Nicotine is more addictive, not more cognitively therapeutic in a neurodevelopmental model of schizophrenia produced by neonatal ventral hippocampal lesions

• Published in: Addiction biology Vol. 19; no. 6; pp. 1020 - 1031
• Main Authors: Berg, Sarah A., Sentir, Alena M., Cooley, Benjamin S., Engleman, Eric A., Chambers, R. Andrew
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2014; John Wiley & Sons, Inc; BlackWell Publishing Ltd
• Subjects: Addiction; Addictions; Analysis of Variance; Animals; Animals, Newborn; Conditioning, Operant - drug effects; Diagnosis, Dual (Psychiatry); Disease Models, Animal; Drug-Seeking Behavior - drug effects; dual diagnosis; hippocampus; Hippocampus - pathology; Illnesses; Male; Maze Learning; Memory Disorders - chemically induced; Memory, Short-Term - drug effects; Mental disorders; Nicotine; Nicotine - pharmacology; nicotine dependence; Nicotinic Agonists - pharmacology; Preclinical Studies; Rats, Sprague-Dawley; Reinforcement Schedule; Rodents; schizophrenia; Schizophrenic Psychology; Self Administration; Tobacco Use Disorder - pathology; nicotine dependence; dual diagnosis; schizophrenia; Addiction; hippocampus; self-administration
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12082

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. Nicotine dependence, the leading cause of death in the U.S., has traditionally been explained in schizophrenia patients as “self‐medication”. However, a well‐validated neurodevelopmental schizophrenia model, produced by neonatal ventral hippocampal lesions (NVHL), suggests that schizophrenia neurobiologically imposes extreme vulnerability to nicotine addiction, even while nicotine does not specifically “medicate” NVHL cognitive symptoms. NVHL rats with or without adolescent nicotine history (NIC/ SAL) show greater acquisition of iv nicotine self‐administration ((a) active vs (b) inactive lever responding) compared to controls (SHAMS).