Effect of chronic m ‐CPP on locomotion, hypophagia, plasma corticosterone and 5‐HT 2C receptor levels in the rat

The present study examined 5‐HT 2C receptor agonist‐induced behavioural tolerance and 5‐HT 2C receptor down‐regulation in adult rat brain. The effect of chronic subcutaneous infusion of the 5‐HT 2C 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 [ 3 H]‐mesulergine binding and hippocampal 5‐HT 2C receptor protein levels. Before chronic infusion, m ‐CPP (2.5 mg kg −1 , i.p.) attenuated the number of turns and rears made in a novel 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‐HT 2C receptor agonist injection. 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‐HT 2C receptor agonist‐induced hypophagia occurred. 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‐HT 2C receptors which contribute, in a tonic manner, to plasma corticosterone secretion under the conditions investigated. Chronic m ‐CPP infusion reduced the amount of [ 3 H]‐mesulergine binding (by 27%, without altering the K D ) in membranes prepared from parietal/occipital/temporal cortex (under conditions to exclude binding to 5‐HT 2A receptors) and 5‐HT 2C receptor protein‐like immunoreactive levels measured by radioimmunoassay in the hippocampus by 38%, confirming that 5‐HT 2C receptor down‐regulation had occurred. Even after 14 days m ‐CPP infusion only partial behavioural tolerance and 5‐HT 2C receptor down‐regulation were observed, which may vary in different brain regions of the rat. Thus the hypophagia produced by m ‐CPP may involve activation of 5‐HT 2C receptors in the hypothalamus, where there is a greater receptor reserve or which are more resistant to agonist‐induced down‐regulation than 5‐HT 2C receptors in limbic areas (striatum and nucleus accumbens) mediating m ‐CPP‐induced hypolocomotion.British Journal of Pharmacology (1998) 123 , 1707–1715; doi: 10.1038/sj.bjp.0701798