Brain lesions disrupting addiction map to a common human brain circuit.

Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data (n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores (n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation.

The effects of aspirin and N-3 fatty acids on telomerase activity in adults with diabetes mellitus.

Type 2 Diabetes mellitus is associated with aging and shortened telomere length. Telomerase replaces lost telomeric repeats at the ends of chromosomes and is necessary for the replicative immortality of cells. Aspirin and the n3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are commonly used therapies in people with type 2 diabetes for reducing cardiovascular disease events, though their relation to telomerase activity is not well studied. We explored the effects of aspirin, EPA + DHA, and the combined effects of aspirin and EPA + DHA treatment on telomerase activity in 30 adults with diabetes mellitus. EPA and DHA ingestion alone increased telomerase activity then a decrease occurred with the addition of aspirin consumption. Crude (F-stat = 2.09, p = 0.13) and adjusted (F-stat = 2.20, p = 0.14) analyses of this decrease showed signs of a trend. These results suggest that aspirin has an adverse effect on aging in diabetics who have relatively high EPA and DHA ingestion.

Implications of insular cortex laterality for treatment of nicotine addiction.

BACKGROUND: Damage to the insula disrupts nicotine-induced cravings and is associated with greater odds of cessation. The role of laterality in regulating these changes is unclear. Neuroimaging studies in cigarette smokers show left hemispheric activation during a period of forced withdrawal and right hemispheric activation after having just smoked. Among current smokers hospitalized for stroke involving their insula, we compared left versus right insular damage and its effect on smoking outcomes. METHODS: A total of 37 smokers hospitalized with unilateral insular strokes (14 right, 23 left) were administered questionnaires to assess urge (Questionnaire on Smoking Urges) before (retrospectively) and during hospitalization and 3 months post-stroke, withdrawal during hospitalization (Wisconsin Smoking Withdrawal Scale), and prolonged abstinence at 3 months post-stroke. Crude and adjusted linear regression models were performed controlling for baseline covariates. RESULTS: Right and left insular-damaged smokers experienced a significant decrease in urge from baseline to hospitalization and three-month follow-up (p < 0.01). Smokers with left-sided insular infarcts relative to right-sided experienced a larger decrease in acute urge (adjusted ß=-1.16, 95% CI: -2.59, 0.27, p = 0.11) but not chronically (adjusted ß=-0.06, 95% CI: -1.53, 1.40, p = 0.93). Left-sided insular damage was also associated with significantly fewer and less severe withdrawal symptoms during hospitalization (adjusted ß=-3.52, 95% CI: -7.01, -0.04, p = 0.05). No differences were noted between groups for prolonged abstinence (p = 0.50). CONCLUSIONS: Left insular adaptations are suggestive to have an impact on acute changes in urge and withdrawal more so than the right insula, however lateral asymmetries did not exist for long-term changes.

Effects of aspirin in combination with EPA and DHA on HDL-C cholesterol and ApoA1 exchange in individuals with type 2 diabetes mellitus.

BACKGROUND/SYNOPSIS: Low-dose aspirin is an effective drug for the prevention of cardiovascular disease (CVD) events but individuals with diabetes mellitus can be subject to 'aspirin resistance'. Thus, aspirin's effect in these individuals is controversial. Higher blood levels of seafood-derived omega-3 polyunsaturated fatty acids (ω3) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have beneficial effects in reducing risk of CVD events but few studies have examined the interaction of plasma EPA and DHA with aspirin ingestion. OBJECTIVE/PURPOSE: Our study examined the combinatory effects of EPA, DHA, and aspirin ingestion on HDL-cholesterol (HDL-C) and apoA-I exchange (shown to be associated with CVD event risk). METHODS: 30 adults with Type 2 diabetes mellitus ingested aspirin (81mg/day) for 7 consecutive days, EPA+DHA (2.6g/day) for 28 days, then both for 7 days. Plasma was collected at baseline and at 5 subsequent visits including 4h after each aspirin ingestion. Mixed model methods were used to determine HDL-C-concentrations and apoA-I exchange compared to the baseline visit values. LOWESS curves were used for non-linear analyses of outcomes to help discern change patterns, which was followed by piecewise linear functions for formal testing of curvilinear relationships. RESULTS: Significant changes (p < 0.05) compared to baseline in both HDL-C-concentrations and apoA-I exchange were present at different times. After 7 days of aspirin-only ingestion, apoA-I exchange was significantly modified by increasing levels of DHA concentration, with increased apoA-I exchange observed up until log(DHA) of 4.6 and decreased exchange thereafter (p = 0.03). These LOWESS curve effects were not observed for EPA or HDL-C (p > 0.05). Aspirin's effects on apoA-I exchange were the greatest when EPA or DHA concentrations were moderate compared to high or low. Comparison of EPA, DHA, and EPA+DHA LOWESS curves, demonstrated that the majority of the effect is due to DHA. CONCLUSION: Our results strongly suggest that plasma concentrations of EPA and DHA influence aspirin effects on lipid mediators of CVD event risk where their concentrations are most beneficial when moderate, not high or low. These effects on HDL-C cholesterol and apoA-I exchange are novel. Personalized dosing of DHA in those who take aspirin may be a beneficial option for patients with type 2 diabetes mellitus.

Immediate and Sustained Decrease in Smoking Urges After Acute Insular Cortex Damage.

INTRODUCTION: Smoking urges are fundamental aspects of nicotine dependence that contribute significantly to drug use and postquit relapse. Recent evidence has indicated that damage to the insular cortex disrupts smoking behaviors and claims to reduce urges associated with nicotine use, although tools that assess urge have yet to be used to validate these findings. We examined the effect of insular versus non-insular damage on urge using a well-accepted urge scale. METHODS: This 3-month observational prospective cohort study consisted of 156 current smokers hospitalized for acute ischemic stroke (38 with insular infarctions, 118 with non-insular infarctions). During hospitalization, the Questionnaire of Smoking Urges (QSU)-brief was assessed retrospectively based on experiences before the stroke (baseline, T0), prospectively immediately following the stroke (T1) and once more via telephone at 3-month follow-up (T2), with higher scores indicating greater urge. Bivariate statistics and multivariable linear regression were used to evaluate differences in QSU-brief scores, relative to baseline, between exposure groups, controlling for age, baseline dependence, stroke severity, use of nicotine replacement, and damage to other mesocorticolimbic regions. RESULTS: A greater reduction in QSU-brief score was seen in the insular group compared to the non-insular group from T0 to T1 (covariate-adjusted difference in means of -1.15, 95% CI: -1.85, -0.44) and similarly from T0 to T2 (covariate-adjusted difference in means of -0.93, 95% CI: -1.79, -0.07). CONCLUSIONS: These findings confirm the potential role of the insula in regulating nicotine-induced urges and support the growing evidence of its novelty as a key target for smoking cessation interventions. IMPLICATIONS: Human lesioning studies that evaluate the insula's involvement in maintaining nicotine addiction make inferences of the insula's role in decreasing urge, but do not use validated instruments that directly assess urges. This study corroborates prior findings using the continuous Questionnaire of Smoking Urges to quantify changes in urge from before lesion onset to immediate and 3-month follow-up time points.

Study of monotherapy versus combination therapy for tobacco dependence among heavily addicted smokers.

OBJECTIVES: Combination therapy for tobacco dependence is becoming a standard of care. We sought to compare benefits and adverse events for combination therapy versus monotherapy for smokers in The Smokers' Health Project. METHODS: This secondary data analysis was derived from adult smokers (n = 198) who initially smoked 15 or more cigarettes per day and participated in The Smokers' Health Project. Participants were grouped as taking 1 medication or 2 concurrent medications for tobacco dependence for 1 year over the 2-year study period. Adverse events were compared between medication groups using chi-square tests. Crude and adjusted odds ratios were calculated for cessation at 6, 12, 18, and 24 months using logistic regression. RESULTS: No differences were seen in the proportion of incident adverse events between the monotherapy (28.3%) and combination therapy (32.3%) groups (P = 0.54). At 6 months, the odds of quitting were less in the combination therapy group relative to those taking monotherapy (adjusted odds ratio = 0.47 [95% CI 0.24-0.93]). At 12, 18, and 24 months, the odds of quitting did not differ between therapy groups (P = 0.07, 0.33, 0.55, respectively). CONCLUSION: Monotherapy and combination therapy for smoking cessation are similarly effective up to 24 months, and they exhibit similar adverse event attributes.

Effects of an evidence-based computerized virtual clinician on low-density lipoprotein and non-high-density lipoprotein cholesterol in adults without cardiovascular disease: The Interactive Cholesterol Advisory Tool.

There is a lack of research on the use of electronic tools that guide patients toward reducing their cardiovascular disease risk. We conducted a 9-month clinical trial in which participants who were at low (n = 100) and moderate (n = 23) cardiovascular disease risk-based on the National Cholesterol Education Program III's 10-year risk estimator-were randomized to usual care or to usual care plus use of an Interactive Cholesterol Advisory Tool during the first 8 weeks of the study. In the moderate-risk category, an interaction between treatment condition and Framingham risk estimate on low-density lipoprotein and non-high-density lipoprotein cholesterol was observed, such that participants in the virtual clinician treatment condition had a larger reduction in low-density lipoprotein and non-high-density lipoprotein cholesterol as their Framingham risk estimate increased. Perceptions of the Interactive Cholesterol Advisory Tool were positive. Evidence-based information about cardiovascular disease risk and its management was accessible to participants without major technical challenges.

A feasibility study of conducting the Montreal Cognitive Assessment remotely in individuals with movement disorders.

Remote assessments of individuals with a neurological disease via telemedicine have the potential to reduce some of the burdens associated with clinical care and research participation. We aim to evaluate the feasibility of conducting the Montreal Cognitive Assessment remotely in individuals with movement disorders. A pilot study derived from two telemedicine trials was conducted. In total, 17 individuals with movement disorders (8 with Parkinson disease and 9 with Huntington disease) had Montreal Cognitive Assessment examinations evaluated in-person and remotely via web-based video conferencing to primarily determine feasibility and potential barriers in its remote administration. Administering the Montreal Cognitive Assessment remotely in a sample of movement disorder patients with mild cognitive impairment is feasible, with only minor common complications associated with technology, including delayed sound and corrupted imaging for participants with low connection speeds. The Montreal Cognitive Assessment has the potential to be used in remote assessments of patients and research participants with movement disorders.

Damage to the insula leads to decreased nicotine withdrawal during abstinence.

BACKGROUND AND AIMS: Current pharmacotherapies for tobacco dependence are generally well tolerated, but have relatively high rates of relapse. They target primarily the brains' mesocorticolimbic 'reward' pathway. However, recent evidence suggests that the insular cortex, a central cerebral hemispheric region historically overlooked in addiction models, may also play an important role in cognitive and emotional processes that facilitate drug use. We examined whether insular versus non-insular damage from ischemic stroke attenuated acute withdrawal from cigarette smoking and reduced the likelihood of nicotine replacement therapy (NRT) use during hospitalization. DESIGN: Data were derived from a longitudinal study with 3 months' follow-up, beginning June 2013 and ending May 2014. SETTING: Three acute care hospitals in Rochester, NY, USA. PARTICIPANTS: One-hundred and fifty-six current smokers hospitalized for acute ischemic stroke (38 with insular infarctions and 118 with non-insular infarctions, assessed by three neuroradiologists). MEASUREMENTS: The Wisconsin Smoking Withdrawal Scale (WSWS) and Minnesota Nicotine Withdrawal Scale (MNWS) were administered during hospitalization (a period of forced abstinence) to assess the frequency and severity of withdrawal symptoms. NRT use was also assessed during hospitalization. FINDINGS: On average, smokers with insular damage had a lower WSWS score during admission [mean=5.89, standard deviation (SD)=4.72] compared with those with non-insular damage (mean=9.20, SD=4.71; P<0.001) [covariate-adjusted difference in means of -3.12, 95% confidence interval (CI)=-4.97, -1.27]. A similar difference was also noted when the MNWS was used (P=0.02). Furthermore, participants with insular lesions appeared to be less likely to use NRT during admission compared with those with non-insular lesions [odds ratio (OR)=0.72, 95% CI=0.32, 1.64]. CONCLUSIONS: Current smokers with damage to their insular cortex brain region appear to experience fewer and less severe tobacco withdrawal symptoms, and appear to be less likely to require nicotine replacement therapy during hospitalization, compared with smokers with non-insular damage. These findings support the potential role of the insular cortex in regulating withdrawal during abstinence, a motivator responsible for the maintenance of addictive behaviors.

Smoking cessation behaviors three months following acute insular damage from stroke.

BACKGROUND: Recent evidence suggests that the insular cortex may play an important role in cognitive and emotional processes that facilitate drug use but it is unclear whether changes to the insula would result in sustained abstinence. To better understand the role of the insula in maintaining abstinence, we examined quitting patterns in smokers with acute damage to their insula relative to other regions. DESIGN: Prospective cohort study with 3month follow-up, beginning June 2013 and ending May 2014. SETTING: Three acute care hospitals in Rochester, NY. PARTICIPANTS: One-hundred-fifty-six current smokers hospitalized for acute ischemic stroke; 38 with insular infarctions and 118 with non-insular infarctions, assessed by 3 neuroradiologists. MEASUREMENTS: Self-reported smoking status (seven-day point prevalence and continuous abstinence), complete abstinence from any nicotine product, and disruption of smoking addiction (defined by criteria on smoking status, difficulty of quitting, and urge) were assessed at three months post-stroke. Time to relapse (in days) after discharge was also assessed. RESULTS: Insular damage was associated with increased odds of three-month continuous abstinence (OR=3.71, 95% CI: 1.59, 8.65) and complete cessation from any nicotine product (OR=2.72, 95% CI: 1.19, 6.22). Average time to relapse was longer in the insular-damaged group (17.50days, SD=19.82) relative to non-insular damage (10.42days, SD=18.49). Among quitters, insular damage was also associated with higher relative odds of experiencing a disruption of addiction compared to non-insular damage (adjusted OR=5.60, 95% CI: 1.52, 20.56). CONCLUSIONS: These findings support the potential role of the insular cortex in maintaining smoking and nicotine abstinence. Further research is needed to establish whether the insula may be a novel target for smoking cessation interventions.

The effects of aspirin on platelet function and lysophosphatidic acids depend on plasma concentrations of EPA and DHA.

Aspirin's prevention of cardiovascular disease (CVD) events in individuals with type 2 diabetes mellitus is controversial. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and aspirin all affect the cyclooxygenase enzyme. The relationship between plasma EPA and DHA and aspirin's effects has not been determined. Thirty adults with type 2 diabetes mellitus ingested aspirin (81 mg/day) for 7 days, then EPA+DHA (2.6g/day) for 28 days, then both for another 7 days. Lysophosphatidic acid (LPA) species and more classic platelet function outcomes were determined. Plasma concentrations of total EPA+DHA were associated with 7-day aspirin reduction effects on these outcomes in a "V"-shaped manner for all 11 LPA species and ADP-induced platelet aggregation. This EPA+DHA concentration was quite consistent for each of the LPA species and ADP. These results support aspirin effects on lysolipid metabolism and platelet aggregation depending on plasma EPA+DHA concentrations in individuals with a disturbed lipid milieu.

The effects of aspirin and fish oil consumption on lysophosphatidylcholines and lysophosphatidic acids and their correlates with platelet aggregation in adults with diabetes mellitus.

Many diabetics are insensitive to aspirin's platelet anti-aggregation effects. The influence of co-administration of aspirin and fish oil (FO) on plasma lysophospholipids in subjects with diabetes is poorly characterized. Thirty adults with type 2 diabetes mellitus were treated with aspirin (81mg/day) for seven days, then with FO (4g/day) for 28 days, then in combination for another seven days. Lysophospholipids and platelet measures were determined after acute (4h) and chronic (7 days) ingestion of aspirin, FO, or both in combination. FO ingestion reduced all lysophosphatidic acid (LPA) concentrations, while EPA (20:5n-3) and DHA (22:6n-3) lysophosphatidylcholine (LPC) concentrations significantly increased after FO alone and in combination with aspirin. In vitro arachidonic acid-induced platelet aggregation was most strongly correlated with palmitoleic (16:1) and oleic (18:1) LPA and LPC concentrations at all time points. The ingestion of these agents may reduce cardiovascular disease risk in diabetic adults, with a disrupted lipid milieu, via lysolipid mediated mechanisms.

Modelling the cost effectiveness of disease-modifying treatments for multiple sclerosis: issues to consider.

Several cost-effectiveness models of disease-modifying treatments (DMTs) for multiple sclerosis (MS) have been developed for different populations and different countries. Vast differences in the approaches and discrepancies in the results give rise to heated discussions and limit the use of these models. Our main objective is to discuss the methodological challenges in modelling the cost effectiveness of treatments for MS. We conducted a review of published models to describe the approaches taken to date, to identify the key parameters that influence the cost effectiveness of DMTs, and to point out major areas of weakness and uncertainty. Thirty-six published models and analyses were identified. The greatest source of uncertainty is the absence of head-to-head randomized clinical trials. Modellers have used various techniques to compensate, including utilizing extension trials. The use of large observational cohorts in recent studies aids in identifying population-based, 'real-world' treatment effects. Major drivers of results include the time horizon modelled and DMT acquisition costs. Model endpoints must target either policy makers (using cost-utility analysis) or clinicians (conducting cost-effectiveness analyses). Lastly, the cost effectiveness of DMTs outside North America and Europe is currently unknown, with the lack of country-specific data as the major limiting factor. We suggest that limited data should not preclude analyses, as models may be built and updated in the future as data become available. Disclosure of modelling methods and assumptions could improve the transferability and applicability of models designed to reflect different healthcare systems.

Effects of low-dose aspirin and fish oil on platelet function and NF-kappaB in adults with diabetes mellitus.

INTRODUCTION: Many diabetics are insensitive to aspirin's platelet anti-aggregation effects. The possible modulating effects of co-administration of aspirin and fish oil in subjects with diabetes are poorly characterized. PARTICIPANTS AND METHODS: Thirty adults with type 2 diabetes mellitus were treated with aspirin 81 mg/d for 7 days, then with fish oil 4 g/day for 28 days, then the combination of fish oil and aspirin for another 7 days. RESULTS: Aspirin alone and in combination with fish oil reduced platelet aggregation in most participants. Five of 7 participants classified as aspirin insensitive 1 week after daily aspirin ingestion were sensitive after the combination. Although some platelet aggregation measures correlated positively after aspirin and fish oil ingestion alone and (in combination) in all individuals, correlation was only observed in those who were aspirin insensitive after ingestion of the combination. CONCLUSIONS: Co-administration of aspirin and fish oil may reduce platelet aggregation more than aspirin alone in adults with diabetes mellitus.

A case-control study of paternal occupational exposures and the risk of childhood sporadic bilateral retinoblastoma.

BACKGROUND: The risk factors for sporadic (ie, non-familial) retinoblastoma remain largely unknown. OBJECTIVES: We examined the relationship between paternal occupational exposures from jobs held 10 years and 1 year prior to conception and the risk of sporadic bilateral retinoblastoma in children. METHODS: Paternal occupational data were obtained for 198 incident cases diagnosed with sporadic bilateral retinoblastoma from January 1998 to May 2006 and 245 referral-based controls from the case child's relatives and friends who were matched to 135 of the cases on birth year. Industrial hygienists independently assigned exposure scores for nine agents. Adjusted ORs and 95% CIs were computed using logistic regression models, using the full sample of cases and controls as well as subset of cases with matched controls only. RESULTS: There was some indication of an elevated risk associated with paternal pesticide exposure in the 10 years prior to conception (OR=1.64; 95% CI 1.08 to 2.50) as well as in the year before conception (OR=2.12; 95% CI 1.25 to 3.61). However, results for pesticide exposure were inconsistent and varied by analysis approach. An increased risk was also observed for non-welding metal exposure during the 10 years prior to conception in the full (OR=1.35; 95% CI 0.86 to 2.12) and matched (OR=1.40; 95% CI 0.82 to 2.37) samples, but not in the year before conception. Exposure-response trends were observed for pesticides and non-welding metal exposures. CONCLUSIONS: Our findings suggest a potential role of paternal occupational exposures to non-welding metals and perhaps pesticides in the aetiology of childhood retinoblastoma.

Potential reliability and validity of a modified version of the Unified Parkinson's Disease Rating Scale that could be administered remotely.

BACKGROUND: By permitting remote assessments of patients and research participants, telemedicine has the potential to reshape clinical care and clinical trials for Parkinson disease. While the majority of the motor Unified Parkinson's Disease Rating Scale (UPDRS) items can be conducted visually, rigidity and retropulsion pull testing require hands-on assessment by the rater and are less feasible to perform remotely in patients' homes. METHODS: In a secondary data analysis of the Comparison of the Agonist pramipexole vs. Levodopa on Motor complications in Parkinson's Disease (CALM-PD) study, a randomized clinical trial, we assessed the cross-sectional (baseline and 2 years) and longitudinal (change from baseline to 2 years) reliability of a modified motor UPDRS (removing rigidity and retropulsion items) compared to the standard motor UPDRS (all items) using intraclass correlation coefficients (ICC), stratified by treatment group. Internal consistency of the modified UPDRS (mUPDRS) was measured using Cronbach's alpha, and concurrent validity was assessed using Pearson's correlation coefficient (r) between the standard motor UPDRS and mUPDRS. RESULTS: The mUPDRS versus standard motor UPDRS is cross-sectionally (ICC ≥ 0.92) and longitudinally (ICC ≥ 0.92) reliable for both treatment groups. High internal consistencies were also observed (α ≥ 0.96). The mUPDRS had high concurrent validity with the standard UPDRS at both time points and longitudinally (r ≥ 0.93, p < 0.0001). CONCLUSIONS: A modified version of the motor UPDRS without rigidity and retropulsion pull testing is reliable and valid and may lay the foundation for its use in remote assessments of patients and research participants.

Nosocomial infections in a pediatric residential care facility.

BACKGROUND: Nosocomial infections have rarely been characterized in pediatric residential care facilities. The purpose of this study is to assess the frequency of and risk factors for infectious diseases in pediatric residential care facilities over a 1-year period and to contrast them with other pediatric extended care facilities. METHODS: A retrospective chart review was performed at a pediatric residential care facility dedicated exclusively to children with severe physical and mental disabilities. Incidence rates of infection were collected on a census of 109 residents from January 1 through December 31, 2009. Infectious diseases were classified using ICD-9-CM codes. PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched to identify similar studies. RESULTS: In 2009, the overall incidence rate of infection was 6.21 per 1,000 resident-days of care, with the most frequent being streptococcal or staphylococcal skin infections (1.11 per 1,000 resident-days) and the least frequent being conjunctivitis (0.16 per 1,000 resident-days). Extensive literature reviews yielded 2 published studies that evaluated infections in pediatric extended care facilities; these studies exhibited distinct prevalences of infectious diseases when compared with the current study. CONCLUSION: Studies examining nosocomial infections should not consider pediatric extended care facilities as 1 single entity given the heterogeneity among these facilities.

Incubation of nicotine seeking is associated with enhanced protein kinase A-regulated signaling of dopamine- and cAMP-regulated phosphoprotein of 32 kDa in the insular cortex.

A recent clinical study demonstrated that damage to the insular cortex can disrupt tobacco addiction. The neurobiological mechanisms for this effect are not yet understood. In this study we used an animal model of nicotine addiction to examine the possibility that changes in insular cortex levels of dopamine (DA)- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a phosphoprotein enriched in DA neurons containing DA D1 receptors, may be associated with changes in vulnerability to nicotine addiction. Once rats acquired self-administration, they were given unlimited access to nicotine (0.01 mg/kg/infusion) for 23 h/day for a total of 10 days. Each infusion was paired with a visual cue (stimulus light) and auditory cue (sound of pump). Nicotine seeking, as assessed under a cue-induced reinstatement paradigm, and markers of DARPP-32 signaling, as assessed using western blot analysis, were examined in separate groups of rats at two different abstinent intervals: 1 and 7 days. Consistent with findings with other drugs of abuse, rats in the 7-day abstinence group took longer to extinguish and responded at higher levels during reinstatement testing as compared with rats in the 1-day reinstatement group. Relative to saline controls, rats in the 7-day but not the 1-day abstinence group had higher levels of DARPP-32 phosphorylated at the protein kinase A site in the insular cortex. These results demonstrate incubation of drug seeking following extended access to nicotine self-administration and suggest that enhanced protein kinase A signaling in the insular cortex via phosphorylation of DARPP-32 at Thr34 is associated with this effect.