N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice.

RATIONALE: N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans. OBJECTIVES: The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice. METHODS: N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured 18-24 h after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.)-precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm. RESULTS: Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine was found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice. CONCLUSIONS: These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence.

Effects of the beta-lactam antibiotic ceftriaxone on nicotine withdrawal and nicotine-induced reinstatement of preference in mice.

RATIONALE: Several studies suggest that repeated nicotine administration causes alterations in glutaminergic transmission that may play an important role in developing and maintaining nicotine addiction. Chronic nicotine administration in rats decreases the expression of the glutamate transporter-1 (GLT-1) and cysteine-glutamate exchanger (system xC-) in the nucleus accumbens. We hypothesized that ceftriaxone, a GLT-1 and system xC- activator, would decrease murine behavioral aspects of nicotine dependence. OBJECTIVE: This study aimed to investigate the effect of repeated ceftriaxone administration on the behavioral effects of nicotine using mouse models of conditioned reward and withdrawal. METHOD: Using male ICR mice, the ability of repeated ceftriaxone injections to modulate the development and reinstatement of a nicotine-conditioned place preference (CPP) was evaluated. Additionally, nicotine withdrawal-associated signs were assessed. These included both physical (somatic signs and hyperalgesia) and affective (anxiety-related behaviors) withdrawal signs in mice. Finally, the effects of ceftriaxone on nicotine-induced antinociception and hypothermia after acute nicotine injection were measured. RESULT: Ceftriaxone had no effect on the development of nicotine preference but significantly attenuated nicotine-induced reinstatement of CPP. Furthermore, ceftriaxone reversed all nicotine withdrawal signs measured in mice. CONCLUSION: Altogether, these findings show that a ß-lactam antibiotic reduces nicotine withdrawal and nicotine-seeking behavior. Our results suggest that the documented efficacy of ceftriaxone against cocaine and morphine dependence-related behaviors effects extends to nicotine.

NAC-1 is a brain POZ/BTB protein that can prevent cocaine-induced sensitization in the rat.

Levels of the mRNA NAC-1 are increased in the rat forebrain weeks after cocaine exposure. This long-term neuroadaptation occurs during the expression of behavioral sensitization, a model of psychostimulant-induced paranoia. NAC-1, the protein encoded by this cocaine-regulated mRNA, contains a Pox virus and zinc finger/bric-a-brac tramtrack broad complex (POZ/BTB) motif, which mediates interactions among several transcriptional regulators. The present studies demonstrate that NAC-1 acts as a transcription factor. NAC-1 was localized to the nucleus of neurons in the brain. Transfection of NAC-1 in cell culture repressed transcription of a reporter gene. NAC-1 was also able to affect the actions of other POZ/BTB proteins in mammalian two-hybrid studies; these interactions required the presence of the POZ/BTB domain. However, NAC-1 appears to be a unique POZ/BTB transcriptional regulator because it does not contain any zinc finger regions found in these other DNA-binding proteins. Adenoviral-mediated overexpression of NAC-1 protein in the rat nucleus accumbens prevented the development but not the expression of behavioral sensitization produced by repeated administration of cocaine. Thus, NAC-1 may modify the long-term behaviors of psychostimulant abuse by regulating gene transcription in the mammalian brain.

Optimization of coherent lidar performance with graded-reflectance transmitter resonator optics in the low equivalent Fresnel number regime.

Using a diffractive eigenmode treatment to model the laser output we show that graded-reflectance resonator optics offer significant efficiency benefits over conventional hard-edge coupled unstable resonators in the context of coherent detection lidar applications. Extending previous research pertinent to the high equivalent Fresnel number regime, we have modeled the optimum performance of a notional super-Gaussian coupled cavity as a function of the key resonator parameters in the low equivalent Fresnel number (<3) regime. The findings from this study are applicable to the design of coherent lidar transmitters operated within this regime.

Frequency shifts in injection-seeded optical parametric oscillators with phase mismatch.

We have observed a frequency shift in the output signal pulses relative to the seed frequency in an injection-seeded, singly resonant, critically phase-matched, pulsed optical parametric oscillator in which phase mismatchwas intentionally introduced. The observed shifts can be large compared with the linewidth of the signal pulse, are approximately linear in phase mismatch, and increase with increasing pump fluence. We observe frequencyshifts of as much as +/-400 MHz for our 532-nm-pumped, potassium titanyl phosphate ring optical parametric oscillator. For zero phase mismatch, we observe nearly transform-limited linewidths of less than 130 MHz. Wecompare the experimental data to a simple analytic model that overestimates the shifts because it ignores pumpdepletion. We also compare our measurements with a numerical model that calculates the two-dimensional, transient electric fields and the resultant spectral distributions while explicitly including walk-off, diffraction, and pump depletion. We find good agreement between the experimental data and the results of this model.

Highly efficient 60-W TEM(00) cw diode-end-pumped Nd:YAG laser.

We have demonstrated a diode-end-pumped Nd:YAG laser that produces an output power of 60 W in a near-diffraction-limited beam (i.e., M(2) < 1.3). In multimode operation, the laser produces an output power of 92 W. The optical-to-optical efficiency (i.e., the ratio of laser power to diode power) is 26% for TEM(00) operation and 44% for multimode operation.

Eigenmodes of misaligned unstable optical resonators with circular mirrors.

It is shown numerically that the diffractive transverse (Fox-Li) eigenmodes supported by an unstable cavity with tilted end mirrors can be computed by expanding these modes in terms of the fully aligned (aberration-free) eigenmodes of the same cavity. Circular mirror resonators are considered in which the aligned cavity eigenmodes can be decomposed into different azimuthal components. The biorthogonality property of the aligned cavity eigenmodes is used to obtain the coefficients in the modal expansion of the misaligned modes. Results are given for two different resonators: a conventional hard-edge unstable cavity with a small tilt of the output coupler and one that uses a graded reflectivity output mirror with a small tilt of the primary mirror. It is shown that the series expansion of the misaligned modes in terms of the aligned modes converges, and the converged eigenvalues are virtually identical to those computed by using the Prony method. Symmetry considerations and other new insights into the effects of a mirror tilt on the modes of a resonator are also discussed.

Numerical solution of the exact cavity equations of motion for an unstable optical resonator.

We solve numerically, we believe for the first time, the exact cavity equations of motion for a realistic unstable resonator with a simple gain saturation model. The cavity equations of motion, first formulated by Siegman ["Exact Cavity Equations for Lasers with Large Output Coupling," Appl. Phys. Lett. 36, 412-414 (1980)], and which we term the dynamic coupled modes (DCM) method of solution, solve for the full 3-D time dependent electric field inside the optical cavity by expanding the field in terms of the actual diffractive transverse eigenmodes of the bare (gain free) cavity with time varying coefficients. The spatially varying gain serves to couple the bare cavity transverse modes and to scatter power from mode to mode. We show that the DCM method numerically converges with respect to the number of eigenmodes in the basis set. The intracavity intensity in the numerical example shown reaches a steady state, and this steady state distribution is compared with that computed from the traditional Fox and Li approach using a fast Fourier transform propagation algorithm. The output wavefronts from both methods are quite similar, and the computed output powers agree to within 10%. The usefulness and advantages of using this method for predicting the output of a laser, especially pulsed lasers used for coherent detection, are discussed.