**3. Perception of feelings of pleasure and happiness**

 (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

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

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,

deserve a more detailed description.

4 Recent Advances in Drug Addiction Research and Clinical Applications

essential role in perceiving pleasure.

PMC = premotor cortex, SMC = supplementary motor cortex.

According to Terence and Mark Sewards [13], the cortical representations of their emotional response types are located on the medial prefrontal and anterior cingulate areas. However, these cortical areas represent the fields initiating the corresponding drives for finding relief and are unlikely directly involved in the perception of feelings of thirst, hunger, sleepiness, somatic pain, etcetera, as these anterior cerebral areas are generally implicated in generating output. A better candidate for the perception of feelings of pleasure (reward) and happiness (euphoria) would be the insular cortex (**Figure 2**) as the posterior part of the insula contains areas for gustation, thermo-sensation, pain, somato-sensation, and viscera-sensation [15]. Indeed, the insular cortex has been demonstrated to be involved in processing emotions, such as anger, fear, happiness, sadness or disgust, and has been shown to display treatmentresponsive changes of activity in different mood disorders [16]. However, the exact position of the insular cortex with respect to the perception of the discussed feelings remains unclear. The insular cortex, being located in the centre of the cerebral hemisphere, is reciprocally connected with almost every other input and output structure of the emotional response system. It could also be suggested that the insula's most important role is the integration and adjustment of the activities of such other brain structures without being primarily involved in the perception of emotional feelings itself.

However, yet another possibility comes into mind, which can be considered a revival of the late nineteenth century hypothesis developed independently by the US American William James (1842–1910) and the Dane Carl Lange (1834–1900) [17]. Their theories on the origin and nature of emotions states that once we become aware of the physiological bodily changes induced by, for example, danger, we feel the corresponding emotion of fear [18, 19]. So, the

**Figure 2. Position of the insular cortex**. The human insular cortex forms a distinct, but entirely hidden cerebral lobe, situated in the depth of the Sylvian fissure. It is a phylogenetically ancient part of the cerebral hemisphere and entirely overgrown by adjacent regions of the hemispheres and the temporal lobe (cf. [15]).

basic premise of this theory is that the perception of interoceptive stimuli instigates the experience of an emotional feeling as well as its phenomenal consciousness. This could easily be expanded with the perception of other changes including environmental factors, which then would induce exteroceptive stimuli [19]. The anteriorly directed processing stream within the insula would make the anterior insula perfectly suitable to fulfil the requirements for the neuronal representative of such functions [20]. The upper part of the anterior insula is strongly and reciprocally connected with the anterior cingulate cortex, and the lower part is functionally linked to the adjacent caudal orbitofrontal cortex, which makes the anterior insula involved in food-related stimuli and the urge to take drugs as well [15].

The orbitofrontal cortex is the neuronal structure, which is most intricately involved in motivating for reward bringing behaviours [21, 22]. Perhaps the insula is involved in experi‐ encing pleasure, but in our opinion, this is unlike to occur directly as sensing these positive feelings. As a matter of fact, the orbitofrontal cortex induces motivation to go for the possibility to obtain food, sex or drugs, which results in an unpleasant urge to exhibit this behaviour, called 'craving' [2–4]. This craving feeling results from hyperactivity of the motivational cortical–striatal–thalamic–cortical (CSTC) reentry circuit, running from the orbitofrontal cortex, through the core part of the NAcb, ventral pallidum and thalamus back to the orbito‐ frontal cortex [23]. It has been suggested that the NAcb itself is responsible for sensing pleasure, but this is unlike to be true. Probably, the nucleus accumbens core (NAcbC) has a classical role of adapting the activity when reward is expected based upon information about other significant factors [24]. We want to hypothesize that the experience of pleasure is more likely related with the sudden ceasing of the urge to obtain the delightful objects once they are acquired.

Evidence for this last proposal can be derived from investigating neuro-activation during a very pleasurable activity; that is having sex. The activity pattern during sexual activity has been extensively studied [24, 25]. In women, first the medial amygdala and insula become activated, among other structures; then, the cingulate cortex is added to this activation; and then, at orgasm itself, the NAcb, paraventricular nucleus of the hypothalamus (secretes oxytocin) and hippocampus become active [25]. Specific experiments by Georgiadis and colleagues [26, 27] have shown that during orgasm, which is the moment that true pleasure is perceived, the activation of brain structures is very much the same in men and women. What is particularly interesting is that they found a profound deactivation in the anterior part of the orbitofrontal cortex (and also in the temporal lobe). Georgiades and colleagues [27] interpret the decreased activity of the orbitofrontal cortex and the temporal lobe to reflect the occurrence of satiety. But this idea may be too limited. In our opinion, they also make a case that the relief that accompanies the disappearance of the urge to reach orgasm is indeed the most important representation of pleasure itself. The reaction within the orbitofrontal cortex may be due to the loss of anticipating achieving the important goal (because it has been reached). The profound deactivation of the motivational reentry circuit would result in abrupt ceasing of craving, what in itself could result in pleasure. This would also indicate that without craving also pleasure cannot occur.

A prefrontal structure that has consistently been implicated in negative mood states (i.e. dysphoria) is the subgenual part of the anterior cingulate cortex (Brodmann's areas 25 and the caudal portions of Brodmann's areas 32 and 24). Anatomical studies have shown that the volume of the infralimbic sgACC is reduced in certain depressed groups [28]. Moreover, the activity of the sgACC is affected following successful treatment with SSRIs, electroconvulsive therapy, transcranial magnetic stimulation (rTMS), ablative surgery and deep brain stimula‐ tion [29]. Moreover, this sgACC has been found to be metabolically overactive in depressed states and reacts to the treatment with a decrease of its activity [30].

basic premise of this theory is that the perception of interoceptive stimuli instigates the experience of an emotional feeling as well as its phenomenal consciousness. This could easily be expanded with the perception of other changes including environmental factors, which then would induce exteroceptive stimuli [19]. The anteriorly directed processing stream within the insula would make the anterior insula perfectly suitable to fulfil the requirements for the neuronal representative of such functions [20]. The upper part of the anterior insula is strongly and reciprocally connected with the anterior cingulate cortex, and the lower part is functionally linked to the adjacent caudal orbitofrontal cortex, which makes the anterior insula involved in

**Figure 2. Position of the insular cortex**. The human insular cortex forms a distinct, but entirely hidden cerebral lobe, situated in the depth of the Sylvian fissure. It is a phylogenetically ancient part of the cerebral hemisphere and entirely

The orbitofrontal cortex is the neuronal structure, which is most intricately involved in motivating for reward bringing behaviours [21, 22]. Perhaps the insula is involved in experi‐ encing pleasure, but in our opinion, this is unlike to occur directly as sensing these positive feelings. As a matter of fact, the orbitofrontal cortex induces motivation to go for the possibility to obtain food, sex or drugs, which results in an unpleasant urge to exhibit this behaviour, called 'craving' [2–4]. This craving feeling results from hyperactivity of the motivational cortical–striatal–thalamic–cortical (CSTC) reentry circuit, running from the orbitofrontal cortex, through the core part of the NAcb, ventral pallidum and thalamus back to the orbito‐ frontal cortex [23]. It has been suggested that the NAcb itself is responsible for sensing pleasure,

food-related stimuli and the urge to take drugs as well [15].

overgrown by adjacent regions of the hemispheres and the temporal lobe (cf. [15]).

6 Recent Advances in Drug Addiction Research and Clinical Applications

As shown in **Figure 3**, the infralimbic subgenual part of the anterior cingulate cortex is one of the structures, which feeds the shell part of the NAcb [31]. Hyperactivity of this structure might well result in hyperactivity within a putative emotional reentry circuit, which starts and ends within the anterior cingulate cortex. The subgenual cingulate gyrus sends efferents to all subcortical structures of our limbic basal ganglia and receives afferents from several hypo‐ thalamic and thalamic nuclei [32]. This hyperactivation of the subgenual cingulate gyrus might in turn results in increased stimulation of the anterior insula [32], which might lead to experiencing feelings of dysphoria. Abrupt termination of this hyperactivity might result in happiness in the same manner as ending craving would result in pleasure.

**Figure 3.** Stimulation of the core and shell of the nucleus accumbens. (Adapted from Ref. [31], reproduced with per‐ mission of the author). VTA = ventral tegmental area; LC = locus coeruleus. Red = glutamatergic, blue = GABAergic, grey = dopaminergic and green = adrenergic.

In conclusion, we want to hypothesize that two parallel cortical–subcortical reentry circuits regulate motivation to exert reward-bringing and misery-escaping behaviours, respectively. These circuits are involved in causing pleasure and happiness. Hyperactivity of the NAcb corecontaining CSTC circuit induces craving and its abrupt ending is experienced as pleasure. Hyperactivity of the NAcb shell-containing CSTC circuit induces dysphoria and abrupt termination of the activity within this circuit would induce happiness.
