Dopamine reuptake inhibitors cocaine

Rothman R. High affinity dopamine reuptake inhibitors as potential cocaine antagonists a strategy for drug development. Life Sci. 46 PL17, 1990. 

Slow-onset, long duration dopamine reuptake inhibitors with reduced potential for substance abuse have been suggested as therapies for psychostimulant addiction [33-35]. A series of slow-onset, long duration N-alkyl analogues of methylphenidate were recently reported to have enhanced selectivity for the dopamine transporter [34]. A representative compound is 13, an RR/SS diastereomer (DAT K, = 16nM, SERT K = 5900 nM, NET K-, = 840 nM). In a locomotor activity assay in mice, 13 has a slow onset of activity (20-30 min) with peak activity occurring between 90 and 120 min. In contrast, both methylphenidate and cocaine are active within 10 min and reach peak activity within 30 min. 

Chlorophenylpyridomorphinan derivatives, (I), effective as k opioid receptor antagonists were prepared by the author (1) in an earlier investigation and used in the treatment of heroin or cocaine addictions. l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, (II), prepared by Lippa (2) was effective as a dopamine-reuptake inhibitor and was used in the treatment of addiction disorders. 

First, the extracts of the roots of Ruscus aculeatus at higher concentrations caused their contractions of canine cutaneous veins in part because the extracts could reveal an indirect sympathomimetic effect for the inhibition to the neuronal uptake such as cocaine (40) (Figure 11) of a serotonin-norepinephrine-dopamine reuptake inhibitor [31]. Here, a selective ai-adrenergic blocker prazosin (41) and a selective a2-adrenergic blocker rauwolscine (a-yohimbine. 42) (Figure 11) are present in the canine saphenous vein [32, 33] might greatly contribute to their contractile response to the extracts of the roots of Ruscus aculeatus. 

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. 

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). 

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 catecholamine hypothesis was then modified to include 5-HT in the etiology of depression (9,10). It should be noted, however, that not all Inhibitors of monoamine reuptake are antidepressants, because cocaine, a potent inhibitor of NE and dopamine reuptake, is not an antidepressant but, rather, an addictive stimulant. Subsequent studies with inhibitors of monoamine biosynthesis appear to confirm Kielholz s opinion and Schiidkraut s modified theory that clinical depression is the result of a deficiency in both 5-HT and NE and that the antidepressive mechanism of action most likely affects levels of both. 

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 high affinity of the reuptake systems for monoamines, as measured by the Michaelis constant, is on the order of 0.1-0.4 pM the low affinity is about 10-fold higher. Specific uptake inhibitors for each monoamine have apparently been developed. Chlorimipramine and Lilly 110/40 are presumed to be specific for serotonergic uptake systems. Benztropine and amphetamine (an action separate from its ability to enhance catecholamine release) are thought to block specifically dopamine uptake and desmethyl-imipramine and cocaine are believed to inhibit norepinephrine uptake. 

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