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Home , Dopaminergic pathways, Nucleus accumbens

Research Article • DOI: 10.2478/s13380-013-0146-x • Translational Neuroscience • 4(4) • 2013 • 419-428 Translational Neuroscience

THE EFFECT OF Yarong Wang#1, Jia Zhu#1, ACCUMBENS LESIONS ON Ling Chen2, Yijun Liu3, Qiang Li1, APPETITE, SEXUAL FUNCTION, Weichuan Yang1, Wei Li1, AND DEPENDENCE IN Liyan Zhao4, Mark S. Gold3, Jifeng Sun5*, RECOVERING HEROIN ADDICTS Wei Wang1*

Abstract 1 Department of Radiology, Tangdu Hospital, The (NAc) is a key part of the neural circuitry that creates reward, and the Fourth Military Medical University, 569 that facilitates human feeding, sexual and smoking behaviors. In the , the NAc is a crucial Xinsi Road, Baqiao District, Xi’an 710038, component responsible for natural and drug-induced behaviors. Yet it is unclear whether NAc is China. indispensible for all reward behaviors in human beings. The present study aimed to investigate the long-term 2 Department of Oncology, the First effects of NAc ablation on sexual function, appetite, and nicotine dependence level in chronic heroin users. A liated Hospital of Xi’an Jiaotong Eighteen former heroin–dependent patients (male) with bilateral NAc ablation via stereotactic radiofrequency University, 766 West Yantan Road, Xi’an surgery for alleviating drug were recruited. Their postoperative time ranged from 12 710061, China. to 103 months. All subjects received MRI scans for assessing the accuracy of the lesion site. Evaluation of appetite, 3 Department of Psychiatry, University of sexual function, and nicotine dependence were measured using the Simplified Nutrition Appetite Questionnaire, Florida College of Medicine, 100 Newell Dr the Brief Sexual Function Inventory, and the Fagerström Test for Nicotine Dependence, respectively. After L4100, Gainesville, Florida 32610, USA. precluding the potential confounding variables, such as drug use (dosage and duration), post-operation 4 National Institute on Drug Dependence, duration, age, body-weight, marital status and education level, ANOVA with repeated measures revealed that Peking University, 38 Xueyuan Road, the NAc ablation improved the patients’ appetite, sexual drive and sexual satisfaction. Yet there was no change in Beijing 100083, China. male erectile function, ejaculatory function, or nicotine dependence levels compared to the preoperative. These 5 Department of Nephrology, Tangdu may suggest that although NAc is a key part of the neural circuitry, the NAc surgical lesions left the fundamental Hospital, the Fourth Military Medical aspects of natural and drug-induced reinforcement and motivation almost intact. University, 569 Xinsi Road, Baqiao District, Keywords Xi’an 710038, China. • Nucleus accumbens (NAc) • Heroin dependence • Human reward behavior Received 18 July 2013 accepted 02 December 2013 © Versita Sp. z o.o.

Introduction conditioning [12], so it is of great significance to in the reinforcing action of primary reinforcers explore the relationship between the NAc and and illicit drugs. In human and animal there exists a specific human reward behaviors. To investigate the functional role of NAc reward mechanism that serves to maintain In this system, especially in the NAc, in human reward behaviors, scholars have and encourage the and activities (DA) predominantly mediates the employed multiple approaches, including beneficial for survival and reproduction. primary reinforcing characteristics of natural neuroanatomical [22], electrophysiological The neural substrate underlying the reward rewards (such as food and sex), in addition to [23], intracranial microinjection [24] and mechanism is mainly based on the meso- those of drug abuse and [13]. When a neuroimaging methods [25]. The intracranial corticolimbic pathway that natural reinforcer or drug of abuse is consumed, microinjection can identify neural circuitry and originates in the ventral tegmental extracellular DA concentration in the NAc is explore the reward effects of multiple chemical area (VTA) with projections to the nucleus increased, which is associated with the feeling transmitters, but cannot directly analyze the accumbens (NAc) and connections with other of “” [13-15]. When anticipating or neural transmission involved in humans [24]. brain regions, including the , ventral actually consuming the reinforcer [13,16,17] Functional neuroimaging is a powerful tool to pallidum, dorsal , and or when activated to encode saliency of a reveal the brain regions associated with reward [1]. Ample evidence confirms given stimulant [17-20], the NAc can also responses [25], but it cannot determine which that almost all drugs of abuse (heroin, , release DA, facilitating the reward behaviors. brain area is essential for reward behavior. , ) may dysregulate this It is noteworthy that a natural reinforcer Studies of patients with NAc lesions are system, inducing the development of addiction differs from drugs of abuse in reinforcing unique in enabling us to examine the specific [2-6]. Further, natural reward and drug abuse action. The primary difference lies in that the NAc-behavior relationships [22]. To date, few share this neural circuitry to accomplish the latter can modify the kinetics and amplitude studies have explored the effects of NAc lesions reinforcement effects [7-11]. In this neural of the dopamine release and form memories on reward behavior in humans. The most circuitry NAc plays an important role in associated with drug consumption [21]. Such notable to mention are a case study [26] and reward/saliency, motivation/drive, memory/ evidence shows that the NAc has a pivotal role two studies in which NAc lesions extensively

* E-mail: [email protected] ; [email protected] # These two authors contributed to this work equally.

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involved adjacent brain structures [27,28]. daily methadone dose. All the participants were The post-surgery follow-up was regularly The lack of literature on specific NAc lesions required to have a urine toxicology screening conducted via telephone after a 6-month makes it difficult to do a clinical-pathological test at the time of study enrollment. interval. Our investigators focused on the correlation analysis to human NAc lesions. Exclusion criteria included: a) incorrect patients’ physical, psychological, neurological The objective of this study was to better NAc target site or lesions that involved an and psychiatric information, especially their understand the structure-function relationship adjacent brain structure according to the MRI illicit drug use. These data were obtained of the NAc by identifying the relations between data (see “Accuracy assessment of ablation via patient self-report or the report of their the NAc and specific reward behaviors in a site”); b) current or past psychiatric illness families living with them. When the patients group of patients who underwent bilateral NAc other than heroin dependence; c) neurological encountered any health problem and sought ablation by stereotactic surgery for alleviating signs, severe mental disorder, or intelligence further medical treatment, physical and drug psychological dependence. dysfunction; d) current medical illness; e) imaging examinations were available. After a Specifically, we investigated the long-term dependence on any other psychoactive period (1~7 years), there were 22 patients lost in uence of bilateral NAc ablation on natural substance other than nicotine or coffee; f) to follow up. Among the remaining 20 patients, reward (appetite, sexual behavior) and drug history of head trauma; and g) MRI examination 19 had no MRI scan contraindication and were reward (nicotine dependence) in these patients. contraindication. None of the participants willing to take part in the present study. experienced strong withdrawal symptoms All telephone interviews were conducted Materials and methods during the study. 1 participant was excluded by 3 highly experienced interviewers in social because the brain structure MRI scan revealed and psychiatric research. The telephone The ethics statement and study that his NAc lesions involved an adjacent conversation was recorded during the population structure. Eventually, 18 participants entered telephone interview. And at least half of the live This study followed the principles outlined in the next analyses. conversations were monitored in real time by a the Declaration of Helsinki (6th revised version, supervisor to ensure the reliability and validity Edinburgh, 2000). Ethics approval was obtained Background of the study population of survey data. from the Ethics Committee of the Fourth and their follow-up investigation Military Medical University (at the Review From 2002 to 2008, a clinical study was Experimental procedures Board Meeting held on 18th March 2002) and conducted to explore a new way to alleviate Tangdu Hospital Ethic Committee (approval opiate drug psychological dependence by All participants were well informed about the no. TDLL-2009039 from 5th March 2009). The ablating the NAc with stereotactic surgery in study and gave their consents to the surgical authors declare no conflict of interest. China [29]. There were a total of 42 intractable treatment, the post-surgery MRI scan for Nineteen of 42 male chronic heroin heroin dependent patients who underwent verifying the lesion loci and the questionnaire users who had received the bilateral NAc the neurosurgery in Tangdu Hospital, the survey for collecting information about neurosurgery [29] were fully informed of Fourth Military Medical University. The demographics, educational level, marital status, the context and procedure of this research, surgery indications included: a) patients drug use history, height and body-weight. The including brain magnetic resonance imaging had a more than 3 year drug-taking history participants’ body-weight before neurosurgery (MRI) scan and psychological tests, and signed (their average heroin daily consumption was was obtained from their medical records, and written consents for their involvement in 300 mg to 1000 mg); b) patients experienced their current body-weight was measured to the the current study. The post-surgery study at least 3 detoxifications that were followed nearest 0.5 kg with a platform scale equipped as a was performed from April 2009 to August by occurring within 3 weeks after standard apparatus in Tangdu Hospital. The scale 2010. Based on the conventional brain MRI the detoxification; c) patients underwent the was regularly checked-up and maintained. Their scans, the 19 participants appeared to have present surgery of their own free will and had body weight at 3 months after the neurosurgery normal cerebral structure with the exception no medical contraindications. All patients was obtained from the patients’ memories and of the necrotic lesion in the NAc due to the provided consents for the neurosurgery. confirmed by their families. The current illicit neurosurgery. Three of the 19 participants had The neurosurgery utilized radiofrequency to drug use information was obtained from both no current use of prescription medication other induce an adequate sized lesion in the NAc self-description and documented follow-up than methadone and the remaining were not based on the coordinates of the bilateral data. All participants were required to undergo taking any medications at the time. In order to NAc on spiral CT. This technique was chosen a drug urinalysis test at the time of enrollment. avoid the negative impacts of acute withdrawal based on a study that demonstrated that the After MRI scans, the participants were asked to on testing results, a series of psychological relapse rate of these patients who received complete a battery of questionnaire tests under tests and brain MRI scans were performed for this neurosurgery was markedly reduced psychiatrist guidance to examine the impact the 3 patients with methadone maintenance compared with those receiving conventional of the neurosurgery on appetite, male sexual treatment at 6 to 8 hours after receiving their therapies [29]. function and nicotine dependence level. These

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questionnaires consisted of the Council on tip of the . When the caudate and using the intensity contour (Figure 1A). MR Nutrition Appetite Questionnaire (CNAQ) [30], putamen were connected, the superior border images in other planes were also used to assist Fagerström Test for Nicotine Dependence (FTND) was the line drawn from the most inferior tip positioning of the surgery target (Figure 1B). [31-33] and Brief Sexual Function Inventory of lateral ventricle to the most lateral–inferior Once two observers reached the consensus (BSFI) [34]. All participants were required to tip of , and the lateral border that the center point of the NAc lesion was complete the instruments for evaluating their was the vertical line drawn from the most seated inside the outline of the NAc without appetite, nicotine dependence level and sexual lateral–inferior tip of internal capsule. The involving an adjacent structure, the accuracy function before the neurosurgery and at the inferior border of the NAc could be achieved of the surgery target was then verified. time of the survey.

MRI data acquisition Neuroimaging examination was conducted using a 3.0T GE Signa Excite HD MRI scanner (GE Medical System, Milwaukee, USA) equipped with a standard head coil in the Imaging Center of Tangdu Hospital, the Fourth Military Medical University. To assess the accuracy of the ablation site, a high-resolution structural scan was performed on contiguous slices with a 1 mm thickness covering the whole brain using an axial Fast Spoiled Gradient Echo (3D-FSPGR) sequence. The MRI scanning parameters for the brain spatial structure were as follows: TR=7.8 ms, TE=3.0 ms, TI=450 ms, FOV=256 mm × 192 mm, slice thickness=1.0 mm, skip=0 mm, matrix=256×256. In order to exclude gross cerebral pathology, a T2-weighted image was also conducted.

Accuracy assessment of the ablation site The accuracy of the ablation site was evaluated mainly based on the reconstructed images in a coronal view by two radiologists with more than 5 years clinical experience following instruction in defining the NAc anatomical border (www.cma.mgh.harvard.edu/manuals/ segmentation_may_2004.doc). The procedure used to locate the NAc region is briefly described below. First, the caudate and putamen were drawn manually. From an anterior to posterior slice, the contour of the NAc was defined according to the intensity of contrast between and gray matter, as well as the location of caudate, putamen, lateral ventricle and internal capsule. On the slice Figure 1. The location of NAc lesion sites in MRI. (A) According to the anatomical border of the NAc on the coronal where the caudate and putamen appeared view of the T1- weighted MRI, accurate lesion sites are assessed and defined as the most inferior one discontinuous, the superior border of NAc was (as indicated by the arrow) in these anatomically delineated brain areas. The other two delineated areas superior to and connecting the NAc are the putamen (1) and (2) adjacent to the the virtual oblique line connecting the inferior lateral ventricle (3). Necrosis of the ablated NAc can be seen bilaterally in these similar lesions with a most tip of the lateral ventricle and the medial homogeneously low MRI signal intensity inside the marked area (arrow). (B) NAc lesions on the axial view of the MRI of another patient (arrows).

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Assessment of sexual function Statistical analysis between the surgery and the survey. All of The BSFI is a self-reported measure of sexual Descriptive data are expressed as mean ± the above statistical analyses were performed function. It is a multidimensional scale covering standard deviation (SD), if not stated otherwise. using STATA version 10.1 (Stata Corp. College three functional domains: sexual drive (two Paired t-tests and χ2 tests were applied to Station, Texas). Statistical significance in this items), erectile function (three items) and compare continuous variables and categorical study was set at p < 0.05 (two-tailed). ejaculatory function (two items), as well as variables before and after the surgery, problem (three items), and overall respectively. Mixed effects models (ANOVA with Results satisfaction (one item). The scores of each repeated measures) were applied in assessing question ranged from 0-4 (0, poor function; 4, the surgical effects on appetite, smoking, and Demographic characteristics, body excellent function) within each domain. sexual function to account for the correlation weight, smoking and illicit drug use between multiple measures within the same information Assessment of appetite individual before and after the surgery. We The details of demographic characteristics, The CNAQ is an 8-item single domain tested the surgical effects by controlling for the weight history, smoking behavior and illicit drug questionnaire to assess the appetite of adults. individual’s age, marital status, weight, drug use information of the participants are presented The CNAQ scores indicate risk for impaired use before surgery, and drug use in the years in Table 1. The mean age of participants was appetite that strongly correlates with weight loss due to anorexia. The total CNAQ score is the Table 1. Demographic characteristics, weight history, drug use information and smoking behavior of study participants (n = 18). sum of scores for 8 items, ranging from 8 to 40 (8, worst; 40, best), and lower scores indicate a Number 18 worsening appetite. The common cut-off of the Age (years) 38.7 ± 3.1 CNAQ score is as follows: more than 28 indicates a good appetite and no risk for anorexia, while Years between surgery and survey 4.8 ± 1.6 less than 28 indicates poor appetite and a risk Weight (Kg) of at least 5% weight loss within 6 months. The Weight before surgery 61.4 ± 7.9

CNAQ has been translated into Mandarin and Weight 3 months after surgery 69.9 ± 8.3 proved to have good reliability among Chinese Weight at the time of the survey 74.3 ± 9.9 populations [35]. Height (cm) 173.8 ± 3.8 Assessment of nicotine dependence Marriage (%) FTND is a common assessment tool for Married 77.8 nicotine dependence. It has been found that Divorced 22.2 FTND scores are correlated with biochemical Education (years) 9.5 ± 3.6 measures of nicotine dependence including Heroin use history exhaled air carbon monoxide, salivary cotinine, and salivary nicotine. FTND is also able to Average dosage of heroin consumption (mg/day) 1069.4± 858.9 predict smoking cessation and craving even Duration of heroin intake (months) 141.8 ± 45.3 in those who have quit smoking [36]. FTND is Current drug use (n) reliable in assessing nicotine dependence in Drug-free 15 different populations [37], including psychiatric Methadone maintenance treatment 3 and non-psychiatric individuals [38]. The first Smoking information item in the FTND is a valid predictor of nicotine dependence [39]. Nicotine dependence can be Smoking duration (years) 21.2 ± 4.5 divided into 5 levels, according to FTND scores: Smoking dosage preoperatively (cigarette/day) 33.6 ± 21.3 very low (0 to 2 points); low (3 to 4 points); Smoking dosage postoperatively (cigarette/day) 23.2 ± 14.3 moderate (5 points); high (6 to 7 points); and Smoking preoperatively (n/18) 18/18 very high (8 to 10 points). At the end of the FTND, Smoking postoperatively (n/18) several questions were designed to investigate the main causes which led to the starting of Quit smoking 1/18 smoking again after the neurosurgery and to Maintained smoking 10/18 investigate when the relapse happened. Refrained from smoking > 7days and relapsed 7/18

Note: Descriptive data are expressed as mean ± standard deviation (SD).

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38.7 ± 3.1 years (range 25-43), the mean year of before they received the neurosurgery. These The eect of ablating the NAc on education 9.5 ± 3.6 years, the mean duration participants’ duration of smoking ranged from 13 male sexual function, appetite and of heroin use 141.8 ± 45.3 months, the average to 29 years. One participant did not smoke from smoking behavior dosage of heroin consumption 1069.4 ± 858.9 the second day after the neurosurgery until the Table 2 shows that the surgery improved mg per day prior to the neurosurgery, and the time of the survey. The remaining 17 participants appetite, after controlling for the years from the average postoperative time 61.78 ± 16.99 months started smoking again within a week after the surgery to the current survey, age, weight, drug (range 12-103 months). Compared with the neurosurgery. Paired t-test revealed a significant use (yes or no), drug use amount before the preoperative, the body weight 3 months after reduction of the postoperative daily cigarette surgery (months mg/day), and marital status surgery (t = 3.701, df = 17, p = 0.002) and at the consumption in the 17 participants compared (married or divorced). The surgery had no effect time of survey (t = 5.151, df = 17, p = 0.000) was with the preoperative (t = 2.334, df = 17, p = on male sexual function and FTND scores. elevated. In addition, the weight at the time of 0.032). the survey was significantly higher than that at 3 There were 15 out of 18 participants who Changes in male sexual function, months after surgery (t = 2.194, df = 17, p = 0.042). discontinued heroin use successfully following nicotine dependence level and All of the 18 participants had been smoking the neurosurgery. The remaining 3 relapsed and appetite before and after ablation of for more than 13 years and their cigarette had been receiving methadone maintenance the NAc via stereotactic surgery consumption per day was more than 10 cigarettes treatment until this survey. Table 3 displays the mean BSFI scores for each domain of sexual function before and after Table 2. Regression results for surgery on sexual function, appetite and smoking (ANOVA with repeated measures). the neurosurgery. There was no significant difference in the total score, erectile function, Outcome Regression coefficients 95% CI P value ejaculatory function, and problem perception *Sex (BSFI total score) between before and after the neurosurgery. Model 1 6.0 -1.22, 13.22 0.10 However, the postoperative sexual drive and Model 2 3.45 -11.56, 18.47 0.65 sexual satisfaction were higher (p < 0.05). Appetite (CNAQ total score) The Wilcoxon signed-rank test showed Model 1 10.53 8.28, 12.78 <0.0001 no significant differences in nicotine Model 2 3.62 3.98, 13.39 <0.0001 dependence level between before and after the neurosurgery (Z = -0.702, p = 0.483). Smoking (FTND total score) When the preoperative appetite score Model 1 -0.15 -1.22, 0.92 0.78 served as the baseline, significant increases Model 2 0.06 2.57, 2.67 0.97 were observed in the appetite scores 3 months after neurosurgery and at the time of survey Note: Regression model: Model 1: surgery; Model 2: surgery + years (from surgery to survey), age, weight, drug use (yes (t = -7.454, p = 0.000; t = -8.513, p = 0.000). or no), drug use amount before the surgery (months mg/day), marriage type (married or divorced). But there was no difference between the two scores 3 months after neurosurgery and at the Table 3. Changes of sexual function, appetite score, weight and nicotine dependence level (n=18). time of the survey.

Sexual function score Nicotine Appetite Weight dependence Sexual Erectile Ejaculatory Problem Overall score (kg) Total score level score drive function function assessment satisfaction

Before 2.18±1.55 5.88±2.55 6.06±2.46 6.59±3.97 1.53±1.23 22.24±9.99 20.05±4.11 62.81±10.12 5.83±2.62 neurosurgery

3 months after the N/A N/A N/A N/A N/A N/A 30.39±4.73 70.64±8.90 N/A neurosurgery

Time of survey 4.29±2.20 7.29±3.10 6.35±2.29 7.65±3.71 2.65±1.22 28.24±11.46 30.11±3.03 75.00±11.42 5.39±2.70

-10.33±5.88a -7.83±8.98 a Difference -2.12±3.08 -1.41±5.02 -0.29±3.85 -1.06±6.39 -1.12±2.15 -6.00±19.21 0.44±2.66 -10.05±5.01b -12.19±10.04 b

0.000 a* 0.002 a* P value 0.012* 0.264 0.757 0.504 0.048* 0.216 0.315 0.000 b* 0.000 b*

Note: a represents 3 months after the neurosurgery vs. before the neurosurgery; b represents the time of the survey vs. before the neurosurgery; * stands for statistical significance. Paired t-test was applied to compare sexual function, appetite score and body weight before and after the neurosurgery. Nicotine dependence level score was analyzed with the Wilcoxon signed-rank test.

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Discussion such as a longer latency to achieve erection heroin use after the neurosurgery and their and intromission or fewer erections, but no sexual drive and overall sexual satisfaction The exact role of the NAc in human reward changes in the number of intromissions [44] or were improved. Evidence shows that the behavior has received intense attention both copulation to ejaculation time [45]. In addition, NAc is not an essential anatomical structure empirically and theoretically [40]. However, earlier research also demonstrated that the NAc for animal sexual motivation [44-46]. So we very few studies have had an opportunity to damage from radiofrequency, electrolytic and think this improvement should be attributed study human subjects with isolated or selective dopamine-depleting lesions had little effect on to the longtime abstinence after surgery and lesions in bilateral NAc. To our knowledge, this is male sexual behaviors, including contact and to some extent should be considered as the the first investigation on the effects of bilateral noncontact sexual responsiveness [44,46,47]. normalization of these functions after stopping NAc ablation on sexual function, appetite and Inconsistent with the animal research, our heroin use and an indirect and complex smoking habits in human subjects. Our data data showed that the postoperative erectile consequence of NAc ablation. suggest that postoperatively these former function of the patients was unchanged. This The appetite of our subjects was improved chronic heroin users had an improved sexual may be associated with the detailed items used after the neurosurgery, presenting with drive, sexual satisfaction and appetite, but by this study to represent the separate aspects significantly increased CNAQ scores at 3 only the enhanced appetite was associated of sexual behavior. These items are not as months after surgery and at the time of with the neurosurgery after excluding the specific as those in the animal experiments, so the survey. This result can be supported by influences of potential confounding variables, it is difficult to detect the possible changes. This the postoperative changes of body weight. such as post-operation duration before the may also be related to the sexual experience Although the data for body weight at 3 months investigation, status of drug use, drug intake that our subjects had before the surgery after surgery was obtained from the patients’ prior to the surgery, age, weight, marital status because this kind of experience may protect memory recall which may have questionable and education level. Our data also reveal that against the disruptive effects of the NAc-lesion accuracy, we think the data is reliable because it the neurosurgery had no impact on male on sexual behavior [48,49]. Previous studies, was not only confirmed by the patients’ families erectile function, ejaculatory function, and focusing on the effect of lesions in the medial but also correlated directly with the change in nicotine dependence level. These results pre-optic area (mPOA) on male copulatory appetite after surgery, meaning for a higher suggest that, although the NAc is a key part of behavior, failed to detect the copulatory increase in appetite, we saw a proportionally reward circuits, the NAc lesions deficits in the rats after destroying the mPOA higher increase in body weight. left the fundamental aspects of natural and cell body or depleting DA, and attributed the Our analysis, after excluding the influences drug-induced reinforcement and motivation failure to a compensation mechanism because of potential confounding variables, suggests almost intact. they detected a remarkable increase in DA that the improved appetite is associated with The NAc is a crucial part of DA systems receptor sensitivity or metabolism secondary the NAc ablation. NAc serves as an important mediating male sexual behavior, including to the lesion [50,51]. We speculate that a similar moderator or “gate” between emotion, the nigrostriatal system and the mesolimbic- compensation mechanism would occur in motivation and action in feeding behaviors mesocortical system [41,42]. The former serves our patients, contributing to the unchanged [58,59]. But the NAc is not the only brain region the sensory-motor coordination required erectile function. Certainly it needs further involved in the mediation of feeding behaviors. for copulation, the latter plays a key role in investigation. Previous studies demonstrate that food sexual arousal (e.g. erection), motivation and Heroin may act on the reward is mediated by brain subsystems which possible reward [43]. However, on the topic pathways in central nervous system, and are distributed anatomically but organized of the importance of the NAc in mediating long-term heroin use leads to the inhibition hierarchically [20,60,61]. In addition, multiple male sexual behavior there are some of gonadotropin-releasing and brain regions, other than the NAc, are involved discrepancies in literature that document further impairs all aspects of sexual function. [62]. Evidence proves that a single lesion or the sexual performance of the NAc-lesioned It has been confirmed that heroin abusers depletion of DA in NAc is not likely to abolish animals. It was reported that the bilateral NAc- have serious sexual dysfunction, including fundamental properties of food reward [63,64] lesioned male rats failed to have an erection decreased sexual drive, erectile dysfunction although it makes the animals with NAc DA and intromission, which provides functional and delayed ejaculation [52-56], and that depletion or antagonism less active and/or evidence for the excitatory role of the NAc heroin-induced sexual potency reduction is less likely to work for food [65]. Consistent with in regulating sexual arousal processes [22]. associated with directing blood flow away from these studies, our results demonstrate that the Contrary to that, other studies suggested that the genitals. Further, it direcly correlates with NAc ablation did not suppress our subjects’ after the depletion of NAc DA through local the deteriorated physical and psychological appetite. injection of a neurotoxic agent or cell body status and living environment of heroin We think the improved appetite and weight lesions, the male rats showed no more than users [57]. Our data show that our subjects gain in our subjects should be attributed minor impairment of copulatory behavior, experienced a longtime abstinence from to their heroin abstinence caused by the

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neurosurgery. Many studies confirm that abstinent heroin users substituted nicotine for abstinence (more than one year) and further there is a causality relationship between heroin to stimulate the DA reward pathway. unethical to create corresponding controls who drug abusers’ malnutrition and their immune We think that their rapid relapse to into their are not heroin dependent patients and have and endocrine system deterioration, dietary smoking habit is to some extent supportive of undergone neurosurgery to create bilateral NAc insufficiency and other concurrent diseases. our hypothesis that the lesions in NAc leave the lesions. Undoubtedly this limitation should be Further the discontinuation of drug use fundamental aspects of reward and motivation taken into consideration when understanding may ameliorate the drug abuser’s physical almost intact. our findings. The small sample size (18 patients) and psychological status, lifestyle, food Our data show that the bilateral NAc ablation is another limitation of this study. Furthermore, characteristics (, food deprivation mainly influenced the heroin-dependent 22 patients were lost to follow up after the and food variety) as well as environmental behavior of our subjects, making most of neurosurgery. The possibility that a large factors, further contributing to the increase of them (15 out of 18) abandon heroin use after majority of subjects undergoing neurosurgery appetite and body weight [66-70]. This may the neurosurgery. But this neurosurgery did relapsed to heroin use after surgery can not be related to a compensatory mechanism, not aect other reinforcing functions such be eliminated. This might also lead to a bias the neurosurgery-induced and complex as food intake, sexual behavior, or smoking. in understanding the role of NAc in human neuroadaption or reallocation of behavior, We speculate that the subjective intention reward behaviors. which helps maintain brain homeostasis or an to abandon heroin use makes a decisive In summary, the bilateral NAc ablation in alternative acquisition for food [71]. contribution to this outcome. All subjects former heroin-dependent patients failed to Although nicotine and heroin use share had a strong willingness to stop heroin use; disrupt male sexual function, appetite and the same DA reward circuitry [72-74], the otherwise they would not have considered nicotine dependency. It indicates that inherent postoperative heroin-dependent behavior surgical therapy, a drastic measure in and drug-related rewards are not completely and smoking behavior of our subjects comparison to more conventional therapies. dependent on the NAc, and that reward appears to be inversely proportional. Fifteen Another contributing factor is that the NAc behavior and drug addiction may share some of the 18 patients discontinued heroin use ablation destroyed the neuronal substrates main neural circuits, however the sub-circuitry successfully. Conversely, only one patient of heroin psychological dependence of the two kinds of behaviors may be different. abandoned smoking immediately after the and caused an abrupt dopaminergic Long term heroin abuse may already impair surgery and maintained cigarette abstinence imbalance in the mesolimbic circuitry [26]. the normal function of NAc which, coupled until this investigation. The remaining 17 took The hypodopaminergic state provided a with other compensation mechanisms, can up smoking again within a short period (7 neurophysiological opportunity to help contribute to the current results. We believe days) after surgery. Many subjects explained patients ignore drugs or drug-related cues. that our results may cast new insight into the that they took up smoking again because Previous studies suggest that the circuits role of NAc in reinforcement behaviors and they were bored and exposed to nicotine- mediating food and drug reward behaviors into the future investigations on substance associated environmental stimuli or craving- are distinct yet overlapping [21]. We think dependence treatment in which the NAc is inducing cues. In China, smoking was a socially the neuronal substrates underlying heroin selected as a target. acceptable behavior but heroin use was illegal. addiction and natural reinforcement are not Our subjects had to face considerable pressure all exactly the same, which may be a reason Acknowledgments from society, family and law if they wanted to for the rapid recovery of our subjects’ appetite continue heroin use, but not if they want to and sexual activity (as natural reinforcer) and This work was supported by the grants from continue smoking. Another reason for their smoking (as a socially acceptable behavior). National Natural Science Foundation of China rapid relapse into their smoking habits after Further contributing to their recovery, subjects (NO: 30870685, 81071143 and 81071142) and surgery may be related to the compensatory after surgery changed their dwelling places, cut Shaanxi Province Science and Technology mechanism of DA reward. This is similarly off their connections with fellow drug-users, Development Projection (NO: 2008k12-02, demonstrated in a study where ex-smokers and improved their nutritional and health 2009K01-65, 2010k16-03-01 and 2010K16- use food as a compensatory mechanism of status. 03-02 ). The authors would like to thank Liwei DA reward [75]. Here, we believe that instead It would be difficult to find corresponding Chen for her contribution in analyzing the of using food, these neurosurgically-induced controls who are heroin users with long-term data.

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