SSRIs and Extracellular Catecholamines

One test of whether changes in catecholaminergic transmission could contribute to the therapeutic effects of SSRIs is to establish that these drugs increase the concentration of extracellular catecholamines in the brain. Although the development of microdialysis in vivo has enabled investigation of this question, the few studies that have been carried out differ in respect of the brain region studied, the compounds tested, the dose administered and the route by which the drug is given. Nevertheless, with the exception of fluvoxamine, published reports generally agree that there is an increase in the concentration of extracellular noradrenaline and dopamine after either local infusion (via the microdialysis probe) or systemic administration of an SSRI (Table 10.1). Despite the dearth of studies from which to form any firm conclusions, it seems that there could be regional variation in the effects of individual compounds. This could well reflect regional differences in the density of monoamine transporters or the spontaneous (resting tonic) release of catecholamines.

There is reason to believe that inhibition of neuronal reuptake of noradrenaline could contribute to the SSRI-induced increase in the extracellular concentration of this neurotransmitter, especially when test drugs are perfused via the probe. For instance, an appreciable increase in the concentration of extracellular noradrenaline is achieved on infusion of 5 ^M of fluoxetine.14 Bearing in mind that probably as little as 10% of the test compound diffuses from the probe, and that its concentration will decline progressively with increasing distance from the probe, the highest concentration of fluoxetine in the extracellular fluid will be close to its Ki for inhibition of noradrenaline reuptake (0.1-10 ^M) (see: Table 10.3). Evidence described below confirms that such concentrations of fluoxetine are also well within the range of those attained in the clinical context. In general, Kis for

Selective Serotonin Reuptake Inhibitors (SSRIs): Past, Present and Future, edited by S. Clare Stanford. ©1999 R.G. Landes Company.

Table 10.1. Effects of SSRIs on catecholamine efflux in rat brain

Noradrenaline

Dopamine

Brain region

Efflux

Reference

Efflux

Reference

Local infusion

Citalopram

frontal cortex

1

ventral tegmentum

2

2

Fluoxetine

frontal cortex

1,3

3

hypothalamus

NC

4

striatum

9

ventral tegmentum

2

Fluvoxamine

frontal cortex

NC

3

3

Paroxetine

hippocampus

NC

5

Systemic

Citalopram

ventral tegmentum

^ (weak)

10

Fluoxetine

frontal cortex

3,6

3,6

hypothalamus

4,7

straitum

NC

11,12

13

nucleus accumbens

13

ventral tegmentum

10

Fluvoxamine

frontal cortex

NC

3

NC

3

Paroxetine

hippocampus

8

increase, decrease, NC; no change increase, decrease, NC; no change inhibition of dopamine uptake are higher than those for noradrenaline and so it is less likely that therapeutic doses of SSRIs will affect reuptake of this neurotransmitter. However, one limitation of microdialysis is that it is hard to distinguish whether an increase in the extracellular concentration of a neurotransmitter is due to a reduction in its rate of reuptake and/or an increase in its rate of release. These alternatives are discussed in the following sections.

Defeat Depression

Defeat Depression

Learning About How To Defeat Depression Can Have Amazing Benefits For Your Life And Success! Discover ways to cope with depression and melancholic tendencies! Depression and anxiety particularly have become so prevalent that it’s exceedingly common for individuals to be taking medication for one or even both of these mood disorders.

Get My Free Ebook


Post a comment