BEHAVIORAL 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-HT(1A)-agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) could be attenuated by the preferential 5-HT(1C)-agonist MK 212, 1-(meta-chlorophenyl)-piperazine (mCCP) and m-trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5-HT(2/1C)-agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). The mixed 5-HT(1A/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-HT(1A)-agonist 8-OH-DPAT was attenuated by the 5-HT(1C)-agonists MK 212 and mCPP. The 5-HT(1C)-agonist TFMPP had a bimodal effect: at low doses (<1 mg kg-1) it potentiated, and at higher doses (>2.2 mg kg-1) it attenuated forepaw treading. The mixed 5-HT(2/1C)-agonist DOI produced 5-HT2-related behaviours and potentiated 8-OH-DPAT-induced forepaw treading. This indicates an attenuating effect of 5-HT(1C)-receptor activation and a potentiating effect of 5-HT2-receptor activation. CGS 12066B had no effect in this respect. 4. Head shakes inrats 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-HT(1A)- or 5-HT(1C)-receptors. CGS 12066B attenuated the head shake response but only at 10 mg kg-1. 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.