Habituation (Neuropsychology)

In this thesis I studied propensity for behavioral sensitization to nicotine in
the LRHR phenotype and associated plasticity in the hippocampal mossy fiber
morphology. I also investigated therapeutic effects of bupropion and a
cannabinoid receptor antagonist on behavioral and morphological indices in
adolescence and adulthood. Male rats were classified into high responders (HR)
and low responders (LR) based on their locomotor response to a novel
environment. LRHR animals underwent behavioral sensitization to nicotine and
after one week of abstinence were challenged with a low dose of nicotine. HRs
expressed behavioral sensitization to nicotine and showed an increase in
hippocampal mossy fiber terminal field size. AM251 administration during
abstinence reversed behavioral sensitization in HRs and bupropion only
attenuated the locomotor response to na"ive nicotine exposure. Therapeutic
agents had differential effects on mossy fiber morphology dependent on
phenotype and age.

A rat model of novelty-seeking phenotype predicts vulnerability to nicotine relapse where locomotor reactivity to novelty is used to rank high (HR) versus low (LR) responders. This dissertation examines the neuropeptidergic and 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 phenotype. Data show the long-lasting nature of behavioral sensitization to nicotine and abstinence-related social anxiety-like behavior in nicotine pre-trained HRs compared to saline pre-trained controls. Moreover, this behavior is accompanied by an imbalance between the brain antistress/antianxiety, i.e., neuropeptide Y (NPY), and stress, i.e., corticotrophin releasing factor (CRF) systems in the amygdala. Moreover, a deficit in NPY signaling marked with decreased NPY and increased NPY Y2 receptor (Y2R) mRNA levels is observed in the hip pocampus, along with mossy fiber reorganization in nicotine pre-trained HRs. Furthermore, a Y2R antagonist administered 1 wk of abstinence reverses these behavioral, molecular and morphological effects in nicotine-exposed HRs. Additionally, the role of amygdalar synaptic plasticity in longlasting social withdrawal is also investigated by assessing brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in HRs following a behaviorally-sensitizing nicotine regimen. A persistent increase in BDNF and spinophilin mRNA levels in the basolateral amygdala (BLA) is observed in nicotine pre-trained HRs even across a long (3-wk) abstinence spanning into young adulthood. This strongly suggests BDNFmediated long-lasting neuroplasticity within the BLA that may regulate abstinence-related negative affect in HRs.