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

Abstract

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.

Behavioral effects of phencyclidine on nicotine self-administration and reinstatement in the presence or absence of a visual stimulus in rats

“…These results are dissimilar to those found by Berg and colleagues (2013), in which the neonatal ventral hippocampal lesion preclinical model increased nicotine self-administration. The two models each encapsulate unique aspects of certain components of schizophrenia.…”

“…To date, only one study to our knowledge has investigated nicotine use in a preclinical model of specific aspects of schizophrenia (Berg et al 2013), which is surprising given that nicotine is used by patients with schizophrenia more than any other drug of abuse (Dolan et al 2004). Berg and colleagues using the neonatal ventral hippocampal model found increased nicotine self-administration, leading to greater intake of nicotine, and later drug-seeking behaviors (see Discussion).…”

“…The present study will extend Berg’s work in three important ways. First, this study will utilize phencyclidine to model the negative symptoms of schizophrenia, examining the generalizability of findings between this model and the neonatal ventral hippocampal model used by Berg and colleagues (2013). Given the inherent behavioral differences seen between varying animal models of schizophrenia symptoms (see Jones et al 2011 for review), exploring the potential similarities and differences between these two paradigms will inform research on preclinical modeling of aspects of schizophrenia.…”

Psychiatric Disorders as Vulnerability Factors for Nicotine Addiction: What Have We Learned from Animal Models?

“…Indeed, in a subsequent study, it was found that neonatal ventral hippocampus rats took more nicotine infusions and required fewer trials to criterion than did those with sham lesions (Berg et al 2014). …”

Comorbidity Between Psychiatric Diseases and Alcohol Use Disorders: Impact of Adolescent Alcohol Consumption

“…), but in regards to studying comorbid use of substances in mental illness, the neonatal ventral hippocampal lesion (NVHL) model described by Lipska and Weinberger [76] has been the most frequently used. Chambers' group has largely investigated the adult consumption of drugs of abuse such as cocaine [77,78], nicotine [79,80], and also alcohol [81,82] with this model showing increased consumption of the different drugs of abuse at adulthood. However, our group was the first to investigate the impact of adolescent alcohol exposure on subsequent AUDs in adulthood in the NVHL model of schizophrenia [83].…”