**8. Conclusions**

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

In order to be considered to have a substance addiction, the individual must start to abuse a drug, he/she should maintain this abuse and/or he/she should relapse to abuse after a period of abstinence. Several lines of evidence suggest that indeed patients go through different stages of substance use, from intoxication, through repeated cycles of withdrawal and increasing tolerance to an end stage of addiction and relapse [3, 4]. It has also been shown that during this process, the motivation to use substances develops from 'liking' to 'wanting/needing' [3, 4]. In line with these findings, the neurobiological changes develop from more ventral striatal, reward-related, circuits to more dorsal striatal circuits involved in habit formation and stress [3, 4]. Moreover, addicted patients no longer use substances because it is nice (positive reinforcement), but because it reduces a negative affective state, related to increased activity of the brain stress systems, including the amygdala and hypothalamus-pituitary axis (negative reinforcement). This theory describes a development of addiction in three stages: *binge/*

Our proposal of staging is slightly different in order to let it correspond better to the described primitive subcortical regulation of behaviour. Abuse is probably largely maintained by the pathological process of craving for drugs, which is activated by the observation of certain phenomena (cues), the getting involved in social and emotional circumstances or executing specific habits which all are related to the individuals' personal circumstances of drug abuse. We want to suggest that this mechanism (i.e. activation of craving by cues) explains the usage of the illicit drug by the individual on a regular basis. It has been described that the craving process is activated by stimulation of the dopaminergic input to the NAcb from the VTA. This VTA is in turn activated by glutamatergic fibres from the prefrontal cortex by a ventral connection, which are reacting upon analysis of the circumstances that predict the availability of the illicit drug [51]. The glutamatergic synapses with mesencephalic dopaminergic neurons carry nicotinic cholinergic receptors, which allow long term potentiation of this excitatory

The above mechanism explains how addiction is maintained, but not how it is initiated. We want to hypothesize that in this second process, the habenula is involved (for a description of the role of the habenula in addiction see Refs. [46, 47]). The lateral habenula stimulates or inhibits the VTA depending upon the result of the behaviour. It stimulates the behaviour when the result is more rewarding than expected [52, 53] and inhibits it when the behaviour has more or less disappointing results [54]. The lateral habenula also encodes reward probability, reward magnitude and the upcoming availability of information about reward [54, 55]. So, when an individual uses an illicit drug and the results are very rewarding (biological, psy‐

response selection of behaviour.

synaptic transmission [51].

**7. Idea for a possible role of habenula in addiction**

14 Recent Advances in Drug Addiction Research and Clinical Applications

*intoxication*, *withdrawal/negative affect* and *preoccupation/anticipation* [3, 4].

Studying the evolution of the vertebrate's forebrain offers interesting clues about the mecha‐ nism of addiction. In lampreys, motor activity is regulated by a striatum, which can be considered to be the forerunner of the nuclear amygdala. The lamprey's striatum contains a quite modern extrapyramidal system (**Figure 5**). The activity of this striatum is regulated by dopaminergic fibres coming from the forerunner of the VTA in the midbrain. The activity of the VTA is in turn regulated by the habenula, with a connectivity that is very well conserved during the evolution into finally humans. During this evolution, the basal ganglia developed in a modular fashion with the addition of new layers on the dorsal side of the basal ganglia once new functions developed (**Figure 6**). The evolution of the ventral part of the basal ganglia is less certain, but these structures also became connected with parts of the (limbic) neocortex via the diencephalon. Therefore, it is possible to distinguish extrapyramidal and limbic CSTC circuits, which regulate the magnitude of reward-seeking and misery-fleeing behaviours. Motivation to express these two behaviours is regulated by the NAcbC and NAcbS, respec‐ tively. In turn, the VTA determines the activity of NAcb, and the locus coeruleus only of the NAcbS (**Figure 3**). Directly and indirectly, the upper raphe nuclei also determine the activity of both parts of the NAcb [57]. As part of a dorsal pathway, the lateral habenula controls the activity of the VTA and the medial habenula the activity of locus coeruleus and raphe nuclei. The activity of both lateral and medial habenula is controlled by the amygdala and hippo‐ campus. Via a ventral route, the prefrontal cortex also influences the activity of the VTA. We hypothesize that this ventral route is involved in maintaining substance abuse, while the dorsal route is primarily involved in initiating addiction and causing relapse into dependence after using illicit drugs after a period of abstinence.
