Effects of repeated daily treatments with a 5-HT3 receptor antagonist on dopamine neurotransmission and functional activity of 5-HT3 receptors within the nucleus accumbens of Wistar rats.

摘要

A previous study indicated that pretreatment with repeated daily injections of serotonin-3 (5-HT3) receptor antagonists subsequently reduced the effectiveness of the 5-HT3 antagonists to attenuate ethanol intake under 24-h free-choice conditions; one possibility to account for this is that the functional activity of the 5-HT3 receptor may have been altered by prior treatment with the antagonists. The present experiments were conducted to examine the effects of local perfusion of the 5-HT3 agonist 1-(m-chlorophenyl)-biguanide (CPBG) on the extracellular levels of dopamine (DA) in the nucleus accumbens (ACB) and ventral tegmental area (VTA) of adult male Wistar rats that had received repeated daily injections of the 5-HT3 antagonist, MDL 72222 (MDL). In vivo microdialysis was used to test the hypothesis that alterations in 5-HT3 receptor function have occurred with repeated antagonist injections. One group was given daily injections of MDL (1 mg/kg, s.c.) for 10 consecutive days (MDL group), and the other group was administered saline for 10 days (saline group). On the day after the last treatment, rats were implanted with a unilateral guide cannula aimed at either the ACB or VTA. Two days later, the microdialysis probe was inserted into the guide cannula; on the next day, microdialysis experiments were conducted to determine the extracellular levels of DA in the ACB or VTA. Local perfusion of CPBG (17.5, 35, 70 microM) in the ACB significantly stimulated DA release in the saline- and MDL-treated animals. In terms of percent baseline, the CPBG-stimulated DA release was higher in the MDL-treated group than in the saline-treated group in both the ACB and VTA; however, on the basis of the extracellular concentration, there were no significant differences in the ACB between the two groups. Using the no-net-flux microdialysis, it was determine that the basal extracellular concentration of DA in the ACB was approximately 60% lower in the MDL group than saline group; there was no difference between the groups in the extraction fraction (clearance). Overall, the results suggest that repeated daily treatments with MDL decreased basal DA neurotransmission in the ACB and did not have a clear effect on functional activity of 5-HT3 receptors in the ACB.