Nicotine dependence is the leading cause of death in the United States. However, research on high rates of nicotine use in mental illness has primarily explained this co-morbidity as reflecting nicotine's therapeutic benefits, especially for cognitive symptoms, equating smoking with ‘self-medication’. We used a leading neurodevelopmental model of mental illness in rats to prospectively test the alternative possibility that nicotine dependence pervades mental illness because nicotine is simply more addictive in mentally ill brains that involve developmental hippocampal dysfunction. Neonatal ventral hippocampal lesions (NVHL) have previously been demonstrated to produce post-adolescent-onset, pharmacological, neurobiological and cognitive-deficit features of schizophrenia. Here, we show that NVHLs increase adult nicotine self-administration, potentiating acquisition-intake, total nicotine consumed and drug seeking. Behavioral sensitization to nicotine in adolescence prior to self-administration is not accentuated by NVHLs in contrast to increased nicotine self-administration and behavioral sensitization documented in adult NVHL rats, suggesting periadolescent neurodevelopmental onset of nicotine addiction vulnerability in the NVHL model. Delivering a nicotine regimen approximating the exposure used in the sensitization and self-administration experiments (i.e. as a treatment) to adult rats did not specifically reverse NVHL-induced cortical-hippocampal-dependent cognitive deficits and actually worsened cognitive efficiency after nicotine treatment stopped, generating deficits that resemble those due to NVHLs. These findings represent the first prospective evidence demonstrating a causal link between disease processes in schizophrenia and nicotine addiction. Developmental cortical-temporal limbic dysfunction in mental illness may thus amplify nicotine's reinforcing effects and addiction risk and severity, even while producing cognitive deficits that are not specifically or substantially reversible with nicotine.

Background High rates of substance disorders in schizophrenia and other mental illnesses may reflect biological vulnerabilities to the addiction process. Interactions between addictive drug effects and mental illness involving circuits that generate motivated behavior may underpin this vulnerability. Methods We examined separate and combined effects of neonatal ventral hippocampal lesions (NVHL)—a neurodevelopmental model of schizophrenia (vs. SHAM-operated controls)—and a behaviorally sensitizing cocaine history (15 mg/kg/day × 5 days vs. saline injections), on acute cocaine-induced neural activation signaled by c-Fos expression. Stereological assessment of activation densities spanned 6 ventral to dorsal cortical-striatal compartments. Results Cortically, NVHLs showed hypo-activation and decreased volume of the ventral-medial prefrontal cortex. In contrast, cocaine history was only expressed sub-cortically, and as a hyper-activating effect in the dorsal striatum where significant NVHL-induced hyper-activation also emerged. Across all subjects and brain regions, only dorsal striatal activation was correlated with differences in sensitized locomotion. However, this activation was tightly correlated to a simple multiplicative function of ventral medial prefrontal hypo-activation and cocaine history-related increases striatal activation. Conclusions These findings suggest drug history and developmental temporal limbic abnormalities associated with prefrontal dysfunction produce compounding effects within cortical-striatal circuits as mechanistic basis for dual diagnosis.

Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents However, it remains undetermined whether cotinine can be selfadministered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg/infusion) under fixed-(FR) and progressive-ratio (PR) schedules.Blood nicotine and cotinine levels were determined following the last FR session. Effects of mecamylamine, a non-selective nAChRs antagonist, and varenicline, a partial agonist for α4β2* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to selfadminister cotinine when reinforcement requirement increased. Blood cotinine levels ranged from 77-792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules, and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine, but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine, and exhibited no sex difference. nAChRs appeared to be differentially involved in selfadministration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse.