Toward early estimation and treatment of addiction vulnerability: radial arm maze and N-acetyl cysteine before cocaine sensitization or nicotine self-administration in neonatal ventral hippocampal lesion rats.

Kalyan N Rao,Alena M Sentir,Eric A Engleman,R Andrew Chambers,Leslie A Hulvershorn,Richard L Bell,Alan Breier

doi:10.1007/s00213-016-4421-8

Abstract

RationalPrefrontal cortical (PFC)–hippocampal–striatal circuits, interconnected via glutamatergic signaling, are dysfunctional in mental illnesses that involve addiction vulnerability.ObjectivesIn healthy and neurodevelopmentally altered rats, we examined how Radial Arm Maze (RAM) performance estimates addiction vulnerability, and how starting a glutamatergic modulating agent, N-acetyl cysteine (NAC) in adolescence alters adult mental illness and/or addiction phenotypes.MethodsRats with neonatal ventral hippocampal lesions (NVHL) vs. SHAM-operated controls were randomized to NAC vs. saline in adolescence followed by cognitive testing (RAM) in early adulthood and then cocaine behavioral sensitization (experiment 1; n = 80) or nicotine self-administration (experiment 2; n = 12).ResultsIn experiment 1, NVHL rats showed over-consumption of food (Froot-Loops (FL)) baiting the RAM with poor working memory (low-arm entries to repeat (ETR)), producing an elevated FL to ETR ratio (“FLETR”; p < 0.001). FLETR was the best linear estimator (compared to FL or ETR) of magnitude of long-term cocaine sensitization (R 2 = 0.14, p < 0.001). NAC treatment did not alter FL, ETR, FLETR, or cocaine sensitization. In experiment 2, FLETR also significantly and uniquely correlated with subsequent drug seeking during nicotine-induced reinstatement after extinction of nicotine self-administration (R 2 = 0.47, p < 0.01). NAC did not alter RAM performance, but significantly reversed NVHL-induced increases in nicotine seeking during extinction and reinstatement.ConclusionsThese findings demonstrate the utility of animal models of mental illness with addiction vulnerability for developing novel diagnostic measures of PFC–hippocampal–striatal circuit dysfunction that may reflect addiction risk. Such tests may direct pharmacological treatments prior to adulthood and addictive drug exposure, to prevent or treat adult addictions.

Highlights

Substance use disorders are concentrated in mentally ill people (Regier et al 1990) producing greater psychiatric and medical morbidity, risk of incarceration, homelessness, and early death (Drake et al 2001; Owen et al 1996)
Psychopharmacology (2016) 233:3933–3945 versed neonatal ventral hippocampal lesion (NVHL)-induced increases in nicotine seeking during extinction and reinstatement. These findings demonstrate the utility of animal models of mental illness with addiction vulnerability for developing novel diagnostic measures of prefrontal cortex (PFC)–hippocampal– striatal circuit dysfunction that may reflect addiction risk
We examined radial arm maze (RAM) measures of PFC–hippocampaldependent cognition (Floresco et al 1997), and the effects of N-acetyl cysteine (NAC), a glutamate-modulating agent (Baker et al 2002) on addiction-related behaviors in neonatal ventral hippocampal lesion (NVHL) rats

Summary

Introduction

Substance use disorders are concentrated in mentally ill people (Regier et al 1990) producing greater psychiatric and medical morbidity, risk of incarceration, homelessness, and early death (Drake et al 2001; Owen et al 1996). Dysfunction of cortical–striatal circuits that utilize glutamate may underpin mental illness (Adler et al 1999; Goff and Coyle 2001; Jentsch and Roth 1999), addiction (Kalivas 2009; Rao et al 2015), and their linkage (Chambers et al 2001, 2007) In testing this theory, we examined radial arm maze (RAM) measures of PFC–hippocampaldependent cognition (Floresco et al 1997), and the effects of N-acetyl cysteine (NAC), a glutamate-modulating agent (Baker et al 2002) on addiction-related behaviors in neonatal ventral hippocampal lesion (NVHL) rats

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