Serotonin/dopamine interaction in learning

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Abstract

Dopamine (DA)–serotonin interactions dealing with learning and memory functions have been apparent from experimental approaches over the past decade. However, since the former evidence showing that these cerebral neurotransmitter systems are involved in the regulation of the same cognitive processes, few experimental studies have been done to further clarify the nature of DA–serotonin interactions for cognitive processes sharing common brain structures. Nevertheless, a regulatory role of 5-HT/DA interactions in cognition and the prefrontal cortex (PFC) and the striatum as a neuroanatomical substrate for these DA/5-HT interactions, are now recognized. Experimental evidence indicates that pharmacological disruption of serotonin neurotransmission results in a facilitative effect on the processing of mnemonic information by cerebral regions under strong, functional DA modulation, such as the striatum and the PFC; on the other hand, increased serotonin neurotransmission appears to have a detrimental effect on cognitive functions integrated in these structures. These effects seem to occur through the interaction of different pre- and postsynaptic DA and serotonin receptor subtypes acting as opposite systems underlying cognitive abilities. Some studies, focused on DA–serotonin interactions underlying the pathophysiology of neurological and psychiatric diseases, which evolve with cognitive dysfunctions in human beings, have shown that drugs that are able to modify DA or serotonin neurotransmission may exert beneficial effects on cognitive functions, even though improvement of motor, mood and behavioural disturbances are the main objectives of pharmacological treatment of these diseases. The complete significance of DA–serotonin interactions in cognitive functions could be addressed by future experimental and clinical studies.

Introduction

Over recent decades, there has been mounting evidence for the participation of a number of different hormonal and neurotransmitter systems in cognitive processes. However, interaction between neurotransmitters in the performance of cognitive tasks is a less developed issue. It has been established that many of the complex actions of the central nervous system (CNS) are determined by the properties of particular neurotransmitter systems, and by the interactions between them (Trimmer, 1999). Neuromodulation is a term that consistently describes non-classical effects of neurotransmitters on neurons. Thus, neuromodulation occurs when a substance released from one neuron alters the cellular or synaptic properties of another neuron (Kupfermann, 1979; Kaczmarek and Levitan, 1987). There are centres in the brain responsible for producing neuromodulatory effects and between these centres are the raphe nuclei (RN) and substantia nigra (SN), which are small clusters of neurons located in the brain stem with diffuse projections to all other areas of the brain. Their divergent projection pattern suggests that these neurons modulate activity in other areas of the brain, and practically all neuronal circuits in the mammalian brain are subject to neuromodulation arising from these centres (Katz, 1999).

There are three major dopaminergic (DArgic) systems in the brain (Wolf et al., 1987): the mesostriatal system originating in the SN pars compacta, the mesolimbic system originating in the ventral tegmental area (VTA) and terminating in the accumbens nucleus (AN) and the mesocortical system originating in the VTA, but terminating in the prefrontal cortex (PFC). The cell bodies and terminal regions of all three DArgic pathways are innervated by serotonergic (5-HTergic) neurons originating in the medial and dorsal raphe nucleus (DRN) (Geyer et al., 1976; Parent et al., 1981; Beart and McDonald, 1982; Nedergaard et al., 1988). Neurons in the DRN make connections with areas innervated by the DArgic system (amygdala, striatum and PFC), whereas medial raphe nucleus (MRN) neurons make connections to the hippocampus and septal nuclei, which are not major DArgic targets (Azmitia and Segal, 1978). The dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system activities are independently related to each other in the modulation of diverse cognitive abilities. However, little is known about the interaction between these two systems in the modulation of cognition. Nevertheless, a neuroanatomical substrate for DA/5-HT interaction exists, and the distribution of DA and 5-HT receptors allows us to deduce the possible interactions between these neurotransmission systems. We will emphasize the DA/5-HT interactions in those cerebral regions implicated in cognition that receive both DA and 5-HT innervation, and where it has been shown that the participation of these neurotransmitters causes modulation of cognitive performance. For this reason, the focus of the present chapter will analyse the participation of 5-HT and DA in cognition separately and then, we will analyse the mesostriatal and mesocortical target areas, their participation in cognitive processes and the regulatory role of 5-HT/DA interactions in cognition sustained by processes principally underlying the PFC and striatum.

Section snippets

The serotonergic system and cognition

Serotonergic systems have been implicated in diverse behavioural processes including motor function, motivation, timing behaviour, behavioural inhibition and response to stress and threat (Iversen, 1984; Fletcher et al., 1999; Misane and Ögren, 2000). Experimental work over recent decades has led to the general notion that experimental pharmacological and neurotoxic manipulations that reduce central 5-HTergic transmission increase the retention, or facilitate the acquisition, of information,

The dopaminergic system and cognition

DA plays a significant role in memory processes, especially through the interconnection of two brain regions: the striatum and the PFC (Jay, 2003). Extensive clinical and experimental findings involve the DArgic system with working memory organization. Parkinson's disease (PD) patients, whose diminished DA release in basal ganglia caused by DArgic nigral cell death, presents a deficit in working memory that is attenuated by levodopa (l-dopa) administration (Lewis et al., 2005). Similarly, DA

Striatal mediated cognitive processes and DA

The striatum (caudate–putamen) part of the basal ganglia is a group of subcortical nuclei that also includes the subthalamic nucleus, globus pallidus and SN (Wilson, 1998). These nuclei participate in voluntary movement regulation, frequently called motor control, and are affected by diseases such as Parkinson's and Huntington's diseases: both diseases cause dementia because cognitive functions sustained by the basal ganglia are altered with the degeneration of these nuclei (Packard and

Prefrontal cortex and cognitive processes

The PFC constitutes a higher level in the cortical hierarchy involved in the representation and execution of actions. In addition to cognitive control, the PFC plays a crucial role in behavioural control and influence (Fuster, 1997, Fuster, 2001; Miller and Cohen, 2001). The key cellular elements in the direction of these functions are the pyramidal neurons, and the basic process in which the PFC participates is working memory: an essential process for human cognition (Goldman-Rakic, 1995).

The

Clinical implications of 5-HT/DA interaction

Studies have been focused on DA–5HT interactions as a part of pathophysiological phenomena and therapeutic possibilities dealing with neurological and psychiatric diseases.

This is the case of PD which primarily results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) at the origin of the nigrostriatal DArgic pathway. Loss of these DArgic neurons leads to striatal deficiency in DA neurotransmission, accounting for the major symptoms of PD, and supporting the

Abbreviations

    AAPA

    active allothetic place avoidance

    AN

    accumbens nucleus

    AS19

    (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino) tetralin

    A69024

    1-[(2-bromo-4,5- dimethoxyphenyl) methyl]-l, 2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoquinolinol

    A77636

    ((1R-cis-)-1-(aminomethyl)-3,4-dihydro-3-tricyclo[3.3.1.13.7]dec-1-yl-[1H]-2-benzopyran-5,6-diol hydrochloride)

    BAYx3702

    R-(−)-2-{4-[(chroman-2-methyl)-amino]-butyl}-1,1-dioxo-benzo-[d]isothiazol one HCl

    BMN

    basal magnocellular nucleus

    CG1

    cingulated cortex 1

    DA

    dopamine

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