The functional sensitisation of sigma receptors following chronic selective serotonin reuptake inhibitor treatment.

Abstract

The purpose of the present study was to investigate the potential impairment of normal motor function following chronic selective serotonin reuptake inhibitor treatment that may result from sensitisation of sigma receptors. Rats were chronically treated with either sertraline, citalopram, paroxetine or fluvoxamine and a selective sigma receptor ligand, di-o-tolylguanidine (DTG), for 28 days. All animals then received an acute intra-rubral injection of either DTG or saline. Following the direct injection of DTG into the red nucleus, rats chronically treated with DTG exhibit a maximal behavioural response characterised as a pronounced dystonia. Animals chronically treated with sertraline and citalopram elicited a response similar to that of control animals following the acute DTG challenge, whereas chronic treatment with paroxetine and fluvoxamine significantly decreased and increased the dystonic response, respectively. Facial spasticity and vacuous chewing movements were associated with, and reflected the extent of, the DTG-induced dystonia. Changes in regional biogenic amine concentrations were also determined. The concentrations of serotonin and noradrenaline were determined in the brain stem and cerebellum following the intra-rubral injection of either saline or DTG in animals that had been chronically treated with a selective serotonin reuptake inhibitor or DTG. There was a significant increase in serotonin concentration in the brain stem as a result of chronic DTG and fluvoxamine treatments. The increase in serotonin correlated with the reported potentiation of dystonia in animals that received 28 days treatment with these drugs. The potentiation of dystonia following chronic DTG and fluvoxamine treatments suggests that these drugs sensitise the sigma2 receptors, an effect that does not appear to be shared by citalopram, sertraline or paroxetine.