The Selectivity of SSRIs as Inhibitors of 5HT Uptake

Evidence that SSRIs selectively inhibit neuronal uptake of 5-HT derives from several different types of experiments carried out both in vitro and ex vivo, some of which have been mentioned already. The most comprehensive approach has been to measure inhibition of [3H]monoamine uptake into synaptosomes prepared from various regions of the rodent brain.

Several points arise from such experiments. The first, and possibly the most important point, is that in all but one of the published synaptosomal studies, inhibition of uptake of different [3H]monoamines was compared across different brain regions. Yet, it cannot be assumed that uptake of any of the monoamines is the same throughout the brain. On the contrary, as early as 1975, Wong et al42 pointed out that inhibition of [3H]5-HT uptake by fluoxetine ranged from 2-70%, being greatest in the cortex, intermediate in the striatum and insignificant in the cerebellum. Similar arguments apply to [3H]dopamine uptake: fluoxetine inhibits uptake of this monoamine at nanomolar concentrations in the hippocampus and frontal cortex but has negligible effects in the striatum.43-44 This is almost certainly a function of the different densities of each type of transporter in different brain regions and/or the rate of spontaneous release of monoamines.

Secondly, it is the IC50 for inhibition of [3H]monoamine uptake which is often quoted when comparing the effects of different compounds (even across different studies). However, as emphasized by Bolden-Watson and Richelson,45 IC50s are influenced by many key experimental variables such as the concentration of competing [3H]monoamine, pH and Na+ concentration in the incubation medium. K;s should not be affected by these variables but, even so, estimates vary considerably from study to study (see also ref.46) (Table 10.3).

There is only one published report in which synaptosomes derived from the same tissue (the hypothalamus) were used to compare K;s for inhibition by SSRIs of uptake of different [ 3H]monoamines.51 Although this has made little difference to their rank order of selectivity (Table 10.4), the absolute selectivity ratio for fluoxetine (20-fold in favor of 5-HT versus noradrenaline) was less than half the 55-fold estimate which is widely quoted. In fact in one study, using slices of rat cortex, the selectivity for inhibition of 5-HT versus noradrenaline uptake was only 2-fold.53 This means that fluoxetine could be even less selective in vivo than clomipramine, a compound which is widely regarded as a preferential inhibitor of 5-HT uptake, but is never described as an SSRI.

Given that even the most conservative estimate of the K for inhibition of noradrenaline uptake by fluoxetine is about 10 ^M, and that of its active metabolite, norfluoxetine, is even less (0.1 ^M), it is worth considering whether noradrenaline reuptake might be inhibited at clinical doses of this drug. After chronic administration of a therapeutic dose in humans, plasma levels of fluoxetine and norfluoxetine are between 0.5-1.5 ^M54,55 and their concentration in the brain is probably even higher.56,57 Even assuming a free fraction of only 5% (see Chapter 2) then, since estimates of the Ki for inhibition of [3H]noradrenaline uptake by this SSRI lie between 0.1-10 ^M (Table 10.3), fluoxetine could cause some inhibition of noradrenaline reuptake in the clinical context. Similarly, the plasma concentration of citalopram (285 nM) after chronic administration of the recommended therapeutic dose (40 mg daily) is about 100 times greater than its Ki for inhibition of 5-HT uptake (1-10 nM) and its corresponding brain concentration is 10-fold greater still.58 This means that, in the therapeutic context, the concentration of citalopram (the most selective SSRI) is close to its Ki for inhibition of noradrenaline reuptake (4 ^M).

A further intriguing finding emerged in the course of investigating whether or not there was a target for inhibition of noradrenaline reuptake by SSRIs on noradrenergic neurons. Whereas, in microdialysis studies, the increase in extracellular noradrenaline concentration caused by intracortical infusion of fluoxetine was abolished by a selective chemical lesion of noradrenergic neurons (induced by the neurotoxin, DSP-4), the lesion did not reduce the inhibition of [3H]noradrenaline uptake by the same concentrations of fluoxetine in cortical synaptosomes.14 This suggests that there could be a target for inhibition of noradrenaline uptake by fluoxetine which is not on noradrenergic neurons. However, in parallel experiments, the DSP-4 lesion affected neither the increase in noradrenaline efflux nor the inhibition of synaptosomal [3H]noradrenaline uptake caused by citalopram.14 These findings cannot be explained by differences in the affinity of these SSRIs for transmitter receptors which might modulate noradrenaline release. In fact, the only explanation consistent with all the findings from this study is that there are at least two functionally distinct transporters for noradrenaline which differ in their sensitivity to fluoxetine and citalopram. It remains to be seen whether these different uptake sites are the products of the different mRNAs detailed above or whether it is their location in relation to the noradrenaline release sites which is the distinguishing factor (see ref. 14).

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