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

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.

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

“…Cocaine self-administration under fixed ratio responding is intact in NVHL rats, yet lesioned rats demonstrate prolonged extinction and exaggerated cue-induced reinstatement of cocaine seeking, suggesting impaired prefrontal control over cueinduced drug-seeking or a general impairment in new actionoutcome learning [73]. Supporting this, working memory deficits in the radial arm maze in adult NVHL rats predict subsequent cocaine behavioural sensitization, suggesting a link between cognition and addiction-relevant behaviours in this model [72]. However, incubation of cocaine craving is not altered in NVHL rats, suggesting specific addiction-relevant behavioural domains are altered following NVHL lesions [73].…”

“…Cocaine-induced locomotor activity during sensitization, as well as locomotion following a cocaine challenge is enhanced in adult NVHL rats compared to sham controls [71,72]. However, when examining gene expression in the caudate-putamen and mPFC using genome-wide microarrays, there is no overlap in the direction of gene expression change induced by NVHL and cocaine sensitization i.e.…”

“…Neonatal ventral hippocampal lesions enhance the rewarding effects of nicotine. Adult NVHL rats demonstrate faster acquisition of nicotine self-administration and higher nicotine intake during self-administration ( [74] but see also [72,75]), modelling the higher levels of smoking observed in schizophrenia patients. Adult NVHL rats are also resistant to reducing nicotine use, exhibiting slower extinction of nicotine seeking and elevated drug-primed reinstatement compared to sham controls [72,74,75].…”

“…NVHL rats exhibit deficits in learning and memory in the radial arm maze [72,74,170]. Unlike some genetic models (e.g.…”

“…In NVHL rats, acute amphetamine-induced locomotion is enhanced compared to sham controls [72,77,85]. The effects of NVHL on amphetamine-induced locomotion may be agedependent, as rats in early adolescence (i.e.…”