic and vasoconstrictor of mucous membranes and is therefore used clinically for nasal surgery, rhinoplasty, and emergency nasotracheal intubation. 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

Atomoxetine (Strattera). Atomoxetine has recently been approved as a treatment for ADHD. Atomoxetine, similar to some of the antidepressants discussed later, is a preferential inhibitor of norepinephrine reuptake. Because nerve terminals in the cerebral cortex have no dopamine reuptake sites, dopamine is taken up at nearby norepinephrine reuptake sites. Consequently, all norepinephrine reuptake inhibitors increase the availability of dopamine in the prefrontal cortex, likely the primary mechanism of atomoxetine action in ADHD. 

Monoamines include the catecholamines (dopamine and norepinephrine) and 5-hydroxytryptamine. Although these compounds are present in very small amounts in the CNS, they can be localized using extremely sensitive histochemical methods. These pathways are the site of action of many drugs for example, the CNS stimulants cocaine and amphetamine appear to act primarily at catecholamine synapses. Cocaine blocks the reuptake of dopamine and norepinephrine, whereas amphetamines cause presynaptic terminals to release these transmitters. 

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. 

These agents have many properties in common. Both are sympathomimetic amines that exert their pharmacologic action by interfering in the reuptake of serotonin and norepinephrine into the presynaptic nerve terminal, thereby increasing their brain levels. In the case of phentermine, there is an increased release of dopamine, whereas with sibutramine, the reuptake into the presynaptic nerve terminal of serotonin, norepinephrine, and to a lesser extent dopamine, is hindered. 

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). 

The illicit drug used most commonly by young people at parties and raves is 3,4-methylenedioxymethamphetamine (MDMA) or ecstasy. The mechanism of action of MDMA is not completely understood, but it is believed to inhibit the reuptake of serotonin, to facilitate serotonin release, and to a lesser extent enhance dopamine and norepinephrine release from presynaptic nerve terminals. The serotonin boost can produce a sense of emotional closeness, elation, and sensory delight, and, along with the potential of MDMA to increase dopamine transmission in the reward pathway, it might be associated with the addictive properties of the drug. 

The morphology of the carotid body resembles chromaffin tissues expressing catecholamines. Now it is fairly established that carotid bodies express dopamine and norepinephrine, whereas there is no convincing evidence for epinephrine. Type I cells from a variety of species express tyrosine hydroxylase (TH) and dopamine jS hydroxylase (DBH), the enzymes responsible for the synthesis of dopamine (DA) and norepinephrine (NE), respectively (10,20,91). In addition, nerve fibers (of sensory as well as autonomic origin) and ganghon cells also show TH immunoreactivity (91). The actions of DA and NE are terminated by a reuptake mechanism involving specific transporters. However, evidence for DA and/or NE transporters in the carotid body is lacking. 

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