Analysis of the role of 5-HT1A receptors in spatial and aversive learning in the rat
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.
References (93)
- et al.
A behavioral analysis of the spatial learning deficit induced by the NMDA receptor antagonist MK-801 (dizocilpine) in the rat
Neuropsychopharmacology
(1999) - et al.
The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain
Brain Research
(2003) - et al.
A review of central 5-HT receptors and their function
Neuropharmacology
(1999) - et al.
Behavorial responses to the 5-HT1A receptor antagonist NAN190 injected into rat CA1 hippocampal area
General Pharmacology
(1997) - et al.
Effects of MDL 73005 on water-maze performances and locomotor activity in scopolamine-treated rats
Pharmacology, Biochemistry and Behavior
(2001) - et al.
Intraseptal infusions of 8-OH-DPAT in the rat impairs water-maze performances: effects on memory or anxiety?
Neuroscience Letters
(2000) - et al.
5HT antagonists attenuate MK801-impaired radial arm maze performance in rats
Neurobiology of Learning and Memory
(1999) - et al.
Stimulation of 5-HT1A receptors in the dorsal hippocampus impairs acquisition and performance of a spatial task in a water maze
Brain Research
(1992) - et al.
8-Hydroxy-2-(di-n-propyloamino)tetralin, a 5-HT1A receptor agonist, impairs performance in a passive avoidance task
European Journal of Pharmacology
(1992) - et al.
Stimulation of hippocampal 5-HT1A receptors causes amnesia and anxiolytic-like but not antidepressant-like effects in the rat
European Journal of Pharmacology
(1993)
8-OH-DPAT impairs spatial but not visual learning in a water maze by stimulating 5-HT1A receptors in the hippocampus
Behavioural Brain Research
WAY 100635, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal administration of scopolamine or 7-chloro-kynurenic acid
Brain Research
WAY 100635, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by blockade of hippocampal NMDA receptors
Neuropharmacology
Comparative anatomical distribution of 5-HT1A receptor mRNA and 5-HT1A binding in rat brain – a combined in situ hybridisation/in vitro receptor autoradiographic study
Brain Research
Stimulation of the 5-HT1A receptor selectively suppresses NMDA receptor-mediated synaptic excitation in the rat visual cortex
Brain Research
Pyramidal neurone modulation: a therapeutic target for Alzheimer's disease
Neurodegeneration
Role of 5-HT1A receptors in a mouse passive avoidance paradigm
The Japanese Journal of Pharmacology
Structural basis of the cholinergic and serotonergic modulation of GABAergic neurons in the hippocampus
Neurochemistry International
The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys
Neuropharmacology
Differential behavioural activation following intra-raphe infusion of 5-HT1A receptor agonists
European Journal of Pharmacology
Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis
Life Sciences
Molecular, pharmacological and functional diversity of 5-HT receptors
Pharmacology, Biochemistry and Behavior
Effects of the serotonin receptor agonists 8-OH-DPAT and TFMPP on learning as assessed using a novel water maze
Pharmacology, Biochemistry and Behavior
Serotonin1A receptors are expressed by a subpopulation of cholinergic neurons in the rat madial septum and diagonal band of Broca – a double immunohistochemical study
Neuroscience
Identification of serotonin and non-serotonin-containing neurons of the mid-brain raphe projecting to the entorhinal area and the hippocampal formation. A combined immunohistochemical and fluorescent retrograde tracing study in the rat brain
Neuroscience
Emotional memory systems in the brain
Behavioural Brain Research
Role of dorsal hippocampus in acquisition, consolidation and retrieval of rat's passive avoidance response: a tetrodotoxin functional inactivation study
Brain Research
Buspirone produces a dose-related impairment in spatial navigation
Pharmacology, Biochemistry and Behavior
5-HT1A receptor agonists induce anterograde amnesia in mice through a postsynaptic mechanism
European Journal of Pharmacology
Multiple 5-HT receptors in passive avoidance: comparative studies of p-chloroamphetamine and 8-OH-DPAT
Neuropsychopharmacology
Spatial localization does not require the presence of local cues
Learning and Motivation
Antinociceptive role of 5-HT1A receptors in rat spinal cord
British Journal of Anaesthesia
Hippocampus, theta, and spatial memory
Current Opinion in Neurobiology
Effects of ventral hippocampal galanin on spatial learning and on in vivo acetylcholine release in the rat
Neuroscience
Blockade of 5-HT1A receptors compensates loss of hippocampal cholinergic neurotransmission involved in working memory of rats
Brain Research
The 5-HT1A receptor antagonist WAY 100635 improves rats performance in different models of amnesia evaluated by the object recognition task
Brain Research
5-HT1A and muscarinic acetylcholine receptors jointly regulate passive avoidance behavior
European Journal of Pharmacology
Distribution and kinetics of galanin infused into the ventral hippocampus of the rat: relationship to spatial learning
Neuroscience
Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons
Neuropharmacology
The role of serotonergic–cholinergic interactions in the mediation of cognitive behaviour
Behavioural Brain Research
Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET
Neuropsychopharmacology
The involvement of subtypes of the 5-HT1 receptor and of catecholaminergic systems in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin in the rat
European Journal of Pharmacology
The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory
Pharmacology, Biochemistry and Behavior
Electrophysiology of serotonin receptor subtypes and signal transduction pathways
An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat
Journal of Comparative Neurology
Comparison of 5-hydroxytryptamine1A-mediated hyperpolarization in CA1 and CA3 hippocampal pyramidal cells
Journal of Pharmacology and Experimental Therapeutics
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These authors contributed equally to the present study.