Involvement of the 5-HT_1AReceptors in Classical Fear Conditioning in C57BL/6J Mice

Abstract

The present study examined the involvement of the 5-HT 1A receptors in classical fear conditioning using the 5-HT 1A agonist 8-hydroxy-2-(di-n-propyloamino)tetralin hydrobromide (8-OH-DPAT) and the selective "silent" 5-HT 1A receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride (WAY 100635). The drugs were administered both subcutaneously and bilaterally into the dorsal hippocampus of male C57BL/6J mice. The training was performed in a single trial in which 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 after 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 fear in both 1 and 24 hr tests, whereas tone-dependent fear was less affected. Pretraining intrahippocampal injections of 5.0 g but not 1.0 g 8-OH-DPAT caused a severe deficit in contextual fear when tested 24 hr after training. When injected both subcutaneously and intrahippocampally, 8-OH-DPAT induced the 5-HT syndrome, indicative of postsynaptic 5-HT 1A receptor activation at the dose ranges that impaired fear conditioning. However, the behavioral changes induced by 8-OH-DPAT at the time of training could not account for inhibitory effects of 8-OH-DPAT on fear conditioning. Neither subcutaneous (0.03 mg/kg) nor intrahippocampal (0.5 g per mouse) WAY 100635 altered context-or tone-dependent fear. However, subcutaneous WAY 100635 blocked both the 5-HT syndrome and the impairment of fear conditioning induced by subcutaneous or intrahippocampal 8-OH-DPAT. In contrast, intrahippocampal WAY 100635 blocked the impairment caused by intrahippocampal but not subcutaneous 8-OH-DPAT, indicating the involvement of extrahippocampal 5-HT 1A receptors in fear conditioning. It is concluded that the deficits in fear conditioning induced by 8-OH-DPAT are a result of postsynaptic 5-HT 1A receptor activation that interferes with learning processes operating at acquisition but not consolidation. Furthermore, the dorsohippocampal 5-HT 1A receptors play an important but not exclusive role in the limbic circuitry subserving contextual fear conditioning.

Transcriptional regulation of the 5-HT1Areceptor: implications for mental illness

“…As well, depression is associated with reduced levels of 5-HT 1A heteroreceptors, particularly in the hippocampus and prefrontal cortex, that may be induced in part by chronic stress [124]. These results suggest that strategies that target preferentially postsynaptic 5-HT 1A heteroreceptors may have greater effects in anxiety [125], while strategies that both augment 5-HT release and enhance post-synaptic 5-HT 1A signalling would be more effective to treat depression. Consistent with this idea, chronic SSRI treatment of anxiety subjects selectively reduced post-synaptic 5-HT 1A receptor levels in hippocampus and prefrontal cortex [126].…”

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

“…Several studies indicate that this task is dependent on both hippocampal and amygdala mechanisms. 41,42 Moreover, hippocampal 5-HT and 5-HT 1A receptors are important for emotional learning in the rat. 42,44 In this context, the finding of gender differences in 5-HT turnover in the St and Hp intriguing indicates the possibility for sexdependent control of the mood-related behavioral functions.…”

“…41,42 Moreover, hippocampal 5-HT and 5-HT 1A receptors are important for emotional learning in the rat. 42,44 In this context, the finding of gender differences in 5-HT turnover in the St and Hp intriguing indicates the possibility for sexdependent control of the mood-related behavioral functions. Depression is a frequent comorbidity in schizophrenic patients with appearance to have changes in serotonergic transmission 43 probably related to some of the negative symptomatology seen in schizophrenia.…”

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

“…Thus, the activation of 5-HT 1A receptors before but not immediately after training has been shown to impair retention in associative learning tasks such as stepthrough passive avoidance and fear conditioning (Misane et al, 1998a;Misane and Ö gren, 2000;Stiedl et al, 2000). It is notable that inhibitory effects of pretraining administration of 8-OH-DPAT on PA retention could not be explained by state-dependent factors (Misane et al, 1998a).…”