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

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

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 synaptic transmission [51].

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‐ chological or social) the habenula disinhibits the VTA to continue and expand this behaviour. The same is true concerning the rapid reactivation of craving for example tobacco, cocaine or GHB in the case of relapse after a period of abstinence. The lateral habenula could then signal vividly that the individual likes these effects very much. So it could be interesting to study the activity of the pathways during a phase of active drug abuse and after re-usage after a period of abstinence. This could also shed some light on the pharmacological mechanisms to prevent relapse.

Besides craving for the positive effects of substances, craving for addictive substances is also often accompanied by dysphoria and anxiety. This process has been described as the 'dark side of addiction' and has been associated with the development of a powerful negative reinforcement process [4]. This dysphoria is particularly true during relatively long-lasting periods of abstinence when even a clear depression can develop. Koob [4] has introduced the term 'anti-reward' to describe the background of this phenomenon. This is unfortunate, because it suggests a fictitious relationship with the reward-seeking system. However, this dysphoria could very well result from a dysfunction of another pathway connecting amyg‐ daloid complex and hippocampus through the epithalamus with the midbrain. The miseryfleeing (fear/flight) response could be regulated via septal nuclei and medial habenula with the interpeduncular nucleus. Through this pathway, the medial habenula regulates the activity of the adrenergic locus coeruleus and the serotonergic dorsal raphe nucleus [47]. This could result in the activation of the misery-fleeing mechanism, causing dysphoria. The rewardseeking response could be regulated by a parallel pathway via a homologue of GPh and lateral habenula with the ventral tegmental area [56]. Hypoactivity of the reward-driven reentry circuit with as first station NAcbC would result in anhedonia and lack of energy, two main symptoms of depression.
