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Abstract Rationale: Previous research found no adaptations in presynaptic 5-HT[sub 1A] receptors in mice lacking 5-HT[sub 1B] receptors (5-HT[sub 1B] KO). Stress and 5-HT[sub 1A] receptor agonists induce corticosterone release in mice via hypothalamus-pituitary-adrenal (HPA) axis activation. 5-HT[sub1] KO mice are hyperreactive to mild stressors and this might be reflected in altered postsynaptic 5-HT[sub 1A] receptor sensitivity. Objectives: Our aim was to determine whether the activity of the HPA axis was increased in 5-HT[sub 1B] KO mice in response to mild stress and pharmacological activation of 5-HT[sub 1A] receptors as an indication of putative adaptive changes in postsynaptic 5-HT[sub 1A] receptor function. Methods: The effect of mild stress [i.e., the stress-induced hyperthermia (SIH) paradigm], induced by rectal temperature measurement, was determined on temperature and corticosterone over time (0, 5, 10, 20, 30, 60, and 90 min) in 5-HT[sub 1B] KO and wildtype mice. In addition, corticosterone was measured 60 min after 5-HT[sub 1A] receptor activation by flesinoxan (0, 0.03, 0.1, 0.3, 1, and 3 mg/kg SC). Blood was collected and plasma corticosterone levels were determined by radioimmunoassay. Results: Both genotypes showed comparable time-dependent SIH responses, whereas basal temperature was higher in 5-HT[sub 1B] KO mice. The effect of SIH on temperature was mirrored by mild increases in plasma corticosterone. Activation of 5-HT[sub 1A] receptors caused a strong dose-dependent release of corticosterone in both genotypes. Neither response observed showed differences between both genotypes. Conclusions: Although 5-HT[sub 1B] KO mice are hyperreactive to mild stress, this reactivity is not reflected by stronger corticosterone responses in the SIH paradigm. The lack of shift in dose response curves for... [ABSTRACT FROM AUTHOR]

Abstract Previous drug discrimination studies with the serotonergic drug m-chlorophenylpiperazine (mCPP) showed conflicting results, with some authors concluding that the cue was mediated by 5-HT[sub 2C] receptors, but others that it was definitively not. We further examined the discriminative stimulus properties of mCPP in rats and reviewed previously published data. We trained rats to discriminate mCPP (2.0 mg/kg, PO) from water. We found that the mCPP cue generalized to m-trifluoromethyl-phenylpiperazine (TFMPP) and 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212), and partially to eltoprazine, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), fenfluramine and trazodone. A moderate level of generalization was obtained with quipazine, 1-(m-chlorophenyl)biguanide and clonidine. No generalization was found with flesinoxan, methiothepin, idazoxan and haloperidol. Mianserin and methysergide antagonized the mCPP stimulus, whereas ketanserin antagonized it partially. Metergoline, methiothepin and clozapine only marginally antagonized the mCPP stimulus. These results show that the discriminative stimulus effects of mCPP are predominantly mediated by 5-HT[sub 2C] receptors, and to some extent by 5-HT[sub 1B] receptors. When considering our results and other research together, the substitution tests clearly point to a 5-HT[sub 2C] receptor mediated stimulus, with an additional role for 5-HT[sub 1B] receptors. Antagonism studies are less clearcut, but are also suggestive of a 5-HT[sub 2C] receptor mediated effect. A definitive answer as to whether other receptors, e.g. 5-HT[sub 2B] and 5-HT[sub 7], are of any importance in mCPP's discriminative stimulus properties has to wait for more selective ligands. [ABSTRACT FROM AUTHOR]