Cannabinoids and value-based decision making: Implications for neurodegenerative disorders

Abstract

In recent years, disturbances in cognitive function have been increasingly recognized as important symptomatic phenomena in neurodegenerative diseases, including Parkinson’s disease (PD). Value-based decision making in particular is an important executive cognitive function that is not only impaired in patients with PD, but also shares neural substrates with PD in basal ganglia structures and the dopamine system. Interestingly, the endogenous cannabinoid system modulates dopamine function and subsequently value-based decision making. This review will provide an overview of the interdisciplinary research that has influenced our understanding of value-based decision making and the role of dopamine, particularly in the context of reinforcement learning theories, as well as recent animal and human studies that demonstrate the modulatory role of activation of cannabinoid receptors by exogenous agonists or their naturally occurring ligands. The implications of this research for the symptomatology of and potential treatments for PD are also discussed.

Introduction

Disturbances in executive cognitive functions, including decision making, are prominent clinical features in various psychiatric disorders, such as attention-deficit hyperactivity disorder, mood and anxiety disorders, schizophrenia and substance use disorders [1]. In recent years, the notion that cognitive disturbances and impairments in decision making are important symptomatic phenomena in neurodegenerative disorders such as Parkinson’s disease (PD) has gained increasing interest [2], [3], [4], [5]. Interestingly, recent evidence suggests that these cognitive impairments might arise in the prediagnostic and early stages of PD [6], [7], [8] and are possibly caused by functional loss in the corticostriatal circuitry subserving cognitive functions [9].

In general terms, decision making refers to the selection of appropriate actions from various available options based on cost–benefit evaluations and subjective values of the outcomes of these actions. As such, decision making is a complex mental construct that is composed of several cognitive functions that should theoretically lead to adaptive behavioral outcomes or to maintain psychological or physiological homeostasis [10]. These functions and goal-directed action selection in decision making are driven by various neurotransmitter systems in the brain and have in particular been associated with dopamine function [11], [12]. Over the last decades there has been a rise in decision making experimental data, partly due to the development and availability of laboratory tasks assessing aspects of real-life decision making in humans and preclinical animal models [13]. Altogether, these studies have greatly increased our understanding of the scientific basis and neurobiology of decision making, not the least because it is a subject that is studied from multiple disciplines including economics, psychology, neuroscience and computer science [14].

In addition to dopamine modulation of decision making, there is accumulating evidence of cannabinoid involvement in executive cognitive functions including decision making [15], [16]. The endocannabinoid neurotransmitter system consists of at least two receptors, cannabinoid CB1 and cannabinoid CB2, of which primarily the former is highly expressed in the central nervous system. These G_i/o-protein coupled receptors, of which the vast majority is expressed presynaptically, are activated by their endogenous signaling molecules, such as anandamide (AEA) and 2-arachydonylglycerol (2-AG), and in response directly modulate the probability of release of several neurotransmitters including GABA, glutamate and indirectly dopamine [17], [18]. Moreover, cannabinoid CB1 receptors are densely expressed in the brain including frontal cortical regions and several nuclei of the basal ganglia such as the striatum, globus pallidus and substantia nigra [19], [20], [21].

Interestingly, despite the cannabinoid CB1 receptor antagonist Rimonabant being withdrawn from the market, there is large therapeutic potential of cannabinoid mechanisms in several metabolic, psychiatric and neurodegenerative disorders [22], [23].

This review aims at providing more insight into this convergence of cannabinoids, dopamine and value-based decision making in the context of neurodegenerative disorders and in particular PD. To this aim, we first will provide background on different theories of reinforcement learning as a framework for value-based decision making, and we will briefly discuss the role of dopamine in these processes. Next, we will discuss the involvement of the basal ganglia and importance of the endogenous cannabinoid system and its interactions with the dopaminergic system in decision making. Finally, we will review and discuss the available empirical evidence obtained from both clinical and preclinical studies of cannabinoid modulation of value-based decision making.