Data concerning 5HT-DA interaction in brain processes of learning and memory have been recently reviewed (Olvera-Cortes et al. 2008), showing the relevant regulatory role of serotonergic neurotransmission on dopaminergic-mediated phenomena in the central nervous system, including those accounting for cognition, under both physiological and pathological conditions.
Nowadays it is recognized that serotonin-dopamine interactions may have important clinical implications since they are involved in pathophysiological mechanisms of some neurological and psychiatric diseases (like schizophrenia, Parkinson and Huntinton diseases, ADHD, Alzheimer disease, anxiety, depression, and drug addiction) that may evolve with cognitive dysfunctions besides motor, mood, or behavioral disturbances and may able to be improved by drugs acting on dopamine or serotonin neurotransmission (Araki et al. 2006; Boulougouris and Tsaltas 2008; Cools 2006; Di Pietro and Seamans 2007; Gray and Roth 2007; Kostrzewa et al. 2005; Remington 2008; Scholes et al. 2007; Scholtissen et al. 2006). Further, even though derangement of different brain dopaminergic neurotransmission systems has been mainly implicated in these pathologies, they also affect other nondopaminergic neuronal structures, including neurotransmitter receptors underlying synaptic serotonergic activity.
Also, degeneration of serotonergic neurons in the medial raphe nucleus (Halliday et al. 1990; Paulus and Jellinger 1991), reduction of several key markers of serotonergic activity in the striatum (Chinaglia et al. 1993; Guttman et al. 2007; Kerenyi et al. 2003; Kim et al. 2003; Kish 2003; Kish et al. 2008), the cerebral cortex (Scatton et al. 1983), and the cerebrospinal fluid (Kuhn et al. 1996; Mayeux et al. 1984) as well as changes in the density and the activity of several types of serotonin receptors (Castro et al. 1998; Cheng et al. 1991; Fox and Brotchie 2000) have been demonstrated in Parkinson disease patients.
On the other hand, altered neurotransmission processes dealing with dopamine and serotonin uptake, synthesis, breakdown, and receptor activation have been described as related to symptoms shown by children and adults with ADHD, including cognitive compulsivity (Oades 2008).
Some pathophysiological phenomena in schizophrenia have also been related to dopamine-serotonin interactions. Thus, the better clinical profile of novel atypical antipsychotic drugs resulting in effective improvement of mood and behavioral alterations and less untoward effects in schizophrenic patients has been ascribed to their actions on both serotonin and dopamine systems (Alex and Pehek 2007; Meltzer and Huang 2008; Richtand et al. 2008; Stone and Pilowsky 2007; Werkman et al. 2006). It has also been shown that some cognitive expressions can be differentially affected in schizophrenic patients depending on the antipsychotic drug treatment they receive (Araki et al. 2006; Di Pietro and Seamans 2007; Gray and Roth 2007). Once experimental evidence showing the important regulatory role of serotonin on cerebral physiological and physiopathological dopamine-mediated processes had been obtained, efforts have been focused on finding out whether the different types of serotonin receptors are involved in motor, mood, behavioral, and cognitive functions mainly dependent on dopaminergic activity. Since alterations of these functions are implicated in some human neurological and psychiatric diseases, it could be assumed that the differential roles of the various serotonin receptor subtypes may result in the variants of clinical manifestations of these cerebral pathologies. In fact, activation of 5HT2A or 5HT2C receptors results in opposite neurochemical effects on dopamine release (Di Matteo et al. 2001), its inhibition being a 5HT2C receptor-mediated phenomena.
However, extensive investigation aimed to obtain direct evidence on the role of 5HT2C and other serotonin receptor subtypes in neural processes and behaviors that require a high cognitive demand, memory improvement, or recovery after an impaired cognitive performance, either under physiological or under physiopatho-logical conditions, in human beings, has been handicapped until now by the lack of selective agonists or antagonists suitable for human use.
Nevertheless, it has been suggested that alterations of some 5HT2C-mediated neural phenomena could be a part of the pathophysiological mechanisms of cerebral diseases such as Parkinson disease, epilepsy, anxiety, depression, attention deficit, and hyperactivity disorder in human beings (Oades 2008; Di Giovanni et al. 2006; Isaac 2005; Scarpelli et al. 2008; Sodhi et al. 2001). A widespread distribution of the 5HT2C receptors has been found in the brain (Pazos et al. 1987), and its functioning may depend on both its agonist-mediated activation and its constitutive active condition, meaning that it is activated even in the absence of an agonist (De Deurwaerdere et al. 2004). Thus, 5HT2C receptors have been proposed as a feasible potential target for pharmacological interventions aimed to improve neurological, behavioral, emotional, or cognitive disorders in patients being affected by these diseases.
Accordingly, attention has been paid to the possible role of 5HT2C receptors in the mechanisms of action of antipsychotic, mainly those atypical, drugs leading to effects on mood, behavioral, or cognitive alterations in schizophrenic patients (Meltzer and Huang 2008). It has been observed that the RNA editing of the 5HT2C receptor in specific brain structures related to mood, behavior, and cognition is reduced in schizophrenia (Sodhi et al. 2001) and that ser23cis single nucleotide polymorphism of 5HT2C receptor gene could be predictive of the clinical response to clozapine (Sodhi et al. 1995). It has also been suggested that the 5HT2C receptor gene may be very important to epigenetic events that may influence the course of schizophrenia and response to treatment (Reynolds et al. 2005; Sodhi et al. 2005).
Differential binding affinity of typical and atypical antipsychotic drugs to cloned serotonin and dopamine receptor subtypes has been found to correlate with their clinical efficacy. Thus, an inverse correlation between clinically effective doses of some typical antipsychotics and 5HT2C receptor affinity has been shown, while effective doses of atypical antipsychotic drugs are strongly correlated to 5HT2C/D2 affinity ratio. However, correlations possibly accounting for antipsychotic effectiveness also have been shown between other serotonergic and dopamine receptor subtypes affinity ratios. These data have been interpreted as suggesting that interaction with constitutive 5HT2C receptor signaling facilitates the antipsychotic effects of typical antipsychotic drugs (Richtand et al. 2008).
An important finding regarding the 5HT2C receptor is the behavioral profile of the 5HT2C selective receptor agonist WAY 163909, similar to that of atypical antip-sychotics, and its effectiveness to revert alterations in cognition induced by drugs in experimental animals (Dunlop et al. 2006). Data from experimental studies also suggest that the 5HT2C receptor antagonism appears to have useful effects on certain types of memory impairment. Thus, SB 200646 antagonizes memory impairment due to some 5HT2A/2C agonists and dizolcipine but not scopolamine (Meneses 2002b). 2A/2C
Experimental data dealing with anatomical and functional characteristics of 5HT2C and 5HT2C receptor-mediated serotonergic activity have shown that this receptor plays a pivotal role for basal ganglia physiology and pathophysiology. Thus, the involvement of 5HT2C receptors in the tonic and phasic regulation of mesencephalic, mesocorticolimbic, and nigrostriatal neuronal dopaminergic activity (Di Matteo et al. 2001; Fox and Brotchie 2000; Pierucci et al. 2004), as well as in the functional relationships between these brain regions underlying movement, mood, behavioral, and cognitive functions, supports the proposal of 5HT2C receptors as a target for novel therapeutic strategies in Parkinson disease (Di Giovanni et al. 2006; Di Matteo et al. 2008). Human postmortem tissue samples from Parkinson disease patients have revealed that dopamine depletion may result in adjustments of 5HT2C receptors that appear to be upregulated in the substantia nigra pars reticu-lata (Fox and Brotchie 2000) without change in its density in the striatum, while other adjustments as those in 5HT2A receptor density are seen in the striatum and substantia nigra.
An association between 5HT2A/2C receptors and increased hyperactivity and impulsivity components of the ADHD has been suggested (Oades 2007). Further, since 5HT2C receptors, among other serotonin receptor subtypes, have been identified on astrocytes (Hirst et al. 1998), their role in glial activities accounting for pathophysiological mechanisms and possible therapeutic proposals for the ADHD, remains to be clarified.
It has been suggested that 5HT2C receptors play an important role in the pathophysiology of anxiety and depression. Thus, beneficial effects can be expected from specific 5HT2C receptor antagonists on mood and cognitive functions that are reduced in depression, since these drugs increase the dopaminergic neurotransmission (Berg et al. 2008; Millan 2006). Density of 5HT2C receptors has been found to be increased in depressed patients, while enhancement of RNA editing leading to changes in the proportions of nonedited and partially edited receptor mRNA transcripts were found in depressed suicide patients (Gurevich et al. 2002; Iwamoto and Kato 2003). On the other hand, feelings of anxiety and panic can be induced by the 5HT2C receptor agonist mCPP in humans (Charney et al. 1987; Gatch 2003; Klein et al. 1991) as well as an anxiogenic-like behavior in animals, which can be blocked by 5HT2C receptor antagonists (Martin et al. 2002; Jones et al. 2002; Bagdy et al. 2001; Klein et al. 1991; Cornelio and Nunes-de-Souza 2007; Hackler et al. 2007).
Some experimental data point out the role of 5HT2C among other 5HT receptors as key modulators of dopamine output in several brain structures, where dopamine is a primary mediator of the rewarding effects of psychostimulants (Bubar and Cunningham 2006). It is known that stimulation of 5HT2C receptors attenuates the cocaine-induced release of dopamine from the rat's nucleus accumbens (Navailles et al. 2008). In addition, interference of agonist-induced 5HT2C receptor phospho-rylation in the ventral tegmental region results in blockade of the conditioned place preference induced by D9-tetrahydrocannabinol and nicotine, by suppressing the rewarding neural processes linked to learning and memory mechanisms associated with this conditioned response (Ji et al. 2006; Maillet et al. 2008).
Although the clinical significance of 5HT2C receptors deserves further research, the above-mentioned data support a role of 5HT2C receptors in cognitive functions in human beings, under both physiological and phatophysiological conditions. In addition, 5HT2C receptors should be a target for drug development, as has been suggested. Accordingly, future clinical trials aimed to obtain direct evidence on the effectiveness of new drugs to improve cognitive alterations associated with some neurological and psychiatric diseases could be based on the use of selective 5HT2C receptor ligands.
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