Dopamine

Animal studies provide evidence that the serotonergic system may exert tonic inhibition on the central dopaminergic system. Serotonin has also been shown to decrease the generation of dopaminergic cells from mesencephalic precursors in rats, an effect mediated by 5-HT4 and 5-HT7 receptors found on glial cells (Parga et al. 2007). Thus, fluoxetine might diminish dopaminergic transmission consistent with anecdotes of extrapyramidal side effects (EPS) during fluoxetine therapy (Bouchard et al. 1989). 5-HT agonists, however, also exert a facilitatory influence on dopamine (DA) release (Benloucif and Galloway 1991), which can be antagonized by the 5-HT1 blocker pindolol, and evidence suggests that SSRIs may actually sensitize mesolimbic DA receptors (Arnt et al. 1984a, 1984b). Furthermore, repeated administration of fluoxetine, citalopram, or paroxetine to rats increased spontaneous dopaminergic neuronal activity (Sekine et al. 2007), and chronic fluoxetine treatment also increased brain-derived neurotrophic factor (BDNF) expression within rat dopaminergic regions (Molteni et al. 2006).

Many structurally diverse antidepressants are associated with a net enhancement of mesolimbic DA (see Klimek and Maj 1990). The benefits of antidepressants in an animal model of depression can be antagonized by a dopamine1 (D1) (SCH-23390) or dopamine2 (D2) blocker (sulpiride) (Sampson et al. 1991). Repeated administration of several SSRIs was found to increase the hypermotility response to several dopaminergic agents, including amphetamine, methylphenidate (Arnt et al. 1984b), quinpirole (Maj et al. 1984), and apomorphine (Plaznik and Kostowski 1987).

The induction of catalepsy or the inhibition of apomorphine-induced catalepsy is not a property of the SSRIs. Both citalopram and fluoxetine have been inactive in displacing D2 blockers (Peroutka and Snyder 1980). Baldessarini et al. (1992) reported that fluoxetine "even at high doses or with repeated treatment" demonstrated "no significant inhibition of the DA metabolism—increasing actions of haloperidol" (p. 191).

In summary, fluoxetine enhances central 5-HT transmission through increased output and/or increased postsynaptic receptor sensitivity (Blier et al. 1987). Fluoxetine's overall effects on the noradrenergic and dopaminergic systems are less straightforward and are also less likely to play a role in the drug's antidepressant effects. However, such changes alone, in any of the neurotransmitter systems, do not guarantee a clinically meaningful response (Charney et al. 1984). A change in baseline 5-HT function or a "permissive" set of interactions with other collocated neurotransmitter receptors is likely involved in the highly individualized responses in patients with depression.

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