Analysis of the 5-HT_1A receptor involvement in passive avoidance in the rat

Abstract

1. The effects of the 5-HT_2A/2C agonist DOB, the selective 5-HT_1A agonist NDO 008 (3-dipropylamino-5-hydroxychroman), and the two enantiomers of the selective 5-HT_1A agonist 8-OH-DPAT (R(+)-8-OH-DPAT and S(−)-8-OH-DPAT) were studied in a step-through passive avoidance (PA) test in the male rat.

2. The 5-HT_1A agonists injected prior to training (conditioning) produced a dose-dependent impairment of PA retention when examined 24 h later. R(+)-8-OH-DPAT was four times more effective than S(−)-8-OH-DPAT to cause an impairment of PA retention. Both NDO 008 and the two enantiomers of 8-OH-DPAT induced the serotonin syndrome at the dose range that produced inhibition of the PA response, thus, indicating activation of postsynaptic 5-HT_1A receptors.

3. Neither NDO 008 nor R(+)-8-OH-DPAT induced head-twitches, a behavioural response attributed to stimulation of postsynaptic 5-HT_2A receptors. In contrast, DOB induced head-twitches at the 0.01 mg kg⁻¹ dose while a 200 times higher dose was required to produce a significant impairment of PA retention.

4. The impairment of PA retention induced by both NDO 008 and R(+)-8-OH-DPAT was fully blocked by the active S(+)- enantiomer of the selective 5-HT_1A antagonist WAY 100135 and the mixed 5-HT_1A/β-adrenoceptor antagonist L(−)-alprenolol. In contrast, the mixed 5-HT_2A/2C antagonists ketanserin and pirenperone were found to be ineffective. Moreover, the β₂-adrenoceptor antagonist ICI 118551, the β₁-antagonist metoprolol as well as the mixed β-adrenoceptor blocker D(+)-alprenolol all failed to modify the deficit of PA retention by NDO 008 and R(+)-8-OH-DPAT. None of the 5-HT_1A or 5-HT_2A/2C receptor antagonists tested or the β-blockers altered PA retention by themselves.

5. A 3 day pretreatment procedure (200+100+100 mg kg⁻¹) with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) did not alter PA retention and did not prevent the inhibitory action of the 5-HT_1A agonists, indicating that their effects on PA do not depend on endogenous 5-HT.

6. The effects of NDO 008 on PA were also studied using a state-dependent learning paradigm. NDO 008 was found to produce a disruption of PA when given either prior to training or retention or both prior to training and retention but it failed to affect PA retention when given immediately after training.

7. These findings indicate that the deficit of passive avoidance retention induced by the 5-HT_1A agonists is mainly a result of stimulation of postsynaptic 5-HT_1A receptors but not 5-HT_2A receptors. The 5-HT_1A receptor stimulation appears to interfere with learning processes operating at both acquisition and retrieval.

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