Elsevier

Neuropharmacology

Volume 48, Issue 6, May 2005, Pages 830-852
Neuropharmacology

Analysis of the role of 5-HT1A receptors in spatial and aversive learning in the rat

https://doi.org/10.1016/j.neuropharm.2005.01.007Get rights and content

Abstract

The role of the brain 5-HT1A receptor in cognition was examined in the water maze (WM) and passive avoidance (PA) tasks in the male rat. Pre-training administration of the 5-HT1A receptor agonist 8-OH-DPAT impaired WM performance and facilitated PA retention at low doses (0.01 and 0.03 mg/kg) and impaired PA retention at higher doses (0.1–1.0 mg/kg). The 5-HT1A receptor antagonist NAD-299 produced a dose-dependent facilitation of PA retention. In contrast, the 5-HT1A receptor antagonists NAD-299 and WAY-100635 failed to alter acquisition and retention in the WM. The impairments in WM and PA (but not facilitation in PA) induced by 8-OH-DPAT were blocked by NAD-299. Furthermore, NAD-299 prevented the PA impairments induced by the muscarinic antagonist scopolamine or the NMDA receptor antagonist MK-801. In contrast, NAD-299 and WAY-100635 failed to attenuate the WM impairment induced by scopolamine, probably due to the failure of 5-HT1A receptor blockade to attenuate the sensorimotor disturbances induced by scopolamine. These results indicate that 5-HT1A receptor stimulation and blockade result in opposite effects in two types of cognitive tasks in the rat, and that 5-HT1A receptor blockade can facilitate some aspects of cognitive function, probably via modulation of cholinergic and glutamatergic transmissions. This suggests that 5-HT1A receptor antagonists may have a potential role in the treatment of human degenerative disorders associated with cognitive deficits.

Introduction

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is implicated in a wide range of behavioral and physiological functions including learning and memory (Ögren, 1985, Ögren, 1986, Barnes and Sharp, 1999, Buhot et al., 2000). The ascending 5-HT neuronal pathways originating in the brainstem raphe nuclei innervate virtually all regions of the forebrain (Dahlström and Fuxe, 1964, Vertes, 1991). Among the 14 identified 5-HT receptor subtypes (Hoyer et al., 2002), the 5-HT1A receptor is of special interest in cognitive functions. The 5-HT1A receptor is enriched in brain areas associated with learning and memory, such as the cerebral cortex, hippocampus and septum (Chalmers and Watson, 1991, Pompeiano et al., 1992), and its density is altered in states and disorders such as aging and Alzheimer's disease (Meltzer et al., 1998, Tauscher et al., 2001, Lai et al., 2002). The cellular and subcellular localization of 5-HT1A receptors allows for a regulatory control of the 5-HT neurons but it can also influence the neuronal activity of several other neurotransmitter systems. Thus, somatodendritic 5-HT1A receptors localized at the midbrain raphe nuclei cell bodies serve as presynaptic autoreceptors, regulating the firing rate of the 5-HT neurons by negative feedback. The 5-HT1A receptors localized in cell bodies and dendrites of neurons postsynaptic (heteroreceptors) to 5-HT nerve terminals also have an inhibitory role since they induce hyperpolarization of the innervated cells (Aghajanian, 1995).

There is a growing body of evidence suggesting a role of the 5-HT1A receptor in learning and memory based mainly on studies in rodents (Ögren, 1985, Buhot et al., 2000). Most studies using pre-training administration of 5-HT1A receptor agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and tandospirone have reported impairment of learning and memory in various rodent tasks such as active and passive avoidance (PA) (Carli et al., 1992b, Carli et al., 1993, Mendelson et al., 1993, Misane et al., 1998), Morris water maze (spatial learning) (Rowan et al., 1990, Carli and Samanin, 1992c, McNaughton and Morris, 1992, Carli et al., 1995, Kant et al., 1996), 8-arm radial maze (Winter and Petti, 1987) and in delayed non-matching-to-position (DNMP) performance (Warburton et al., 1997). Also studies in humans indicate a possible role for brain 5-HT1A receptors in cognition. Oral administration of the 5-HT1A receptor agonist tandospirone was found to impair verbal memory in human volunteers (Yasuno et al., 2003).

The learning impairments caused by 8-OH-DPAT in different tests have been attributed to stimulation of postsynaptic 5-HT1A receptors (Mendelson et al., 1993, Misane et al., 1998, Stiedl et al., 2000). However, there is evidence for a dissociation of the effects following stimulation of pre- and postsynaptic receptors (Warburton et al., 1997). Facilitated learning performance has been observed after low, presumably presynaptic doses of 8-OH-DPAT (Cole et al., 1994). Moreover, infusions of 8-OH-DPAT into medial raphe nucleus, which presumably reduce 5-HT transmission in the hippocampus, improved DNMP performance (Warburton et al., 1997).

In contrast to the well documented results after 5-HT1A receptor activation, the available evidence with 5-HT1A receptor antagonists is still controversial. Studies with different 5-HT1A receptor antagonists in the rat have reported facilitation (Sanger and Joly, 1989, Belcheva et al., 1997, Pitsikas et al., 2003, Schneider et al., 2003), impairment (Galeotti et al., 2000) or no effects (Carli et al., 1997, Stiedl et al., 2000, Misane and Ögren, 2003) on cognitive performance in various rodent tasks. These contradictory findings may be explained by different behavioral procedures, differential effects on pre- and postsynaptic 5-HT1A receptors, as well as lack of receptor specificity of the 5-HT1A receptor antagonists used in the different studies. Constitutive 5-HT1A receptor knockout mice have also failed to provide a clear answer regarding the physiologic role of 5-HT1A receptors in cognition. Contrary to many of the pharmacological studies, 5-HT1A receptor knockout mice displayed impaired spatial performance in the water maze (WM) task (Sarnyai et al., 2000).

In view of the inconsistent results on cognition obtained after blockade of 5-HT1A receptors, the main aim of the present study was to examine the effects of stimulation and blockade of the 5-HT1A receptor using two different learning and memory tasks in the rat and two different 5-HT1A receptor antagonists. NAD-299 [(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)tartrate monohydrate] has been characterized as a potent and selective rat 5-HT1A receptor antagonist in vitro (Johansson et al., 1997). In vitro receptor binding has shown that NAD-299 has more than a 400-fold preference for the 5-HT1A receptor (Ki = 0.59 nM) vs the α1 receptor (Ki = 260 nM) and the β receptor (Ki = 340 nM) with very low affinity (Ki > 1000 nM) for a number of other serotonergic receptors besides the 5-HT1A receptor (Johansson et al., 1997). The “silent” 5-HT1A receptor antagonist WAY-100635 has been extensively used to study the functional role of brain 5-HT1A receptors. Both NAD-299 and WAY-100635 are potent 5-HT1A receptor antagonists which penetrate easily into the brain and bind with high specificity to 5-HT1A receptors (Fletcher et al., 1996, Johansson et al., 1997, Stenfors et al., 1998). The “reference compound” WAY-100635 has a higher affinity for the 5-HT1A receptor (Ki = 0.24 nM) but it is somewhat less selective in its receptor binding profile than NAD-299 (Johansson et al., 1997).

The effects of 5-HT1A receptor ligands on spatial learning and memory were studied using a computerized variant of the WM task (Ögren et al., 1996) and the PA task. The WM task is a behavioral test, which involves mainly hippocampal mechanisms (Morris, 1981, Morris et al., 1982, O'Keefe, 1993). Hippocampus plays a critical role in memory formation for spatial information and tasks involving processing of context-dependent information (Eichenbaum et al., 1996). The PA task is an associative learning paradigm, based on Pavlovian fear conditioning, involving neuronal circuits in the limbic forebrain, such as hippocampus and amygdala (LeDoux, 1993, Lorenzini et al., 1996). The PA test was modified in order to be able to elucidate any enhancing effects of the treatments on PA retention (see Section 2).

The effects of the 5-HT1A receptor antagonists were investigated alone or in combination with the agonist 8-OH-DPAT to elucidate the involvement of pre- vs postsynaptic 5-HT1A receptors. Moreover, since 5-HT1A receptors can modulate both cholinergic and glutamatergic transmissions in the hippocampus and cortex (Steckler and Sahgal, 1995, Francis, 1996), we examined whether the 5-HT1A receptor antagonist NAD-299 could modify memory deficits induced by blockade of cholinergic muscarinic receptors or by glutamatergic N-methyl-d-aspartate (NMDA) receptors (Åhlander et al., 1999). In addition, the contribution of sensorimotor disturbances for spatial learning performance was analyzed. A non-stationary visually cued platform was used in a complementary experiment to further evaluate putative sensory and motivational disturbances produced by the 5-HT1A receptor active compounds and scopolamine. In addition, the effects of 8-OH-DPAT, NAD-299 and scopolamine on locomotor activity were also studied, since 5-HT1A receptor ligands are known to interfere with motor function (Tricklebank et al., 1984, Jackson et al., 1998).

Section snippets

Subjects

Male Sprague–Dawley rats (2 months of age) weighing 300–350 g at the time of testing were obtained from B&K Universal (Sollentuna, Sweden). The animals were housed in groups of four in standard plastic cages (Type IV Macrolon®) in a temperature- and humidity-controlled room with a constant 12 h light/dark cycle (lights on at 6.00 a.m.) and free access to standard lab chow and tap water up to the time of experiments. Animals were allowed to habituate to the animal maintenance facilities for a

Effects of the 5-HT1A receptor antagonists NAD-299 and WAY-100635

Fig. 1 shows that neither NAD-299 nor WAY-100635 influenced the performance in the water maze hidden platform task. Both the control group and the NAD-299-treated groups (0.05–1.5 mg/kg, 30 min prior to training) performed this task well and learned the position of the platform, as indicated by decreasing escape latencies (F4,35 = 82.71, P < 0.001) over training days. There was no significant effect of treatment on escape latency, swim distance, or swim speed and no significant interactions between

Discussion

The main aim of the present study was to analyze the role of the 5-HT1A receptor in cognition using two different behavioral procedures with different cognitive demands. Another important aim was to differentiate between cognitive and non-cognitive factors for the performance in the WM task. In addition, this work investigated whether 5-HT1A receptors can interact with brain cholinergic and glutamatergic systems of importance for learning and memory.

Stimulation of 5-HT1A receptors by the

Conclusions

The present results strongly support the hypothesis that brain 5-HT1A receptors have an inhibitory role in cognition. Moreover, blockade of these receptors can facilitate certain aspects of cognition and ameliorate cognitive deficits induced by a reduction in cholinergic and NMDA receptor-mediated transmission. Thus, 5-HT1A receptor antagonists may be beneficial for the symptomatic treatment of dementias associated with reduced cholinergic and glutamatergic transmission, e.g. Alzheimer's

Acknowledgements

This work was supported by grants from the Swedish Medical Research Council (project No 14X-11588), Alzheimerfonden, Karolinska Institutets fonder, Loo och Hans Ostermans fond, Kapten Artur Erikssons fond and Wallenberg Consortium North. We thank Carina Stenfors (AstraZeneca R&D, Södertälje, Sweden) for the supply of NAD-299.

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