Selective serotonin reuptake inhibitors mediation

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. 

Monaca, C., Boutrel, B., Hen, R., Hamon, M. Adrien, J. (2003). 5-HTia/b receptor-mediated effects of the selective serotonin reuptake inhibitor citalopram, on sleep studies in 5-HTia and 5-HTib knockout mice. Neuropharmacology 28, 850-6. 

Numerous antidepressants were synthesized, developed and marketed on the basis of the serotonin hypothesis. The selective serotonin reuptake inhibitors (SSRIs) are similarly effective as the older tricyclic antidepressants, but have the advantage of being less toxic and not inducing anticholinergically mediated side effects (Chapter 1). From the scientific point of view1 they represent an example of mechanistic, hypothesis-driven research and development in psychopharmacology (Chapter 2). 

Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions an update. Curr Drug Metab 2002 3 13-37. 

Simpson DA, Headley PM, Lumb BM (2008) Selective inhibition from the anterior hypothalamus of C- versus A-fibre mediated spinal nociception. Pain 136 305-312 Singh VP, Jain NK, Kulkarni SK (2001) On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor. Brain Res 915 218-226 Sipe JC, Arbour N, Gerber A, Beutler E (2005) Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism possible risk for autoimmune disorders. J Leukoc Biol 78 231-238... 

A mechanism for altering synaptic availability of 5-HT is inhibition of presynaptic reaccumulation of neuronally released 5-HT. Selective serotonin reuptake inhibitors (SSRIs e.g., fluoxetine [PROZAC]) potentiate and prolong the action of 5-HT released by neuronal activity. Effects of 5-HT-active drugs, like the SSRIs, in anxiety and depressive disorders strongly suggest an effect of 5-HT in the neurochemical mediation of these disorders. SSRIs are the most widely used treatment for endogenous depression (see Chapter 17). 

Reuptake of serotonin by enteric neurons and epithelium is mediated by the same mechanism as 5-HT reuptake by serotonergic neurons in the CNS. This reuptake therefore also is blocked by selective serotonin reuptake inhibitors (see Chapter 17), which explains the common side effect of diarrhea that accompanies the use of these agents. 

Serotonin mediates many central and peripheral physiological functions, including contraction of smooth muscle, vasoconstriction, food intake, sleep, pain perception, and memory, a consequence of it acting on several distinct receptor types. Although 5-HT may be metabolized by monoamine oxidase, platelets and neurons possess a high-affinity mechanism for reuptake of 5-HT. This mechanism may be inhibited by the widely prescribed antidepressant drugs termed selective serotonin re-uptake inhibitors (SSRl), e.g. fluoxetine (Prozac ), thereby increasing levels of 5-HT in the central nervous system. 

There are several antipsychotics that are substrates to CYP2D6 (von Bahr et ah, 1991 Jerling et ah, 1996 Ring et ah, 1996 (Fang and Gorrod, 1999 Flockhart and Oesterheld, 2000) (Table 26.3). Moreover, several antipsychotics may act as inhibitors of CYP2D6-mediated biotransformation. These include thioridazine, chlorpromazine, haloperidol, fluphenazine, and pimozide (Desta et ah, 1998 Shin et ah, 1999). Of particular salience is the fact that the serotonin selective reuptake inhibitors (SSRIs) fluoxetine and paroxetine are metabolized to a significant extent by this isoenzyme. 

FIGURE 6-39. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 5. Finally, once the SSRIs have blocked the reuptake pump (Fig. 6-36), increased somatodendritic serotonin (Fig. 6-36), desensitized somatodendritic serotonin 1A autoreceptors (Fig. 6—37), turned on neuronal impulse flow (Fig. 6-38), and increased release of serotonin from axon terminals (Fig. 6— 38), the final step shown here may be the desensitization of postsynaptic serotonin receptors. This has also been shown in previous figures demonstrating the actions of monoamine oxidase (MAO) inhibitors (Fig. 6-4) and the actions of tricyclic antidepressants (Fig. 6—6). This desensitization may mediate the reduction of side effects of SSRIs as tolerance develops. 

Stahl, S.M. (1998) Mechanism of action of serotonin selective reuptake inhibitors serotonin receptors and pathways mediate therapeutic effects and side effects (mechanism of action of SSRIs). Journal of Affective Disorders 12 51(3), 215—35. 

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