Involvement of the 5-HT1A receptors in classical fear conditioning in C57BL/6J mice

The present study examined the involvement of the 5-HT1A receptors in class ical fear conditioning using the 5-HT1A agonist 8-hydroxy-2-(di-n-propyloam ino)tetralin hydrobromide (8-OH-DPAT) and the selective "silent" 5- HT1A re ceptor antagonist (N[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyrid inyl)cyclohexane carboxamide trihydrochloride (WAY 100635). The drugs were administered both subcutaneously and bilaterally into the dorsal hippocampu s of male C57BL/6J mice. The training was performed in a single trial in wh ich a tone was followed by a footshock. The retention of context- and tone- dependent fear was examined in separate tests conducted either 1 or 24 hr a fter training. Subcutaneous 8-OH-DPAT (0.1-1.0 mg/kg), when injected before but not after training, caused a dose-dependent impairment of contextual f ear in both 1 and 24 hr tests, whereas tone-dependent fear was less affecte d. Pretraining intrahippocampal injections of 5.0 mug but not 1.0 mug 8-OH- DPAT caused a severe deficit in contextual fear when tested 24 hr after tra ining. When injected both subcutaneously and intrahippocampally, 8-OH-DPAT induced the 5-HT syndrome, indicative of postsynaptic 5-HT1A receptor activ ation at the dose ranges that impaired fear conditioning. However, the beha vioral changes induced by 8-OH-DPAT at the time of training could not accou nt for inhibitory effects of 8-OH-DPAT on fear conditioning. Neither subcut aneous (0.03 mg/kg) nor intrahippocampal (0.5 mug per mouse) WAY 100635 alt ered context- or tone-dependent fear. However, subcutaneous WAY 100635 bloc ked both the 5-HT syndrome and the impairment of fear conditioning induced by subcutaneous or intrahippocampal 8-OH-DPAT. In contrast, intrahippocampa l WAY 100635 blocked the impairment caused by intrahippocampal but not subc utaneous 8-OH-DPAT, indicating the involvement of extrahippocampal 5-HT1A r eceptors in fear conditioning. It is concluded that the deficits in fear co nditioning induced by 8-OH-DPAT are a result of postsynaptic 5- HT1A recept or activation that interferes with learning processes operating at acquisit ion but not consolidation. Furthermore, the dorsohippocampal 5- HT1A recept ors play an important but not exclusive role in the limbic circuitry subser ving contextual fear conditioning.