Blocks Dopamine Transporter

The reinforcing effects of cocaine and cocaine analogues correlate best with their effectiveness in blocking the dopamine transporter, which leads to increased dopaminergic stimulation at critical brain sites. However, cocaine also blocks both norepinephrine (NE) and serotonin (5-HT) reuptake, and chronic use of cocaine produces changes in these neurotransmitter systems as measured by reductions in the neurotransmitter metabolites MHPG (3-methoxy-4 hydroxyphenethyleneglycol) and 5-HIAA (5-hydroxyindoleacetic acid). 

---

Volkow N., Wang G., Fowler J. et al. Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain. Life Sci. 65 7, 1999. 

Cocaine Blocks dopamine transporter, thus increasing dopaminergic stimnlation Increases alertness and energy, euphoria, insomnia, restlessness, fear, paranoia, hallucinations. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Dopamine depleting agents. Reserpine, a natural alkaloid that blocks vesicular transport of monoamines, depletes stored monoamines, including DA. DA depletion is associated with the emergence of parkinsonism. This effect of reserpine was among the first clues that PD is the result of DA deficiency (see above). Generally, the parkinsonism resulting from reserpine is reversible. 

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). 

Bupropion is an atypical antidepressant drug that is the only nonnicotine-based prescription medicine approved for smoking cessation by the FDA. Its mechanism of action is presumed to be mediated by its capacity to block neuronal reuptake of dopamine and/or norepinephrine (Fiore et al. 2000). Relative to other antidepressants, bupropion has a relatively high affinity for the dopamine transporter (Baldessarini 2001). There is also evidence that bupropion acts as a functional nicotine antagonist, suggesting another potential mechanism by which bupropion could reduce smoking rates (Slemmer et al. 2000). 

Cocaine (8), from Erythroxylum coca Lam., besides causing euphoria by inhibiting the dopamine transport protein (DAT) responsible for its recreational and illegal use, exerts a local anesthetic activity through blocking sodium channels and is still used as a probe for this target. 

Ultimately, the effects of virtually aU existing antidepressants can be traced to the improvement of neurotransmission in the brain by one or more monoamine neurotransmitters, that is serotonin (5-HT, 4), norepinephrine (NE, 5), and dopamine (DA, 6). By blocking monoamine transporters, which remove the neurotransmitter from the synapse and extracellular space by uptake processes, the drugs increase extracellular levels of the transmitter and cause a cascade of intracellular events leading to the desired CNS effect. 

Dopamine is removed from the synapse via two mechanisms. First, COMT degrades intrasynaptic DA. Second, the dopamine transporter (DAT) [see (4) in Fig. 2.9], a Na /CD-dependent neurotransmitter transporter, transports DA in either direction, depending on the concentration gradient. The DAT is blocked selectively by drugs such as cocaine, amphetamine, bupropion, and nomifensine. 

Methylphenidate s mode of action is not completely known, but it is believed that ADHD symptoms are related to the dopaminergic areas of the brain. Animal studies indicate that methylphenidate affects several neurotransmitters to counteract ADHD behavior. Methylphenidate binds to dopamine transporters in the presynaptic neuron, blocking the reuptake of dopamine and increasing extracellular dopamine. Methylphenidate also influences norepinephrine reuptake and influences serotonin to a minor degree. 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

The most commonly used agents to enhance attention in attention deficit disorder are the stimulants methylphenidate and ( -amphetamine. Other effective stimulants are not as widely used, pemoline because of liver toxicity and methamphetamine because of its greater abuse potential. Methylphenidate and ( -amphetamine act predominantly by releasing dopamine from presynaptic dopamine terminals (Figs. 12— 2 and 12—3). These agents not only block the dopamine transporter but may actually... 

FIGURE 12-3. When (/-amphetamine binds to the presynaptic dopamine transporter on the dopamine neuron, it not only blocks dopamine reuptake but actually causes dopamine release. There may be a preference or selectivity for cortical over striatal dopamine presynaptic terminals by (/-amphetamine, so lower doses may have preferential effects on attention rather than on motor activity. Methylphenidate has a similar action, which is not quite as rapid but longer-lasting in many patients. 

Cocaine (Fig. 13—3) has two major properties it is both a local anesthetic and an inhibitor of monoamine transporters, especially dopamine (Fig. 13—4). Cocaine s local anesthetic properties are still used in medicine, especially by ear, nose, and throat specialists (otolaryngologists). Freud himself exploited this property of cocaine to help dull the pain of his tongue cancer. He may have also exploited the second property of the drug, which is to produce euphoria, reduce fatigue, and create a sense of mental acuity due to inhibition of dopamine reuptake at the dopamine transporter. Cocaine also has similar but less important actions at the norepinephrine and the serotonin transporters (Fig. 13—3). Cocaine may do more than merely block the transporter—it may actually release dopamine (or norepinephrine or serotonin) by reversing neurotransmitter out of the presynaptic neuron via the monoamine transporters (Fig. 13—4). 

FIGURE 13—4. Pharmacology of cocaine. Cocaine is a powerful inhibitor of the dopamine transporter. Blocking this transporter acutely causes dopamine to accumulate, and this produces euphoria, reduces fatigue, and creates a sense of mental acuity. Cocaine has similar but less important actions at the norepinephrine and serotonin transporters. 

In 1997, researchers at Brookhaven National Laboratory published a report that provided further evidence to support what other scientists have discovered about addiction. Cocaine addicts were given cocaine by vein, and then brain scans were performed to measure the activity of the system that governs the reabsorption of dopamine (dopamine transporter system, or DAT). 2 The researchers discovered that their subjects reported feeling high when at least 50 percent of the DAT molecules were blocked. The more transporter sites that were blocked by cocaine, the more intense the high. 

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. 

Fig. 15. Dopamine transporter binding (as revealed by [3H] mazindol in the presence of desmethylimipramine, to block binding to the norepinephrine transporter) in the post-mortem striatum of a human cocaine user and normal control subject. A reduction of the dopamine transporter binding sites was found in association with cocaine use in this population (taken from Hurd and Herkenham, 1993).

Weakly blocks dopamine reuptake pump (dopamine transporter), and may increase dopamine neurotransmission... 

---