**4. Two complementary regulating circuits**

In a previous paper, we have proposed to distinguish two separate circuits regulating skilled (cognitively controlled) and intuitive (emotionally controlled) behaviour: extrapyramidal and limbic circuits [11].

The 'extrapyramidal' circuit is often mainly associated with motor activity but also regulates other behavioural responses. The first relay station of this cortical–subcortical circuit is formed by the striatum, which consists of three parts that correspond to three parallel divisions of the extrapyramidal system: the caudate nucleus (cognitive system), putamen (motor system) and ventral striatum (emotional/motivational system) [23, 33–35]. This last part is formed by the NAcb, which consists of a core (NAcbC) and a shell (NAcbS). The core belongs to the extrap‐ yramidal basal ganglia and is primarily involved in motivating the organism to exhibit skilled behaviour. The shell belongs to the limbic basal ganglia and is primarily involved in facilitating intuitive (emotional) behaviour [23, 35].

**Figure 4. Position of the limbic basal ganglia (centromedial amygdala, extended amygdala, bed nucleus of the stria terminalis and nucleus accumbens shell) relative to the extrapyramidal basal ganglia (caudate nucleus, putamen, nucleus accumbens core) and hippocampus**. The figure only shows the first relay stations of the extrapyramidal (light and dark blue) and limbic (orange and green) cortical–subcortical circuits.

**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,

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

In a previous paper, we have proposed to distinguish two separate circuits regulating skilled (cognitively controlled) and intuitive (emotionally controlled) behaviour: extrapyramidal and

The 'extrapyramidal' circuit is often mainly associated with motor activity but also regulates other behavioural responses. The first relay station of this cortical–subcortical circuit is formed by the striatum, which consists of three parts that correspond to three parallel divisions of the extrapyramidal system: the caudate nucleus (cognitive system), putamen (motor system) and

termination of the activity within this circuit would induce happiness.

**4. Two complementary regulating circuits**

8 Recent Advances in Drug Addiction Research and Clinical Applications

grey = dopaminergic and green = adrenergic.

limbic circuits [11].

The 'limbic' circuit is for a significant extent covered by the amygdala. The amygdala consists of a heterogeneous group of nuclei and cortical regions and is divided into cortical (basolateral) and ganglionic (centromedial) sections [36–38]. The various nuclei differ in the number and type of brain areas to which they are connected. Apart from extensive connectivity with a variety of cortical areas [37], the various parts of the complex are mutually massively connected with each other [37, 38]. Nevertheless, it is possible to consider the centromedial (ganglionic) part as an output channel to the diencephalon and brain stem, while the basolateral (cortical) part is more easily regarded as an input channel for cortical information. Moreover, the amygdaloid complex has widespread connectivity with many subcortical regions [37], including the dorsal and ventral striatum, the bed nucleus of the stria terminalis, and the basal forebrain nuclei. The centromedial amygdala is continuous with the extended amygdala, which is in turn continuous through the bed nucleus of the stria terminalis with the shell part of the NAcb [23, 39]. This extended amygdala takes a position to the allocortex (olfactory cortex and hippocampus) that is similar to that which the neocortex takes to the striatum [39]. This idea can be extended to distinguishing limbic and extrapyramidal basal ganglia. The centromedial amygdala, proper extended amygdala, bed nucleus of the stria terminalis, and the shell of the NAcb form the limbic basal ganglia, with a function for the limbic cortex that reflects that of the extrapyramidal basal ganglia for the rest of the neocortex (**Figure 4**).

#### **5. The evolution of the forebrain in vertebrates**

We have developed an anatomical model how the intensity of reward-seeking and miseryfleeing behaviours is regulated. We propose that the first type of reward-seeking behaviours is controlled within a converging extrapyramidal neocortical–subcortical–frontocortical circuit containing as first stations, the caudate nucleus, putamen and core of the accumbens nucleus (NAcbC). The second type of misery-fleeing behaviours is then regulated by a limbic cortical– subcortical–frontocortical circuit containing as first relay stations, the centromedial amygdala, extended amygdala, bed nucleus of the stria terminalis and shell of the accumbens nucleus (NAcbS). As these types of behaviours must also have been exhibited by our most ancient ancestors, we studied the evolutionary development of the forebrain [6]. We found out that the earliest vertebrates, supposed to have a brain comparable with the modern lamprey, had an olfactory bulb, forebrain, diencephalon, brain stem and spinal cord, but not yet a true cerebellum. The forebrain of the lamprey contains a striatum with a modern extrapyramidal system, which is activated by dopaminergic mesostriatal fibres coming from the nucleus of the tuberculum posterior (NTP) [5], which is comparable with human ventral tegmental area

**Figure 5. Simplified representation of the extrapyramidal system of lampreys (left) and humans (right)**. In lamp‐ reys, the internal and external parts of the globus pallidus are intermingled within the dorsal pallidum but functional‐ ly segregated. For further explanations, consult Refs. [33, 40, 41]. GPe = globus pallidus externa; GPi = globus pallidus interna; NTP = nucleus tuberculi posterior; PPN = pedunculopontine nucleus; SNr = substantia nigra pars reticulata; STh = subthalamic nucleus. Left figure: red = glutamatergic, blue = GABAergic, green = dopaminergic, orange = choli‐ nergic; Right figure: red = excitatory, blue = inhibitory.

(VTA). An extrapyramidal circuit has not yet been developed and the extrapyramidal output ganglia directly activate motor control centres of the brainstem (**Figure 5**). In addition, the dorsal thalamus is very small and the forerunner of the neocortex has hardly developed.

the shell of the NAcb form the limbic basal ganglia, with a function for the limbic cortex that reflects that of the extrapyramidal basal ganglia for the rest of the neocortex (**Figure 4**).

We have developed an anatomical model how the intensity of reward-seeking and miseryfleeing behaviours is regulated. We propose that the first type of reward-seeking behaviours is controlled within a converging extrapyramidal neocortical–subcortical–frontocortical circuit containing as first stations, the caudate nucleus, putamen and core of the accumbens nucleus (NAcbC). The second type of misery-fleeing behaviours is then regulated by a limbic cortical– subcortical–frontocortical circuit containing as first relay stations, the centromedial amygdala, extended amygdala, bed nucleus of the stria terminalis and shell of the accumbens nucleus (NAcbS). As these types of behaviours must also have been exhibited by our most ancient ancestors, we studied the evolutionary development of the forebrain [6]. We found out that the earliest vertebrates, supposed to have a brain comparable with the modern lamprey, had an olfactory bulb, forebrain, diencephalon, brain stem and spinal cord, but not yet a true cerebellum. The forebrain of the lamprey contains a striatum with a modern extrapyramidal system, which is activated by dopaminergic mesostriatal fibres coming from the nucleus of the tuberculum posterior (NTP) [5], which is comparable with human ventral tegmental area

**Figure 5. Simplified representation of the extrapyramidal system of lampreys (left) and humans (right)**. In lamp‐ reys, the internal and external parts of the globus pallidus are intermingled within the dorsal pallidum but functional‐ ly segregated. For further explanations, consult Refs. [33, 40, 41]. GPe = globus pallidus externa; GPi = globus pallidus interna; NTP = nucleus tuberculi posterior; PPN = pedunculopontine nucleus; SNr = substantia nigra pars reticulata; STh = subthalamic nucleus. Left figure: red = glutamatergic, blue = GABAergic, green = dopaminergic, orange = choli‐

nergic; Right figure: red = excitatory, blue = inhibitory.

**5. The evolution of the forebrain in vertebrates**

10 Recent Advances in Drug Addiction Research and Clinical Applications

It has been suggested that during evolution of vertebrates, the development of the cerebral cortex resulted in the successive addition of concise modules to the extrapyramidal basal ganglia, each regulating a newly acquired function of the species (**Figure 6**) [5]. What happened on the limbic side is not entirely clear. The amygdaloid complex was moved laterally to the pole of the temporal lobe. The centromedial amygdaloid nuclei can be considered to be a remaining part of the lampreys striatum, but whether the extended amygdala and the bed nucleus of the stria terminalis also evolved from this structure is uncertain. Amphibians already have a bed nucleus of the stria terminalis, which is closely associated with the central and medial nuclear amygdala [42]. The nucleus accumbens can be considered to be the interface between motor and limbic basal ganglia [35]. So, our theory is to a certain extent supported by these evolutionary considerations. We suggest that the core of the accumbens nucleus regulates the motivation to exhibit reward-driven (approach) behaviour and the shell of the accumbens nucleus regulates the motivation to exhibit misery-driven (avoidance) behaviour.

**Figure 6.** Modular expansion of the basal ganglia during evolution of vertebrates (adapted from [5]). The figure only shows the first relay stations of the extrapyramidal (light and dark blue) and limbic (yellow and green) cortical–sub‐ cortical circuits.

But how is this motivation to show these two types of behaviours adapted to the changing demands of environment? At this point, again, considering the forebrain of lampreys can shed some light on this matter. Within the lamprey's forebrain, a specific nuclear structure has been identified within the subhippocampal region, called the habenula-projecting globus pallidus (GPh) [6]. This nucleus receives inhibitory control from the striatum and excitatory input from both thalamus and pallium. It activates the lateral habenula, and from there, glutamatergic fibres run directly to the dopaminergic NTP (excitatory) or indirectly via the GABAergic rostromedial tegmental nucleus (inhibitory). These dopaminergic fibres of the NTP regulate the activity of the striatum. So, in lampreys, the activity of the dopaminergic NTP is under the control of an evaluative system with input from the striatum and pallium in order to decide whether the locomotor activity should be increased or not (**Figure 7**). These structures increase activity during reward situations and decrease activity when an expected reward does not occur. A cholinergic circuitry from the medial habenula to the interpeduncular nucleus and periaqueductal grey regulates the fear/flight response.

**Figure 7. Circuitry of habenula-projecting globus pallidus of lampreys**. Red = glutamatergic, blue = GABAergic, green = dopaminergic.

#### **6. The habenula**

The habenula in the epithalamus has recently received much attention for possibly playing a role in depression and addiction [43–47]. This is strongly related to the influence of the habenula on the activity of monoaminergic control centres of the brainstem [46, 47]. The habenula is subdivided into two nuclei: the medial habenula and lateral habenula. In lampreys, a direct pathway runs from the homologue of the lateral habenula to the nucleus of the tuberculum posterior (NTP; considered to be a homologue of the SNc/VTA), next to a pathway to a homologue of the GABAergic rostromedial tegmental nucleus (RMTg; which inhibits the NTP) [5, 48]. Other efferents of the lateral habenula run to (diencephalic) histaminergic and serotonergic areas. In lampreys, a projection system from the homologue of the medial habenula to the interpeduncular nucleus was also identified. These habenular output struc‐ tures are well conserved across species. All the vertebrates examined possess the same efferent pathway, called fasciculus retroflexus, running to the ventral midbrain [9, 46, 47]. In mammals, the medial habenula projects, almost exclusively, to the cholinergic interpeduncular nucleus [49], whereas the lateral habenula projects to a variety of nuclei including the rostromedial tegmental nucleus (RMTg), raphe nuclei, substantia nigra, ventral tegmental area, and the nucleus incertus [9]. Moreover, the medial habenula has direct output to the lateral habenula and may regulate the latter's activity [46, 47] (**Figure 8**).

fibres run directly to the dopaminergic NTP (excitatory) or indirectly via the GABAergic rostromedial tegmental nucleus (inhibitory). These dopaminergic fibres of the NTP regulate the activity of the striatum. So, in lampreys, the activity of the dopaminergic NTP is under the control of an evaluative system with input from the striatum and pallium in order to decide whether the locomotor activity should be increased or not (**Figure 7**). These structures increase activity during reward situations and decrease activity when an expected reward does not occur. A cholinergic circuitry from the medial habenula to the interpeduncular nucleus and

**Figure 7. Circuitry of habenula-projecting globus pallidus of lampreys**. Red = glutamatergic, blue = GABAergic,

The habenula in the epithalamus has recently received much attention for possibly playing a role in depression and addiction [43–47]. This is strongly related to the influence of the habenula on the activity of monoaminergic control centres of the brainstem [46, 47]. The habenula is subdivided into two nuclei: the medial habenula and lateral habenula. In lampreys, a direct pathway runs from the homologue of the lateral habenula to the nucleus of the tuberculum posterior (NTP; considered to be a homologue of the SNc/VTA), next to a pathway to a homologue of the GABAergic rostromedial tegmental nucleus (RMTg; which inhibits the NTP) [5, 48]. Other efferents of the lateral habenula run to (diencephalic) histaminergic and serotonergic areas. In lampreys, a projection system from the homologue of the medial habenula to the interpeduncular nucleus was also identified. These habenular output struc‐ tures are well conserved across species. All the vertebrates examined possess the same efferent pathway, called fasciculus retroflexus, running to the ventral midbrain [9, 46, 47]. In mammals, the medial habenula projects, almost exclusively, to the cholinergic interpeduncular nucleus [49], whereas the lateral habenula projects to a variety of nuclei including the rostromedial tegmental nucleus (RMTg), raphe nuclei, substantia nigra, ventral tegmental area, and the

periaqueductal grey regulates the fear/flight response.

12 Recent Advances in Drug Addiction Research and Clinical Applications

green = dopaminergic.

**6. The habenula**

However, the input to the epithalamus appears to be less well conserved during evolution. In lampreys, the input of the homologue of the medial habenula comes from the medial olfactory bulb, the parapineal organ, the pretectum and the striatum [48]. The input of the lateral habenula comes from subhippocampal lobe (habenula-projecting globus pallidus; GPh) and the lateral hypothalamus, but not from the diagonal band of Broca. Mammals do not have a distinct GPh. It has been suggested that its homologue in primates is localized in the border of the globus pallidus interna (GPb) [5, 50]. Whether the function of the lampreys' GPh is retained within this GPb, is far from certain. The mammalian habenula receives input via the stria medullaris from the posterior septum, as well as from the medial septum, the nucleus of the diagonal band and midbrain structures [47, 49]. Major input to the medial habenula arises from septal nuclei, which in turn receive the majority of their input from the hippocampus [48]. Afferents of the lateral habenula come from the hippocampus, ventral pallidum, lateral hypothalamus, globus pallidus and other basal ganglia structures [46]. It is hypothesized that during evolution from lampreys to mammals, the originally direct sensory innervation of the habenula has been replaced by inputs from the so-called limbic system (i.e. the septum and diagonal band of Broca) [48]. We prefer to say that this is not a replacement, but a maintainment as the human limbic system is considered to be a derivative of the lamprey's forebrain.

**Figure 8. Connectivity through the epithalamus**. GPh = habenula-projecting globus pallidus, IPN = interpeduncular nucleus, RMTg = rostromedial tegmental nucleus, SNc = substantia nigra, pars compacta, VTA = ventral tegmental nu‐ cleus (adapted from Ref. [47]).

In our opinion, the amygdala plays an essential role in value-based selection of behaviour (salience attribution) and this idea is supported by the history of the amygdaloid complex in our ancestors. When the habenula-projecting globus pallidus still exists and functions in humans, this structure should receive input from the amygdala and hippocampus and give glutamatergic output to the lateral habenula. The amygdala and hippocampus would then regulate both the activity of the medial habenula (misery-fleeing behaviour) via septal nuclei as well as the activity of the lateral habenula (reward-seeking behaviour) via the homologue of the GPh. The amygdala and hippocampus should then be in an essential position for response selection of behaviour.
