Responsiveness of 5-HT(1A) and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition

BACKGROUND: The only antidepressant drugs that are effective in the treatment of obsessive-compulsive disorder (OCD) are those that effectively block the reuptake of serotonin (5-hydroxytryptamine; 5-HT). In humans, positron emission tomography studies have implicated the orbitofrontal cortex (OFC) in the mediation of OCD symptoms. In animals, administration of selective serotonin reuptake inhibitors (SSRIs) for 8 weeks (but not 3 weeks) led to increased release of 5-HT in the OFC, because of desensitization of the terminal 5-HT autoreceptors. However, the increase in synaptic levels of 5-HT in the OFC after long-term administration of SSRIs might be cancelled out by desensitization of postsynaptic 5-HT receptors. This study was undertaken to investigate if these OFC receptors adapt under such conditions. METHODS: In vivo electrophysiologic techniques were used in this animal study. Male Sprague-Dawley rats received the SSRI paroxetine or vehicle control, delivered by implanted osmotic minipumps, for 3 or 8 weeks. With the rats under anesthesia, neuronal responsiveness to the microiontophoretic application of various drugs was assessed by determining the number of spikes suppressed per nanoampere of ejection current. RESULTS: After administration of paroxetine for either 3 weeks or 8 weeks, there was no modification in the inhibitory effect of 5-HT, the preferential 5-HT(2A) receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) or the preferential 5-HT(2C) receptor agonist 3-chlorophenyl piperazine dihydrochloride (mCPP). In contrast, the inhibitory effect of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT) was attenuated in the OFC after both 3 and 8 weeks of paroxetine administration. CONCLUSION: These results indicate a desensitization of postsynaptic 5-HT(1A) receptors in the OFC but a lack of compensatory adaptation of the 5-HT receptor(s) mediating the main effect of 5-HT in this brain region. These observations imply that the activation of normosensitive postsynaptic 5-HT2-like receptors may mediate the effect of enhanced 5-HT release in the OFC.