Nicotine self‐administration is associated with decreased expression of the glial glutamate transporter (GLT‐1) and the cystine‐glutamate exchange protein xCT within the nucleus accumbens core (NAcore). N‐acetylcysteine (NAC) has been shown to restore these proteins in a rodent model of drug addiction and relapse. However, the specific molecular mechanisms driving its inhibitory effects on cue‐induced nicotine reinstatement are unknown. Here, we confirm that extinction of nicotine‐seeking behavior is associated with impaired NAcore GLT‐1 function and expression and demonstrates that reinstatement of nicotine seeking rapidly enhances membrane fraction GLT‐1 expression. Extinction and cue‐induced reinstatement of nicotine seeking was also associated with increased tumor necrosis factor alpha (TNFα) and decreased glial fibrillary acidic protein (GFAP) expression in the NAcore. NAC treatment (100 mg/kg/day, i.p., for 5 d) inhibited cue‐induced nicotine seeking and suppressed AMPA to NMDA current ratios, suggesting that NAC reduces NAcore postsynaptic excitability. In separate experiments, rats received NAC and an antisense vivo‐morpholino to selectively suppress GLT‐1 expression in the NAcore during extinction and were subsequently tested for cue‐induced reinstatement of nicotine seeking. NAC treatment rescued NAcore GLT‐1 expression and attenuated cue‐induced nicotine seeking, which was blocked by GLT‐1 antisense. NAC also reduced TNFα expression in the NAcore. Viral manipulation of the NF‐κB pathway, which is downstream of TNFα, revealed that cue‐induced nicotine seeking is regulated by NF‐κB pathway signaling in the NAcore independent of GLT‐1 expression. Ultimately, these results are the first to show that immunomodulatory mechanisms may regulate known nicotine‐induced alterations in glutamatergic plasticity that mediate cue‐induced nicotine‐seeking behavior.
N‐acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug‐induced changes in glutamatergic neurophysiology. In rats, nicotine‐seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue‐induced nicotine‐seeking is associated with rapid, transient synaptic plasticity (t‐SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine‐seeking behavior and reverses reinstatement‐associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self‐administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue‐induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine‐seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine‐seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse.
The importance of integrating measures of juvenile corewood mechanical properties, modulus of elasticity in particular, with growth and disease resistance in tree improvement programs has increased. We investigated the utility of in-tree velocity stiffness measurements to estimate the genetic control of corewood stiffness and to select for trees with superior growth and stiffness in a progeny trial of 139 families of slash pine, Pinus elliottii Engelm. grown on six sites. Narrow-sense heritability estimates across all six sites for in-tree acoustic velocity stiffness at 8 years (0.42) were higher than observed for height (0.36) and diameter at breast height (DBH) (0.28) at 5 years. The overall type B genetic correlation across sites for velocity stiffness was 0.68, comparable to those found for DBH and volume growth, indicating that family rankings were moderately repeatable across all sites for these traits. No significant genetic correlations were observed between velocity stiffness, DBH, and volume growth. In contrast, a significant, but small, favorable genetic correlation was found between height and velocity stiffness. Twenty percent of the families had positive breeding values for both velocity stiffness and growth. The low cost, high heritability and nearly independent segregation of the genes involved with in-tree velocity stiffness and growth traits indicate that acoustic methods can be integrated into tree improvement programs to breed for improved corewood stiffness along with growth in slash pine.
Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared to men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, i.p.) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous-cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle-and NAC-treated groups significantly reinstated nicotine seeking behavior compared to extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely-cycling women smokers.
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