The influence of aspirin on the interaction of SSRIs at their principle molecular drug target in the rodent brain: in vitro & ex vivo studies

Filippo Andreetta, Stefania Faedo, Paul Wren

GlaxoSmithKline S.p.A., Neuroscience Centre of Excellence for Drug Discovery, Verona, Italy

Recent evidence has suggested that the combination of non steroidal anti-inflammatory drugs (NSAIDs) with marketed antidepressant drugs (such as serotonin selective reuptake inhibitors; SSRIs) have the potential to increase the speed of onset of action and efficacy of drug treatment in both animals and man (Brunello et al., 2006; Mendlewicz et al., 2006). However the underlying molecular mechanisms involved in this apparent increased responsiveness are unknown. In this study we explored the functional sensitivity of the 5-HT transporter (SERT) in rat brain synaptosomes to the SSRI paroxetine in the presence and absence of the non-selective cyclooxygenase inhibitor aspirin in both in vitro and ex vivo experiments using previously established methods (Thomas et al., 2007).

Paroxetine potently inhibited [3H]5-HT uptake into rat brain synaptosomes in vitro with as pIC50 value of 9.16 ± 0.06 (n=5) whereas aspirin (up to 1mM) was inactive. In addition, aspirin did not alter the potency of paroxetine in inhibiting [3H]5-HT uptake and did not alter the Km or Vmax values of [3H]5-HT uptake in tissue derived from naïve non-drug treated rats. Ex vivo experiments were also conducted to measure the inhibition of [3H]5-HT uptake in rat brain symaptosomes after oral drug treatment (acute and chronic) in male rats (225-250g, Sprague Dowley, n=4 animals per group) with either; vehicle, paroxetine (3mg/kg), aspirin (45mg/kg) or the combination of these doses of paroxetine and aspirin. After acute (2 hour) treatment, the vehicle [3H]5-HT uptake parameters (Km = 31 ± 4.59 nM and Vmax = 1.25 ± 0.13 fmol/min/μg protein) and the potency of paroxetine to inhibit [3H]5-HT uptake (pKi value = 9.41 ± 0.01) were not affected by any of the drug treatments (p>0.05). After chronic (7 day) drug treatment, the vehicle [3H]5-HT uptake parameters (Km = 23 ± 0.89 nM and Vmax = 1.06 ± 0.01 fmol/min/μg protein and the potency of paroxetine to inhibit [3H]5-HT uptake (pKi value = 9.34 ± 0.03) were also not affected by any of these prolonged drug treatments (p>0.05).

These data collectively suggest that NSAIDs like aspirin, that block pro-inflammatory cytokines, have no effect on the functionality of SERT in rats and do not alter the pharmacological interaction of SSRIs with their main molecular target. It is however been suggested that such pro-inflammatory mediators can regulate the function of SERT (Zhu et al., 2006). Cytokines can not only induce depressive symptoms in man but are elevated in some depressed patients and in animal models of sickness behaviour (Dantzer et al., 2008). It remains feasible therefore that the sensitivity of SERT to the drug treatments explored in this study may be different in immune challenged rats and ultimately in depressed patients

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Dantzer et al., (2008). Nat Rev Neurosci. 9(1): 46-56.

Mendlewicz et al., (2006). Int Clin Psychopharmacol. 21(4): 227-231.

Thomas DR et al., (2007). Psychopharmacology (Berl). 93(2): 193-200.

Zhu et al., (2006). Neuropsychopharmacology. 31(10): 2121-2131.