**4. Mechanism of action**

ethically complex problems. The entry into the neurosurgical practice of neuromodulation methods has opened up a new scenario due to their flexibility and reversibility in their possible application to the treatment of addiction, such as substance abuse, gambling and internet gaming. The term "addiction" generally indicates a model of persistent redundant behaviors despite adverse medical or psychological results. The common element is recurrent problematic behavior accompanied by a preoccupation with the behavior [1, 2]. It is attested that the development of addiction is not simply the effect of the acute impact of the substance or behavior [3–5] but instead represents a state of imbalance in the reward system [6]. Alterations in prefrontal, limbic and cortical areas seem to be involved in addiction and maladaptive behavior not only in animal models but also in human neuroimaging studies [7–9]. The areas most involved in the manifestations of addiction are represented by the dopaminergic connections between ventral tegmental area (VTA) and nucleus accumbens (NAcc), which modulates learning, memory and repetitive behaviors. Stimulation of NACC in animals has proven to control

The development of addiction finds its anatomical and neurobiological bases in the so-called neurocircuitry of reward, and it is important to better understand when and how the reward system is activated [13]. The term "reward" is defined as any event that increases the probability of a response with a positive hedonic component. The ascending meso-cortico-striatal dopamine systems seem to have a key role in the rewarding properties of nearly all drugs of abuse [14]. In humans, positron emission tomography studies have shown that intoxicating doses of alcohol and drugs release dopamine and opioid peptides into the ventral striatum [15, 16], activating low-affinity dopamine D1 receptors, which are necessary for the rewarding effects of drugs [17]. This specific circuitry includes not only dopamine and opioid peptides but also γ-aminobutyric acid (GABA), glutamate, serotonin, acetylcholine and endocannabinoid systems that act at the level of either the ventral tegmental area or nucleus accumbens. Balanced circuits result in proper inhibitory control and decision-making and normal functioning of reward, motivation, stress and memory circuits. These circuits also interact with circuits that are involved in mood regulation, including stress reactivity (which involves the amygdala, hypothalamus and habenula) and interception (which involves the insula and anterior cingulate cortex and contributes to the awareness of negative emotional states). Drugs of abuse usurp executive function circuits, motivational circuits and stress circuits via multiple neurotransmitter-specific neuroplasticity circuits. Key neurotransmitters that are implicated in these neuroadaptations include dopamine, enkephalins, glutamate, γ-aminobutyric acid, norepinephrine, corticotropin-releasing factor (CRF), dynorphin, neu-

The use of deep brain stimulation (DBS) for the treatment of addiction was fortuitous, starting from observation in some PD patients the escalation of their intake of dopamine replacement

acquired behaviors as a result of alcohol and cocaine consumption [10–12].

**2. Neurobiological mechanism**

2 Drug Addiction

ropeptide Y and endocannabinoids.

**3. DBS for the treatment of addiction**

The mechanism of action of DBS remains unclear. As to the anatomical organization of the nucleus accumbens, it is divided into two major subregions, the core and shell, which differ from each other both functionally and anatomically. The core receives projections from the anterior cingulate and dorsal prelimbic, while the shell receives projections from the infralimbic and ventral prelimbic cortices [26, 27]. DBS of the accumbens shell or core increased c-Fos immunoreactivity, a measure of neuronal activation in these nuclei. c-Fos study indicates that DBS of the accumbens shell activates the infralimbic cortex, which could have contributed to the DBSinduced activation of the shell [12]. DBS applied to either the accumbens core or shell reduced alcohol consumption [11]. In contrast, DBS of the medial accumbens shell, but not the accumbens core, attenuated cocaine priming-induced reinstatement of drug seeking [12]. Moreover, since enhancing neuronal activity in the nucleus accumbens actually promotes the reinstatement of cocaine seeking [28, 29], DBS-induced inactivation of the nucleus accumbens via depolarization inactivation and/or activation of inhibitory neurons may be responsible for the attenuation of cocaine reinstatement [30–32]. Electrophysiological studies showed that accumbens DBS attenuated the spontaneous activity of cortico-accumbal glutamatergic neurons but also stimulated cortical interneurons, apparently via recurrent inhibition [33]. However, GABA agonist-induced inactivation of the infralimbic cortex attenuated the reinstatement of cocaine seeking induced by a priming injection of cocaine [12], which is consistent with accumbens DBS indirectly activating GABAergic interneurons. These results suggested that DBS of the accumbens shell produced complex effects throughout the circuit in which the shell is embedded. It is generally agreed that cocaine self-administration results in aberrant activity in the cortico-accumbal system and it appears that normalization of this system is one of the main effects of accumbens DBS [34, 35].
