Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice.

1. Different 5-hydroxytryptamine (5-HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5-HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction between different 5-HT receptor subtypes was studied. 2. Hypothermia and hypoactivity in mice induced by the 5-HT1A-agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) could be attenuated by the preferential 5-HT1C-agonists MK 212, 1-(meta-chlorophenyl)-piperazine (mCPP) and m-trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5-HT2/1C-agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). The mixed 5-HT1A/1B-agonist CGS 12066B at 10 mg kg-1 potentiated hypothermia and had no effect on hypoactivity. 3. Forepaw treading in rats induced by the 5-HT1A-agonist 8-OH-DPAT was attenuated by the 5-HT1C-agonists MK 212 and mCPP. The 5-HT1C-agonist TFMPP had a bimodal effect: at low doses (less than 1 mg kg-1) it potentiated, and at higher doses (greater than 2.2 mg kg-1) it attenuated forepaw treading, the mixed 5-HT2/1C-agonist DOI produced 5-HT2-related behaviours and potentiated 8-OH-DPAT-induced forepaw treading. This indicates an attenuating effect of 5-HT1C-receptor activation and a potentiating effect of 5-HT2-receptor activation. CGS 12066B had no effect in this respect. 4. Head shakes in rats induced by DOI could be attenuated by 8-OH-DPAT, TFMPP, mCPP and MK 212. The ID50S were 0.03, 0.7, 0.1 and .2 mg kg-1, respectively. This suggests that a 5-HT2-receptor-mediated effect may be attenuated by activation of 5-HT1A- or 5-HT1c-receptors. CGS 12066B attenuated the head shake response but only at 10mg kg- '. 5. The results suggest that interactions exist between the different 5-HT receptor subtype-mediated events. Therefore, care is needed in drawing conclusions from functional measurements when compounds have more or less equal affinities for more than one 5-HT-receptor subtype.