**5.3. Amygdala**

**5.1. Nucleus accumbens (Nacc)**

4 Drug Addiction

**5.2. Lateral hypothalamus (LH)**

There is considerable preclinical evidence to support a role for the nucleus accumbens in mediating the motivational effects of conditioned stimuli associated with the drug leading to its anticipation. DBS in the NAcc has been successful in treating the behavioral component in addiction disorders and substance abuse [36, 37]. Ablative surgeries targeted at the NAcc have been used for several years (between 2000 and 2004) in China with mixed results, but a relapse rate of 50% and ethical concerns now limit the use of destructive procedures in the treatment of addiction [38–40]. The limited outcome and the consecutive side effects (poor concentration, poor short-term memory, aconuresis, changes in sexual desire and decreased interest to various degrees) are nevertheless expected considering the preclinical data investigating the role of the nucleus accumbens. However, there is no clear evidence for a specific alteration of the nucleus accumbens in addicted individuals. Despite the reserves considered earlier, few clinical studies are considering application of DBS in the accumbens of addicts and therefore as first indication with successful results as for example on one case of heroin addiction [41, 42]. Clinical data about the efficacy of NAcc stimulation exist in the literature in small case series. In two single case studies, two patients who underwent bilateral NAcc stimulation for heroin addiction experienced abstinence from opioids to the last follow-up, respectively, at 6 years and 6 months [42, 43]. A similar outcome was observed in other two separate cases of patients with chronic, severe alcoholism who were treated with DBS in the NAcc reporting abstinence at 1 year [24, 25, 44]. In a single case of NAcc DBS for obsessive compulsive disorder (OCD), quit smoking was reported [45], but a subsequent analysis of 10 patients who received DBS of the NAcc for OCD, TS, or anxiety found that only three patients achieved nicotine abstinence within 30 months [46]. These case reports show the potential for treatment of substance abuse disorders with DBS of the NAcc, but randomized and blinded studies are lacking. However, DBS of NAcc, as any other basal ganglia targets, can be associated with unpredictable limbic symptoms such as mania and depression [47]. A recent study showed that the DBS of different NAcc subregions had different effects on a natural reward such as the motivation for food intake. Specifically, the stimulation of the lateral shell decreased the motivation to food while the stimulation of the core was without effects [48]. According to some authors, there would be a different response of NAcc neurons to natural rewards with respect to secondary rewards to drug intake even if it was not possible to demonstrate a preferential localization of such neurons in the core or in the shell [49]. The NAcc shell is unlikely to be a good candidate for DBS, considering the empirical evidence for its detrimental effect on general motivation and impulse control [50]. In conclusion, the NAcc DBS seems to be able to exercise a significant control over drug abuse and behavioral components mostly in alcohol and oppiate addictions; therefore, alternative structures have been considered for DBS with limited preclinical empirical or theoretical support.

The hypothalamic drive control of food-motivated behavior has been extended to drug reward [51]. The lateral portion of the hypothalamus (LH) may be a possible target in the treatment of addiction as it has been demonstrated at this level of important transcriptional modifications in subjects with compulsive drug intake and significant control of alcohol intake following radiofrequency stereotactic lesions of the ventromedial nucleus [52]. Amygdala is involved in the process of evaluating the positivity or negativity of experience and in the formation of connections between experience and other signals becoming the center of emotional memory and learning [55]. In humans, the reduction of amygdala volume has been related to increase in desire for alcohol and cocaine intake and greater tendency to relapse [56], while in rats its functional block leads to increase in compulsivity of cocaine intake and seeking and reduction of its anxiety-producing effect [57, 58]. However, DBS of the amygdala does not find a clinical application in the treatment of addiction at present, even if it has been proposed by some authors [59].
