**Circuits Regulating Pleasure and Happiness: A Focus on Addiction, Beyond the Ventral Striatum**

Anton J.M. Loonen, Arnt F.A. Schellekens and Svetlana A. Ivanova

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/62707

#### **Abstract**

in alcohol drinking and reward. It reviews the efficacy and tolerability of pharmacological treatments targeting dopamine transmission and suggests that newer agents that stabilize or indirectly modulate the mesolimbic dopamine system may be superior therapies, reflecting the paradigm shift from potent selective pharmaceuticals to more moderate approaches that target drug reward with fewer side effects. Chapter 5 further illustrates how our under‐ standing of addiction now extends well beyond the mesolimbic dopamine system. This chapter highlights how dysregulation of serotonin and noradrenaline within the basolateral amygdala results in stress-induced negative emotional states upon alcohol withdrawal and subsequent craving and vulnerability to relapse. The potential of several putative pharmaco‐ therapies for alcohol use disorders that target these transmitter systems are addressed.

Despite being endorsed by the majority of psychological and medical organizations, the medical or disease model of drug addiction remains overshadowed by the view that drug addiction represents a moral failing among wide swaths of the population. The continued controversy surrounding these theoretical perspectives can be seen across Chapter 6, which provides an overview of major approaches to treating substance use disorders, outlining their origins and core features. Moreover, this chapter provides the reader with a platform to consider advances in clinical practices, the importance of evidence-based approaches to treating addiction, and considers how drug courts may represent a potential reconciliation of the medical and moral approaches to addressing substance use disorders. The value of appreciating the dynamic nature of factors related to the development of drug addiction is well illustrated in Chapter 7, which compares two cohorts of dual diagnosis patients admit‐ ted to an acute psychiatry ward 10 years apart. This chapter highlights that while our cur‐ rent knowledge of substance use disorders can be informed by past research, we cannot solely rely on our previous understanding as a variety of changing demographic, societal, and pharmacological influences can shape the nature of problems faced by addicts and healthcare professionals alike. Chapter 8 reviews recent neuroimaging studies examining the effects of prenatal exposure across of a variety of addictive drugs on brain structure, function, developmental trajectory, and behavior. While emphasizing the challenges associ‐ ated with research examining the effects of prenatal drug exposure this chapter also raises the possibilities that biomarkers will emerge that might ultimately inform prevention and

Perhaps believing we will one day be saying that drug addiction is no longer a major public health concern is both optimistic and unrealistic? It is our hope that in coming decades we will see many of the ideas and translational approaches articulated here come to fruition and the next wave of technological advances will build upon our cumulative understanding of addictive processes and reduce the suffering of those directly and indirectly impacted by

> **William M. Meil Ph.D.** Professor of Psychology

**Christina L. Ruby Ph.D.** Assistant Professor of Biology Indiana University of Pennsylvania

Indiana University of Pennsylvania

intervention programs.

VIII Preface

substance use disorders.

A recently developed anatomical model describes how the intensity of reward-seeking and misery-fleeing behaviours is regulated. The first type of behaviours is regulated within an extrapyramidal cortical–subcortical circuit containing as first relay stations, the caudate nucleus, putamen and core of the accumbens nucleus. The second type of behaviours is controlled by a limbic cortical–subcortical circuit with as first stations, the centromedial amygdala, extended amygdala, bed nucleus of the stria terminalis and shell of the accumbens nucleus. We hypothesize that sudden cessation of hyperactivity of the first circuit results in feelings of pleasure and of the second circuit in feelings of happiness. The insular cortex has probably an essential role in the perception of these and other emotions. Motivation to show these behaviours is regulated by monoaminergic neurons projecting to the accumbens from the midbrain: dopaminergic ventral tegmental nuclei, adrenergic locus coeruleus and serotonergic upper raphe nuclei. The activity of these monoaminergic nuclei is in turn regulated through a ventral pathway by the prefrontal cortex and through a dorsal pathway by the medial and lateral habenula. The habenula has this role since the first vertebrate human ancestors with a brain comparable to that of modern lampreys. The lateral habenula promotes or inhibits reward-seeking behav‐ iours depending upon the gained reward being larger or smaller than expected. It is suggested that the ventral pathway is essential for maintaining addiction based on the observation of specific cues, while the dorsal pathway is essential for becoming addicted and relapsing during periods of abstinence.

**Keywords:** addiction, mood, habenula, basal ganglia, amygdala, insula

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1. Introduction**

The dominant view on the neuro-pathology of addiction is that of deficient control processes resulting from impaired prefrontal cortex function and increased saliency of drug-related cues over normal rewarding stimuli [1]. The latter results from altered reward processing in the ventral striatum [1]. An important starting point in this respect has been the work of Koob [2, 3], who integrated knowledge from different fields of science in order to describe a scheme for the neuro-circuitry of addiction. An important component of the work of Koob [4] is the characterization of anti-reward or negative reinforcement in particularly in the more ad‐ vanced stages of addiction. In his work, he assigns a major role to the activation of the brain stress systems, the amygdala, in particular, in addiction. In line with Koob's work, we pro‐ pose additional neuro-circuitry to be involved in addiction. In this review, we apply a neuroevolutionary approach to addiction, in order to identify potential additional subcortical structures that might have relevance for addiction.

Two basic principles of animal life are essential for survival of the individual and as a species. Firstly, the animal should be motivated to obtain food, warmth, sexual gratification and comfort. Secondly, the animal should be motivated to escape from predators, cold, sexual competitors and misery. As the human species currently exists, even our oldest ocean-dwelling ancestors living over 540 million years ago must have been capable to react to the environment to feed, evade predators, defend territory and reproduce. Thus, their primitive nervous systems must have regulated the necessary behaviours and incorporated the most essential structures of all today's freely moving Animalia. However, since then the human brain passed through a long evolutionary pathway during which particularly the forebrain showed major changes. The earliest vertebrate's brain almost completely lacked the human neocortex and the dorsal parts of the basal ganglia [5, 6]. These newer parts of the brain are believed to determine human behaviour to a high extent and consequently receive most attention in research of processes explaining the genesis of mental disorders. This contrasts the involve‐ ment in psychiatric disorders of those behavioural processes described above as also being displayed by the most primitive vertebrates. We want to suggest that these actions are still regulated in humans by brain structures derived from the primitive forebrain of the earliest vertebrates. Therefore, we describe the anatomy of the forebrain of the earliest human vertebrate ancestors [6]. From a comparison of the striatum of lampreys to that of anuran amphibians and younger vertebrates, it can be concluded that the striatum of lampreys is the forerunner of the human centromedial (i.e. nuclear) amygdala. In anuran amphibians (frogs and toads), the lamprey's striatum is retrieved as central and medial amygdaloid nuclei, while a dorsal striatum for the first time appears in its direct vicinity [6, 7]. The lampreys forebrain also contains a structure of which the connections are very well conserved in more recent human ancestors: the habenula. The habenula constitutes—together with the stria medullaris and pineal gland—the epithalamus and consists of medial and lateral parts [8]. The habenula has received much attention because of it asymmetry in certain vertebrate species [9] and its role in mediating biorhythms [10]. The habenula regulates the intensity of reward-seeking and misery-fleeing behaviour probably in all our vertebrate ancestors. In lampreys, the activity of the lateral habenula is in turn regulated by a specific structure: the habenula-projecting globus pallidus. It is tempting to speculate that this structure has a similar role in humans, but a clear anatomical human equivalent with the same function has not yet been identified. Based upon the evolution of the basal ganglia in vertebrates and the mechanism of the emotional response, we postulate the existence of two systems regulating the intensity of the aforementioned behaviours [11]. These two circuits include the extrapyramidal and limbic basal ganglia, which are collaborating in a reciprocal (i.e. Yin-and-Yang) fashion. The two basal ganglia systems are linked together by the core and shell parts of the nucleus accumbens (NAcb), which regulates motivation to show reward-seeking and misery-fleeing behaviour, respectively. Hijacking of the reward-seeking mechanism by certain substances such as alcohol or illicit drugs is considered the essential mechanism behind addiction.

In this chapter, we will describe the evolution of the vertebrate forebrain and the functioning of the described regulatory circuits in somewhat more detail. Thereafter, the putative role of the habenula in initiating addiction and causing relapse after abstinence is depicted. The described model also explains the mood and anxiety symptoms that accompany the addictive process. We will start with a brief description of the mechanism of the emotional process [11, 12].
