Behavioural Pharmacology
5-HT7 receptor stimulation by 8-OH-DPAT counteracts the impairing effect of 5-HT1A receptor stimulation on contextual learning in mice

https://doi.org/10.1016/j.ejphar.2008.08.026Get rights and content

Abstract

The principal 5-HT1A receptor agonist 8-Hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) impairs several different types of learning. Besides 5-HT1A receptors, 8-OH-DPAT stimulates 5-HT7 receptors, but it is not known whether 5-HT7 receptors contribute to the impairments. The 5-HT7 receptor antagonist (2R)-1-[(3-Hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl] pyrrolidine (SB-269970) was combined with 8-OH-DPAT to dissociate 5-HT1A from 5-HT7 receptor-mediated effects, in the passive avoidance task for emotional learning. SB-269970 intensified impairments caused by 8-OH-DPAT. SB-269970 alone had no effect on memory performance, but moderately decreased retention under suboptimal learning conditions. These findings indicate that 5-HT7 receptor stimulation by 8-OH-DPAT counteracts 5-HT1A receptor-mediated impairments in hippocampal-dependent contextual learning.

Introduction

The 5-HT1A receptor agonist 8-OH-DPAT has been used as the principal agonist in studies on the functional role of the 5-HT1A receptor (Arvidsson et al., 1981, De Vry, 1995). However, subsequent studies revealed that 8-OH-DPAT also has high affinity for 5-HT7 receptors (Bard et al., 1993, Lovenberg et al., 1993, Ruat et al., 1993). Although 8-OH-DPAT displays larger agonistic potency at 5-HT1A receptors than 5-HT7 receptors, accumulating data point out that 5-HT7 receptors contribute to the physiological effects of 8-OH-DPAT. Due to the lack of specific 5-HT7 receptor agonists, 8-OH-DPAT or other unselective agonists have been combined with the selective 5-HT7 receptor antagonist SB-269970, to reveal the functional role of 5-HT7 receptors (Hagan et al., 2000, Lovell et al., 2000). Such studies have reported both additive and opposite effects of 5-HT1A and 5-HT7 receptors on different physiological functions. For example, the hypothermic effect of 8-OH-DPAT involves stimulation of both 5-HT1A and 5-HT7 receptors (Hedlund et al., 2004), while the phase-advancing effect of 8-OH-DPAT on circadian rhythms is counteracted by 5-HT7 receptor stimulation (Sprouse et al., 2004).

The 5-HT1A receptor is abundant in brain areas associated with learning and memory functions, including the hippocampus, cerebral cortex and septum (Azmitia et al., 1996, Kia et al., 1996), while the 5-HT7 receptor is located primarily in hippocampal, thalamic and cortical areas (Bard et al., 1993, Gustafson et al., 1996, Lovenberg et al., 1993, Plassat et al., 1993, Ruat et al., 1993). Several studies have shown that the 5-HT1A receptor modulates different types of learning. Indeed, the 5-HT1A receptor antagonists WAY-100635 or NAD-299 blocks the impairments induced by systemic and intrahippocampal administration of 8-OH-DPAT in several learning and memory tasks (Carli et al., 1995, Madjid et al., 2006, Misane et al., 1998, Ögren, 1985, Stiedl et al., 2000). Recent studies also implicate the 5-HT7 receptor in regulation of hippocampus-dependent functions, since 5-HT7 receptor knock-out mice display decreased long-term synaptic potentiation (LTP) in the CA1 region of the hippocampus and impaired contextual fear conditioning (Roberts et al., 2004). The aim of the present studies was to clarify whether the 5-HT7 receptor contributes to the impairing effects of 8-OH-DPAT on aversive contextual learning in the passive avoidance task in mice.

Section snippets

Materials and methods

Male C57BL/6 mice (age 2 months, 22–27 g; Charles River, Germany and Taconic, Denmark) were housed in groups of four in plastic Macrolon type III cages (22 × 16 × 13 cm) in a temperature- and humidity-controlled environment with a 12-h light:dark cycle (lights on at 7 am) and ad libitum access to food and water. The animals were allowed to habituate to the animal facility for 6 days after delivery, and were then handled on 3 consecutive days prior to the experiments. Behavioral testing was

Results

None of the control mice that were tested with the standard passive avoidance procedure stepped through to the dark compartment at the retention test (step-through latency 300 ± 0 s), indicating that they had learned the task well (Fig. 1). Administration of 8-OH-DPAT prior to passive avoidance training impaired retention performance (105 ± 14 s) (F3, 28 = 95.79; P < 0.001). Co-administration of SB-269970 (10 and 20 mg/kg) intensified the impairments induced by 8-OH-DPAT (10 mg/kg: 85 ± 16 s; 20 mg/kg: 51

Discussion

The present results demonstrate that stimulation of 5-HT7 receptors does not contribute to the contextual learning deficit caused by the 5-HT1A/5-HT7 receptor agonist 8-OH-DPAT. Indeed, SB-269970 could not attenuate the impairing effects of 8-OH-DPAT, in contrast to selective 5-HT1A receptor antagonists that prevents effects induced by 8-OH-DPAT on passive avoidance learning (Carli et al., 1992, Madjid et al., 2006, Misane et al., 1998). The combination of SB-269970 and 8-OH-DPAT resulted in an

Acknowledgements

This work was supported by grants from the Swedish Medical Research Council (project No 14X-11588), funds from Karolinska Institute and Wallenberg Consortium North.

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