Dopamine tricyclic antidepressant action

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-rotransmitfers, such as norepinephrine and serotonin, at CNS presynaptic membranes, increasing their availability at postsynaptic receptor sites. The metabolite, 7-OH-amoxapine has significant dopamine receptor blocking activity similarto halo-peridol. Therapeutic Effect Produces antidepressant effects. 

Tricyclic antidepressants are the most commonly used drugs. They produce antidepressant effect by blocking the neuronal uptake of noradrenaline and exert anti-cholinergic activity. They also inhibit neuronal uptake of 5HT and dopamine. The exact mechanism of action is not known. The antidepressant effect is noticed after three to four weeks of drug administration. 

A growing number of drugs are used that affect the many neurotransmitters in the brain benzodiazepines and others act on GABAergic transmission antidepressants, such as monoamine oxidase inhibitors and tricyclic antidepressants, are thought to increase the concentration of transmitter amines in the brain and so elevate mood—these will also act at peripheral nerve terminals, so interactions with them are a combination of peripheral and central actions. Levodopa (L-dopa) increases central as well as peripheral dopamine, and the newer class of psychoactive drugs, the selective serotonin reuptake inhibitors (SSRIs) of which the ubiquitous fluoxetine (Prozac) is best known, act in a similar way on serotonergic pathways. 

FIGURE 6-48. Shown here is the icon of a norepinephrine and dopamine reuptake inhibitor (NDRI). In this case, four of the five pharmacological properties of the tricyclic antidepressants (TCAs) (Fig. 6—27) were removed. Only the norepinephrine reuptake inhibitor (NRI) portion remains to this is added a dopamine reuptake inhibitor action (ORI). 

Clomipramine has also aroused interest because of an action on prolactin release, which occurs with major tranquillizers but not with other tricyclic antidepressants (289). This action of clomipramine is related to its chemical structure and reflects a greater effect on dopamine metabolism and serotonin uptake compared with other antidepressants. 

So overall it is difficult to know what sort of drugs the tricyclic antidepressants are. They combine many different types of pharmacological action. They show some similarities to neuroleptics, to whom they are closely related structurally and there is some evidence that they too block the effects of dopamine. However there is not enough data currently to determine whether they share the neuroleptics most characteristic property of psychomotor deactivation. Most of them are powerful sedatives but it is not clear that they have any advantages over the use of safer sedatives like benzodiazepines. 

Brodie demonstrated that the tricyclic antidepressants do not reverse reserpine depression if the animal has been depleted of both dopamine and NE hence, he concluded that their action depends on the presence... 

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. 

Noradrenaline is transported by uptake systems that have been extensively studied. On release of noradrenaline from sympathetic nerve varicosities in the peripheral nervous system, it is subject to two uptake systems. Uptake 1 (UJ is a reuptake process where the noradrenaline is recovered by the nerve via a process that has a high affinity but relatively low maximum rate, whereas a second process, uptake 2 (Uj), clears noradrenaline from the tissues into extraneuronal sites by a low affinity, but fast, process (which is inhibited by GLUCOCORTICOIDS, phenoxybenzamine and normetanephrine). The first - the neuronal system - has been studied in detail, and is essentially the same process as used for dopamine and 5-hydroxytryptamine in the CNS. The U transport protein has now been cloned, and is one of a famiiy of transporter proteins which act as co-transporters for Na, Cl and the amine, driven by the ATP-generated electrochemical gradient for Na . This Ui noradrenaline reuptake process is inhibited by cocaine and amphetamine (thus accounting for some of their actions, particularly within the CNS), phenoxybenzamine and the extensive class of tricyclic and related compounds that are used as ANTIDEPRESSANTS (e.g. desipramine). 

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