Trends in Pharmacological Sciences
ReviewA role for the 5-HT1A, 5-HT4 and 5-HT6 receptors in learning and memory
Introduction
Learning and memory is currently a major area of research because not only do these processes underpin normal human behaviour but they are also essential abnormal behavioural components in disorders ranging from addictions, anxiety, depression, schizophrenia and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. There are currently no effective treatments for these learning and memory impairments so there is considerable interest in developing novel therapeutic approaches to treat this aspect; and drugs acting at specific serotonin, or 5-hydroxytryptamine (5-HT), receptors are one such strategy. The search for compounds that either reverse cognitive deficits associated with disease or even improve normal cognitive functioning, the so-called cognitive enhancers (Box 1), is an active area of neuropharmacological research. The serotonergic system innervates specific forebrain areas that are important in the regulation of memory and learning processes (Box 2); this innervation is closely associated with the expression of a range of 5-HT receptors (Figure 1), making serotonin an obvious target for investigation. Important features of the serotonergic system are the extensive nature of the forebrain innervation derived from discrete clusters of neurones situated in the raphe nuclei and the diversity of its receptors, of which there are 14. These receptors include 5-HT1A, 5-HT4 and 5-HT6, all of which are densely expressed in brain regions associated with learning and memory and have been implicated in various human cognitive disorders. Furthermore, selective agonist and/or antagonist compounds seem to have potent pro-cognitive effects in preclinical behavioural paradigms by acting on these three receptors, which are each located postsynaptically in relation to serotonergic terminals. Binding of these compounds to their receptor also modulates similar neurotransmitter systems, indirectly modifying cholinergic, γ-aminobutyric acid (GABA)ergic and/or glutamatergic pathways thought to control learning and memory, rather than altering 5-HT release. Work over several years has identified the function of specific 5-HT receptors. For example, the 5-HT1A receptor functions both as the somatodendritic inhibitory autoreceptor, involved in the autoregulation of 5-HT neuronal function in the raphe nuclei, in addition to being found at postsynaptic locations in the brain (such as on hippocampal pyramidal and granule cells, where it causes neuronal inhibition; Figure 1). This dual functional distribution makes it important to identify which synaptic location behavioural responses are derived from because responses mediated by the autoreceptor implicate reduced serotonergic neuronal activity and release, whereas postsynaptic receptor activation is associated with increased 5-HT release. The 5-HT4 receptor is expressed in abundance in hippocampal, cortical and striatal regions and is known play an important part in the regulation of hippocampal acetylcholine release (Figure 1). The 5-HT6 receptor is also expressed in abundance in the frontal cortex, hippocampus, amygdala and striatum, where it seems to be prevalent on GABAergic neurones and activation indirectly regulates a variety of neurotransmitters, including acetylcholine, glutamate and dopamine, in a brain-region-specific manner, as identified in more detail later.
A wide range of preclinical cognitive paradigms have been developed to assess particular aspects of learning and memory (see Box 2), such as prefrontal-cortex executive function (delayed response and problem-solving tasks), hippocampal-dependent spatial working memory (Morris water maze; see Glossary) or striatal-dependent associative learning. In the assessment of any potential novel therapeutic agent, it is essential that performance is assessed in a variety of these cognitive paradigms to establish the specificity and full potential utility of these compounds. Therefore, here, we focus largely on preclinical studies that examine the role of three particular 5-HT receptors – 5-HT1A, 5-HT4 and 5-HT6 – all of which have been implicated in various human cognitive disorders and for which selective agonist and/or antagonist compounds seem to have potent pro-cognitive effects in preclinical behavioural paradigms.
Section snippets
5-HT1A receptors and learning and memory
It is well established that the 5-HT1A receptor, which (as mentioned) functions as the somatodendritic inhibitory autoreceptor in addition to an inhibitory postsynaptic heteroceptor, is abundant in areas important for learning and memory, such as the frontal cortex, hippocampus and septum [1]. Several groups have consistently reported that 5-HT1A receptors are decreased in Alzheimer's disease and through ageing 2, 3. However, recent evidence [4] indicates that, after training (in an autoshaping
5-HT4 receptors and learning and memory
The distribution of 5-HT4 receptors is also consistent with an involvement in learning and memory processes. Expression is highest within the basal ganglia and hippocampus (granule cell layer of the dentate gyrus and pyramidal cell layer of the CA fields and subiculum), with moderate levels in the frontal cortex, septum and amygdala, and low levels in the raphe nuclei (Figure 1). Lesion studies indicate that the receptor is present on GABAergic and glutamatergic (but probably not dopaminergic)
5-HT6 receptors and learning and memory
The 5-HT6 receptor is expressed almost exclusively within the CNS, offering the possibility that pro-cognitive compounds operating through this mechanism could have only a few peripheral side effects. Particularly high levels of 5-HT6-receptor mRNA occur in the striatum, nucleus accumbens and olfactory tubercles and in limbic and forebrain regions, including the hippocampus and cortex. Neither hippocampal nor striatal 5-HT6 mRNA is altered by the 5-HT neurotoxin 5,7-DHT, indicating the
Concluding remarks
Serotonin-containing neurones in the dorsal and/or medial raphe nuclei (DR and/or MR) project to the hippocampus, medial septum and prefrontal cortex. The activity of serotonergic neurones in the raphe nuclei is under autoinhibitory control mediated by 5-HT1A receptors. Selective activation of these presynaptic 5HT1A receptors leads to reduced serotonergic function and facilitation of cognition. Conversely, activation of the inhibitory postsynaptic 5-HT1A receptors in the hippocampus and septal
Glossary
- Attentional set shifting
- discrimination of the salient stimulus category to locate food reward, requiring attention and executive function involving the frontal cortex.
- Autoshaping
- food-motivated conditioned operant response task, involving associative learning.
- Contextual-fear conditioning
- conditioned emotional associative memory involving hippocampal and amygdala function in contextual retention trials.
- Delayed non-match to sample
- working memory task, distinguishing re-presentation of a familiar
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