Hippocampal Y2 receptor-mediated mossy fiber plasticity is implicated in nicotine abstinence-related social anxiety-like behavior in an outbred rat model of the novelty-seeking phenotype

Abstract

Experimentally naïve outbred rats display varying rates of locomotor reactivity in response to the mild stress of a novel environment. Namely, some display high rates (HR) whereas some display low rates (LR) of locomotor reactivity. Previous reports from our laboratory show that HRs, but not LRs, develop locomotor sensitization to a low dose nicotine challenge and exhibit increased social anxiety-like behavior following chronic intermittent nicotine training. Moreover, the hippocampus, specifically hippocampal Y2 receptor (Y2R)-mediated neuropeptide Y signaling is implicated in these nicotine-induced behavioral effects observed in HRs. The present study examines the structural substrates of the expression of locomotor sensitization to a low dose nicotine challenge and associated social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR hippocampi. Our data showed that the expression of locomotor sensitization to the low dose nicotine challenge and the increase in social anxiety-like behavior were accompanied by an increase in mossy fiber terminal field size, as well as an increase in spinophilin mRNA levels in the hippocampus in nicotine pre-trained HRs compared to saline pre-trained controls. Furthermore, a novel, selective Y2R antagonist administered systemically during 1 wk of abstinence reversed the behavioral, molecular and neuromorphological effects observed in nicotine-exposed HRs. These results suggest that nicotine-induced neuroplasticity within the hippocampus may regulate abstinence-related negative affect in HRs, and implicate hippocampal Y2R in vulnerability to the behavioral and neuroplastic effects of nicotine in the novelty-seeking phenotype.

Neuropeptide Y: A stressful review

“…In addition, the brain-penetrant Y2 receptor antagonist JNJ31020028 has also anxiolytic properties. JNJ31020028 reverses the anxiogenic effect of alcohol withdrawal and nicotine-induced social anxiety-like behaviour (62–64). Surprisingly, conventional Y2 receptor knockout has yielded mixed results.…”

Cognitive Dysfunction, Affective States, and Vulnerability to Nicotine Addiction: A Multifactorial Perspective

“…Consistently, other authors showed that rats classified as low responders according to their locomotor response to novelty following an injection of nicotine, showed nicotine-induced CPP after a long- but not short-term conditioning procedure, while rats classified as high responders did not show CPP under any condition ( 212 ). Also, rats selected as high locomotor responders to novelty showed enhanced social anxiety-like behavior during abstinence after repeated nicotine exposure ( 213 – 216 ).…”

Chronic Lorcaserin Treatment Reverses the Nicotine Withdrawal-Induced Disruptions to Behavior and Maturation in Developing Neurons in the Hippocampus of Rats

“…Such an enhanced locomotor response to novelty is useful for studying sensation seeking in humans [ 41 ]. Kahler et al [ 42 ] revealed that increased sensation seeking was a predictor of a reduced smoking cessation rate in humans, while in rats, an increased motor response to novelty contributed to the enhanced social anxiety-like phenotype during nicotine withdrawal [ 43 ]. It can therefore be assumed that the inhibitory effect of subchronic lorcaserin on motility in drug-weaned rats reflected a positive rather than negative (i.e., sedative effect) effect on withdrawal signs in animals.…”