Distribution of 5-HT and DA receptors in primate prefrontal cortex: implications for pathophysiology and treatment

Abstract

The prefrontal cortex (PFC) has attracted great research interest because of its involvement in the control of executive functions in both health and disease, and particularly in cognitive functions such as working memory. In schizophrenia, alterations in the PFC are documented at many different levels: molecular, cellular and functional. Furthermore, deficits in cognitive abilities are considered a core feature of schizophrenia and remain a major unmet medical need with respect to this disorder. In order to understand the sites of action of currently-used drugs, as well as of the new experimental treatments being developed and acting in this brain region, it is important to have detailed knowledge of the corresponding chemical Fallon et al. 2003). The PFC is described as a six-layered structure, as other neocortical regions, and it is distinguished by a granular layer IV (see Figure 1).In primates the PFC orchestrates thoughts and actions, as well as the planning of complex cognitive and affective functions, and it is therefore implicated in mood disorders (Ebert and Ebmeier 1996). The orbital and medial regions are involved in the control of emotional behavior, whereas the lateral regions, which are highly developed in humans, provide cognitive support to the temporal organization of behavior, speech, reasoning and the execution of complex behaviors that require working memory, as already mentioned; for reviews see (Cavada et al. 2000;Elston 2003;Fuster 1997; Goldman-Rakic et al. 1984).The PFC receives projections from the amygdala (Barbas and de Olmos 1990), the ventral striatum (Kunishio and Haber 1994) and thalamus (Barbas et al. 1991).Specifically, it receives dopaminergic efferents from the ventral tegmental area (VTA) (Berger et al. 1988; Conde et al. 1995;Lindvall et al. 1978) and serotonergic innervation from the median and dorsal raphe nuclei (Berger et al. 1988;Smiley and Goldman-Rakic 1996b), while it sends glutamatergic projections to both the VTA and the nucleus accumbens (Sesack and Pickel 1992;Taber et al. 1995), as well as to the raphe nuclei (Sesack et al. 1989). The PFC is connected with other association cortices but not with primary sensory or motor cortices. There is an important internal network of connectivity between the different divisions of the PFC; indeed, each of the three major prefrontal regions (orbital, medial and lateral) is connected with itself and with the other two. Some of the cortico-cortical connectivity of the PFC is interhemispheric and the majority is organized in a reciprocal and topographical 4 manner (Cavada and Goldman-Rakic 1989a; 1989b). These cortico-cortical connections originate and terminate in upper cortical layers II and III (Andersen et al. 1985).As in other cortical regions, there are two main cell types in the PFC. One is the pyramidal and spiny stellate cells characterized by the excitatory asymmetric synapses which they form (glutamatergic). The majority of cortical neurons are pyramidal output neurons, found mainly in layers II-VI. The othe...

Dopamine Effects on Human Error Processing Depend on Catechol-O-Methyltransferase VAL158MET Genotype

“…Consistent with recent calls to acknowledge the 5-HT system when investigating the effects of dopaminergic drugs (de Almeida et al, 2008), we further found that the COMT ϫ Substance interaction was potentiated in carriers of the less functional 5-HTTLPR variant, which is linked to reduced 5-HT uptake (Lesch et al, 1996). The 5-HT system is a relevant modulator of dopaminergic processes and influences mPFC DA release induced by D2 receptor antagonists (Kuroki et al, 1999).…”

“…The 5-HT system is a relevant modulator of dopaminergic processes and influences mPFC DA release induced by D2 receptor antagonists (Kuroki et al, 1999). Glutamatergic pyramidal neurons presumably involved in ERN generation (Ullsperger, 2010) receive inputs not only from dopaminergic but also from serotoninergic fibers and GABAergic interneurons, which receive projections from raphe nuclei serotoninergic neurons (de Almeida et al, 2008). Of relevance, the less functional 5-HTTLPR alleles have previously been linked to increased risk for depression after stressful life events (Caspi et al, 2003), which also affect the DA system (Pruessner et al, 2004), and for schizophrenia when individuals also carry the Val allele of the COMT Val158Met polymorphism (Borroni et al, 2006).…”

Functional 5‐HT1a receptor polymorphism selectively modulates error‐specific subprocesses of performance monitoring

“…In support of our findings, another line of evidence suggests that 5-HT1A receptor agonists increase dopamine release in the PFC (for review: de Almeida et al, 2008). Therefore, the stronger Ne in homozygous carriers of the À1019 C allele may be explained by stronger stimulating effects on the DA system in carriers of the CC genotype compared to the CG and GG genotypes.…”

“…The DA system is crucially modulated by the serotonergic system within the prefrontal cortex (PFC) (for review: de Almeida et al, 2008). These interactions may form the neurobiological basis of the observed influence of the serotonergic system on error processing functions that has been shown in studies examining depression (e.g.…”

“…It has been shown that especially the error-specific ''cognitive'' subprocess is likely influenced by factors modulating DA activity (Beste et al, 2007). Based upon the interaction of the DA and serotonergic system (de Almeida et al, 2008), it may be hypothesized that modulations depending on the 5-HT1A polymorphism may selectively affect these ''cognitive'' subprocesses and spare more general response monitoring subprocesses occurring irrespective of the outcome of a trials (i.e., error or correct), which are evident in correct as well as error trials.…”