Serotonin and decision making processes

Abstract

Serotonin (5-HT) is an important player in decision making. Serotonergic antidepressant, anxiolytic and antipsychotic drugs are extensively used in the treatment of neuropsychiatric disorders characterized by impaired decision making, and exert both beneficial and harmful effects in patients. Detailed insight into the serotonergic mechanisms underlying decision making is needed to strengthen the first and weaken the latter. Although much remains to be done to achieve this, accumulating studies begin to deliver a coherent view. Thus, high central 5-HT levels are generally associated with improved reversal learning, improved attentional set shifting, decreased delay discounting, and increased response inhibition, but a failure to use outcome representations. Based on 5-HT's evolutionary role, I hypothesize that 5-HT integrates expected, or changes in, relevant sensory and emotional internal/external information, leading to vigilance behaviour affecting various decision making processes. 5-HT receptor subtypes play distinctive roles in decision making. 5-HT_2A agonists and 5-HT2c antagonists decrease compulsivity, whereas 5-HT_2A antagonists and 5-HT_2C agonists decrease impulsivity. 5-HT₆ antagonists univocally affect decision making processes.

Introduction

Serotonergic antidepressant and antipsychotic drugs are widely used in the treatment of depression, schizophrenia and obsessive compulsive disorder (OCD), although it is not clear how these drugs affect such cognitive functions as decision making. This is critical given that serotonin (5-HT) is an important player in decision making, a daily activity that represents the outcome of a variety of cognitive, and affective functions. Decision making benefits our well-being when good decisions are made given the circumstances. Proper decision making is also helpful in reducing emotional or otherwise negative symptoms associated with psychiatric disorders. Bad decisions, on the other hand, can lead to harmful and even pathological outcomes. Serotonergic antidepressant, anxiolytic and antipsychotic drugs beneficially affect decision making, but have harmful effects as well despite amelioration of specific disease symptoms. For instance, chronic, but not acute, antidepressant serotonin reuptake inhibitors (SSRIs) are used in the treatment of depression and obsessive compulsive disorder (OCD) (Baumgarten and Grozdanovic, 1998, El Mansari and Blier, 2006), and their efficacy may be, at least in part, due to improved decision making and increased sensitivity to positive feedback (Bari et al., 2010). However, atypical antipsychotics, exerting 5-HT_2A, 5-HT_1A, 5-HT₆ and dopamine D₂ receptor antagonism (Ichikawa et al., 2001, Newman-Tancredi, 2010, Garzya et al., 2007), have inconsistent effects on set shifting and other cognitive deficits in schizophrenia (Goldberg et al., 1993, Lee et al., 1994), and exacerbate compulsive behaviours in schizophrenic patients (Poyurovsky et al., 2008). Furthermore, polymorphisms in serotonergic genes are typically studied in the context of emotion, while there is accumulating evidence that these polymorphisms also affect cognitive functions. As recently reviewed, insight in the role of 5-HT in decision-making processes significantly alters/enriches our view on how 5-HT modulates emotional responses to adversity, and brings advances in the treatment of aberrant emotional responses (Homberg and Lesch, 2010). This view is further underlined by changes in the conception of 5-HT functions. Thus, central 5-HT has long been thought to play a critical role in the adaptation of the animals to aversive events (Deakin, 1991), more recently to mediate a punishment prediction error signal for future threat and punishment (Cools et al., 2008a), and most recently to mediate biases to positive stimuli as well (Bari et al., 2010).

The aim of the present essay is to review the role of 5-HT in various types of decision making processes. 5-HT, a highly conserved monoamine neuromodulator, plays key roles in the regulation of sleep, reproduction, feeding behaviour, emotion, and cognition. The serotonergic system is highly complex; in addition to the serotonin transporter (5-HTT) – which is responsible for ending the serotonin signal and serotonin recycling – 14 different 5-HT receptors have been identified. These receptors differ in their expression patterns in the brain, interact differentially with several other neurotransmitter systems, and thereby have distinct roles in decision making. What further complicates the understanding of 5-HT's role in decision making is that decision making is not a unitary construct, and requires several processes which include flexibility, attentional set shifting, delay discounting, and response inhibition. Other types of decision making are effort and risky decision making. The effort type of decision making does not seem to be modulated by 5-HT (Denk et al., 2005), while risky decision making is significantly affected by 5-HT, although the specific effects have not been clearly elucidated (Zeeb et al., 2009). Therefore, I do not explicitly address these types of decision making processes. To comprehend experimental findings, to be able to place together the pieces of the puzzle, and to follow-up excellent reviews published elsewhere (Chudasama and Robbins, 2006, Cools et al., 2008a, Fineberg et al., 2010, Dalley et al., 2008, Robbins and Arnsten, 2009, Rogers, 2011), I here review and provide an update of recent findings in the 5-HT decision making research field, across rodents, non-human primates, and humans. In addition, I include studies which associate genetic polymorphisms and decision making and 5-HT receptor manipulations, propose a hypothesis for unifying 5-HT's role in decision making, and discuss the role of 5-HT receptor subtypes in decision making and the implication for pharmacogenetics.