Effect of chronic m-CPP on locomotion, hypophagia, plasma corticosterone and 5-HT2C receptor levels in the rat

1 The present study examined 5-HT2C receptor agonist-induced behavioural tolerance and 5-HT2C receptor down-regulation in adult rat brain. The effect of chronic subcutaneous infusion of the 5-HT2C receptor agonist, m-chlorophenylpiperazine (m-CPP, 10 mg kg(-1), day(-1)), for 14 days was examined on daily food intake, the ability of acute m-CPP (2.5 mg kg(-1), i.p.) to induce hypolocomotion in a novel arena and elevate plasma corticosterone levels and on ex vivo cortical [H-3]-mesulergine binding and hippocampal 5-HT2C receptor protein levels. 2 Before chronic infusion, m-CPP (2.5 mg kg(-1), i.p.) attenuated the number of turns and rears made in a navel open field arena. In contrast, while m-CPP still elicited this hypolocomotion following 14 days, saline infusion, no such hypolocomotion occurred in rats given chronic m-CPP (10 mg kg(-1) day(-1)), indicating that almost complete tachyphylaxis of this behaviour occurred with chronic 5-HT2C receptor agonist injection. 3 During chronic infusion of m-CPP, rats consumed less food per day than saline-treated controls. Acute challenge with m-CPP following two weeks, treatment still attenuated food intake over the next four hours (by 43% and 30%, respectively from that on the previous day) in saline and m-CPP infusion groups, showing that only partial tolerance to 5-HT2C receptor agonist-induced hypophagia occurred. 4 In naive home cage rats, plasma corticosterone was elevated in a dose-dependent manner 35 min after m-CPP injection (0.5, 1 and 3 mg kg(-1), i.p.) but levels were comparable to control values 16 h after m-CPP (2, 5 and 10 mg kg(-1), i.p.). Sixteen hours after a single m-CPP injection (2.5 mg kg(-1), i.p.), plasma corticosterone levels were comparable in a group of rats which had received 14 days infusion of m-CPP or saline. However, following a similar acute m-CPP injection (2.5 mg kg(-1), i.p., -16 h) in rats previously infused for 14 days with m-CPP, plasma corticosterone levels were lower than those in a separate group which received no chronic infusions (but only acute m-CPP injection), even though the plasma m-CPP levels were comparable in both groups. The data are consistent with the proposal that chronic m-CPP induced some down-regulation of hypothalamic 5-HT2C receptors which contribute, in a tonic manner, to plasma corticosterone secretion under the conditions investigated. 5 Chronic m-CPP infusion reduced the amount of [H-3]-mesulergine binding (by 27%, without altering the K-D) in membranes prepared from parietal/occipital/temporal cortex (under conditions to exclude binding to 5-HT2A receptors) and 5-HT2C receptor protein-like immunoreactive levels measured by radioimmunoassay in the hippocampus by 38%, confirming that 5-HT2C receptor down-regulation had occurred. 6 Even after 14 days m-CPP infusion only partial behavioural tolerance and 5-HT2C receptor downregulation were observed, which may vary in different brain regions of the rat. Thus the hypophagia produced by m-CPP may involve activation of 5-HT2C receptors in the hypothalamus, where there is a greater receptor reserve or which are more resistant to agonist-induced down-regulation than 5-HT2C receptors in limbic areas (striatum and nucleus accumbens) mediating m-CPP-induced hypolocomotion.