Kappa opioid receptors mediate yohimbine-induced increases in impulsivity in the 5-choice serial reaction time task.

Dynorphin (DYN), and its receptor, the kappa opioid receptor (KOR) are involved in drug seeking and relapse but the mechanisms are poorly understood. One hypothesis is that DYN/KOR activation promotes drug seeking through increased impulsivity, because many stimuli that induce DYN release increase impulsivity. Here, we systematically compare the effects of drugs that activate DYN/KOR on performance on the 5-choice serial reaction time task (5-CSRTT), a test of sustained attention and impulsivity. In Experiment 1, we determined the effects of U50,488 (0, 2.5, 5 mg/kg), yohimbine (0, 1.25, 2.5 mg/kg), and nicotine (0, 0.15, 0.3 mg/kg) on 5-CSRTT performance. In Experiment 2, we determined the effects of alcohol (0, 0.5, 1.0, 1.5 g/kg) on 5-CSRTT performance before and after voluntary, intermittent alcohol exposure. In Experiment 3, we determined the potential role of KOR in the pro-impulsive effects of yohimbine (1.25 mg/kg) and nicotine (0.3 mg/kg) by the prior administration of the KOR antagonist nor-BNI (10 mg/kg). Premature responding, the primary measure of impulsivity, was reduced by U50,488 and alcohol, but these drugs had a general suppressive effect. Yohimbine and nicotine increased premature responding. Yohimbine-, but not nicotine-induced increases in premature responding were blocked by nor-BNI, suggesting that impulsivity induced by yohimbine is KOR dependent. This may suggests a potential role for KOR-mediated increases in impulsivity in yohimbine-induced reinstatement.

Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats.

RATIONALE AND OBJECTIVES: Alpha-1 adrenoceptor antagonists, such as prazosin, show promise in treating alcoholism. In rats, prazosin reduces alcohol self-administration and relapse induced by footshock stress and the alpha-2 antagonist yohimbine, but the processes involved in these effects of prazosin are not known. Here, we present studies on the central mechanisms underlying the effects of prazosin on yohimbine-induced reinstatement of alcohol seeking. METHODS: In experiment 1, we trained rats to self-administer alcohol (12 % w/v, 1 h/day), extinguished their responding, and tested the effects of prazosin, administered ICV (2 and 6 nmol) or systemically (1 mg/kg) on yohimbine (1.25 mg/kg)-induced reinstatement. In experiment 2, we determined potential central sites of action by analyzing effects of prazosin (1 mg/kg) on yohimbine (1.25 mg/kg)-induced Fos expression. In experiment 3, we determined the effects of doxazosin (1.25, 2.5, and 5 mg/kg), an alpha-1 antagonist with a longer half-life on yohimbine-induced reinstatement. RESULTS: Yohimbine-induced reinstatement of alcohol seeking was reduced significantly by ICV and systemic prazosin (50 and 69 % decreases, respectively). Systemic prazosin reduced yohimbine-induced Fos expression in the prefrontal cortex, accumbens shell, ventral bed nucleus of the stria terminalis, and basolateral amygdala (46-67 % decreases). Doxazosin reduced yohimbine-induced reinstatement of alcohol seeking (78 % decrease). CONCLUSIONS: Prazosin acts centrally to reduce yohimbine-induced alcohol seeking. The Fos mapping study suggests candidate sites where it may act. Doxazosin is also effective in reducing yohimbine-induced reinstatement. These data provide information on the mechanisms of alpha-1 antagonists on yohimbine-induced alcohol seeking and indicate their further investigation for the treatment of alcoholism.

Inhibition of alveolar macrophages by pentoxifylline.

BACKGROUND AND METHODS: Pentoxifylline can inhibit blood leukocyte functions in vitro, and some inflammatory processes in the lung in vivo. Therefore, we examined the effects of pentoxifylline on alveolar macrophage functions in vitro. Alveolar macrophages were harvested from normal rat lungs by airway lavage. The dose-response relationship of varying concentrations of pentoxifylline and in vitro cell functions were examined. Macrophage functions studied included adherence to nylon wool, random (unstimulated) and zymosan-activated serum-stimulated migration through 5 microns millipore filters, and superoxide generation induced by zymosan-activated serum as assayed by cytochrome c reduction. RESULTS: Pentoxifylline inhibited superoxide generation and stimulated migration (but not random migration or adherence) in a dose-dependent fashion. Statistically significant inhibition was demonstrated at 0.5 mM and 5.0 mM concentrations of pentoxifylline, respectively, for stimulated migration and superoxide generation. CONCLUSIONS: Pentoxifylline can inhibit some alveolar macrophage functions in vitro. These effects may inhibit some forms of inflammatory lung injury, particularly when iv infusion of high doses of pentoxifylline are utilized. However, potentially adverse effects on inflammatory defense mechanisms must be considered as well.