**2. Model for emotional regulation**

**1. Introduction**

structures that might have relevance for addiction.

2 Recent Advances in Drug Addiction Research and Clinical Applications

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

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

A suitable model for the regulation of the emotional response can be derived from the paper of Terence and Mark Sewards [13]. According to their model, the control centre for emotional response types such as *sexual desire*, *hunger*, *thirst*, *fear*, *nurturance* and *sleep-need* drives and *power-dominance* drives is the hypothalamus. The output of the hypothalamus proceeds along three channels. The first route projects via the thalamus to the cortex, including a pathway that contributes to the perception of emotion and one for the initiation and planning of cognitive and motor responses (drives). The second output pathway is a projection at least partly via the periaqueductal grey (PAG) to several brainstem nuclei, including nuclei that regulate the autonomic components of the emotional response (e.g. increased circulation and respiration). The PAG also activates the serotonergic raphe nuclei, the adrenergic locus coeruleus complex and the dopaminergic ventral tegmental area. From these nuclei, projections pass back to the hypothalamus (e.g. regulating hypophysiotropic hormones) and through the medial forebrain bundle to the forebrain (activating the frontal cortex). The PAG also constitutes an important input structure generating signals to the emotional forebrain. Apart from hormone release mediated through various brainstem nuclei, a third direct hypothalamic projection system regulates the endocrine component of the emotional response (also by releasing hypophysio‐ tropic hormones), enabling adaptation of the milieu interne, or correction of a possible misbalance. The hypothalamus also exerts a receptor function for various substances in the circulating blood.

This model corresponds to a significant extent with the model of Liotti and Panksepp [14]. However, they follow a different approach, describing seven emotional systems for *seeking*, *rage*, *fear*, *panic* (separation distress and social bonding), *care* (nursing and empathy), *lust*  (sexual love) and *play* (joy and curiosity), which are not all regulated by the autonomic hypothalamus. Within the context of this article, the first three systems of Liotti and Panksepp deserve a more detailed description.

The appetitive motivation-*seeking* system stimulates the organism to acquire the many things needed for survival. This motivation is coupled to a reward feeling that can—but not neces‐ sarily does—result from these activities. The nature of the specific rewards is of a lesser importance; the system works equally well for seeking food, water, warmth, and illicit drugs, as well as for social goals such as sexual gratification, maternal engagement and playful entertainment. The system promotes interest, curiosity and desire for engagement with necessary daily life activities. The process of reward pursuing consists of at least three psychological components: learning to value (attentive salience), incentive salience or 'want‐ ing' and experiencing pleasure resulting in 'liking'. The first component is believed to be addressed by the amygdala. The amygdala can 'learn' by conditioning to appreciate sensory appetitive information within the context of external and internal circumstances and to initiate a proper response. Incentive salience is regulated by mesocorticolimbic mechanisms, with a central role for the NAcb. Later, in this chapter, we will describe that the insula plays an essential role in perceiving pleasure.

The amygdala additionally takes a central position with respect to valuing aversive stimuli, playing a critical role in anxiety and aggression. The anger-promoting rage system is associated with irritation and frustration. In this system, the emotional circuit is stimulated by projections

**Figure 1. Simplified model for the regulation of emotional response**. The hypothalamus is considered to be the prin‐ ciple controller and the amygdala the initiator of emotional response. In this depiction, the amygdala represents all limbic structures involved in emotional response. The amygdala is inhibited by the mPFC (blue arrow). MC = motor cortex, PAG = periaqueductal grey substance, dPFC = dorsolateral prefrontal cortex, mPFC = medial prefrontal cortex, PMC = premotor cortex, SMC = supplementary motor cortex.

between the medial amygdala and the medial hypothalamus via the stria terminalis. Neurons also project reciprocally between specific parts of the PAG in the mesencephalon and the medial hypothalamus. The fear system is organized in a fashion parallel to the rage system, in which both the amygdala and the PAG project to the medial hypothalamus. Activity within this system can lead to freezing or flight behaviour. Sustained fear (anxiety) is also mediated by the amygdala but follows a slightly different anatomical route and links the fear and stress systems.

Taken together, the regulation of the described forms of emotional output can be summarized and simplified into the scheme in **Figure 1**. The hypothalamus can be considered one of the principle control centres for emotional (non-behavioural) output (especially gratification, fear and aggression-driven). The hypothalamus regulates three components of this response: a thalamic one, a brainstem one and a pituitaric one. As explained above, the hypothalamus itself receives a stimulating input function from the amygdala, among other regions. The amygdala is responsible for the initiation of a suitable response type. In this process of initiating the emotional response, the amygdala is inhibited by the medial prefrontal cortex. This scheme describes the process of response selection, but another mechanism is regulating the level of motivation to exhibit the selected response type.
