Michael L. Adams

Nitric oxide control of steroidogenesis: Endocrine effects of NG-nitro-L-arginine and comparisons to alcohol

Recent studies suggest that nitric oxide (NO) may regulate hormone biosynthesis and secretion. This was tested by treating male rats with NG-nitro-L-arginine methyl ester (NAME), a NO synthase inhibitor, and measuring serum and testicular interstitial fluid testosterone and serum corticosterone, luteinizing hormone (LH), and prolactin (PRL). The effect of NG-nitro-L-arginine (NA), a less-soluble form of the same NO synthase inhibitor, on the reproductive suppressant actions of alcohol was also examined. NAME increased testosterone and corticosterone secretion dose-dependently without affecting LH and PRL secretion. The alcohol-induced suppression of testosterone or LH secretion was not altered by treatment with NA. Although effects of NAME and NA on other systems may be involved, these results indicate that testicular and adrenal steroidogenesis are negatively regulated by endogenous NO and that NO does not regulate LH and PRL secretion or inhibit the testicular steroidogenic pathway in the same way as alcohol.

Inhibition of the morphine withdrawal syndrome by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester

The hypothesis that an arginine-nitric oxide (NO) synthase-NO system mediates the morphine abstinence syndrome was tested in adult male rats implanted subcutaneously for 3 days with one morphine (75 mg) pellet followed by naloxone-precipitated withdrawal (0.5 mg/kg). Injection with a NO synthase inhibitor, NG-nitro-L-arginine methyl ester (NAME, 100 mg/kg subcutaneous), shortly before naloxone-induced withdrawal significantly inhibited abstinence signs by 25-80%. Continuous infusion of NAME via subcutaneous osmotic pumps during the development of morphine physical dependence and during naloxone-precipitated withdrawal also inhibited morphine abstinence signs. In addition, treatment with isosorbide dinitrate, a NO donor, induced a quasi morphine-abstinence syndrome (QMAS) that was significantly suppressed by implantation of a morphine pellet 3 days before isosorbide dinitrate treatment. These results indicate that NO mediates part of the expression of the morphine abstinence syndrome.

Alcohol Intoxication and Withdrawal: The Role of Nitric Oxide

Nitric oxide is an important messenger in the central nervous system and several types of evidence suggest that it mediates various alcohol effects. Treatment with a nitric oxide synthase inhibitor enhances the acute central depressant or anesthetic effect of alcohol and decreases some stimulatory effects of alcohol withdrawal after chronic alcohol treatment. Conversely, treatment with a nitric oxide donor inhibits the anesthetic effect of alcohol, blocks the effect of the nitric oxide synthase inhibitor on alcohol anesthesia, and enhances the severity of some alcohol withdrawal signs. These results indicate that changes in nitric oxide synthesis mediate some aspects of alcohol intoxication and withdrawal and that nitric oxide systems represent an important therapeutic target for the development of agents to treat alcoholism and alcohol intoxication.

Nitric oxide mediates mecamylamine- and naloxone-precipitated nicotine withdrawal

A nitric oxide synthase inhibitor blocked nicotine abstinence signs and increased weight loss in male, nicotine-dependent rats during withdrawal precipitated by the nicotinic receptor antagonist mecamylamine or the opioid receptor antagonist naloxone. These results indicate that nitric oxide systems mediate important aspects of the expression of nicotine physical dependence and suggest the potential use of nitric oxide synthase inhibitors as aids in tobacco smoking cessation.

Acute alcohol exposure markedly influences male fertility and fetal outcome in the male rat

Although it is recognized that drugs ingested by pregnant females produce marked cognitive and physiological deficits in their offspring, the possibility that paternal exposure to drugs prior to mating may have adverse effects on fertility and fetal outcome has not received much attention. The purpose of the present studies was to examine whether a single, acute exposure to alcohol influences the subsequent ability of adult male rats to mate and produce healthy and viable litters. Our results showed that a relatively large dose of alcohol 24 hours prior to breeding had little effect on the mating behavior of male rats, but there were markedly fewer pregnancies in females mated with alcohol-exposed male rats than in controls. Of equal importance, we found that, even when conception occurred and live births were produced, there were striking differences in fetal outcome. Alcohol-treated males sired many fewer pups than control males and there was a markedly enhanced mortality rate in their offspring. Collectively, these data suggest that acute paternal alcohol administration 24 hours prior to breeding does not affect mating behavior, but results in a greatly diminished fertility rate and fewer and less viable offspring. These studies suggest that paternal alcohol use may be as important as maternal alcohol abuse as a negative variable in pregnancy and fetal outcome.

Acute paternal alcohol exposure impairs fertility and fetal outcome.

An acute injection of an intoxicating dose of alcohol to male rats 24 hours prior to breeding with drug-naive females produced no discernible effect on copulatory activity, as reflected in vaginal plugs, but resulted in markedly (> 50%) reduced pregnancy rates. Fetal outcome was also markedly affected in offspring sired by alcohol-treated males: litter sizes were appreciably smaller (30%) and fetal mortality was more than 2 times higher than in controls. These results suggest that paternal alcohol use, like maternal alcohol abuse, may adversely affect fertility and fetal outcome.

The ontogeny of immunoreactive β-endorphin and β-lipotropin in the rat ovary

Abstract We have investigated the ontogeny of, and the effect of hypophysectomy on, immunoreactive β-endorphin in rat ovaries. Total levels rose with ovarian weight from nondetectable levels at 5 days of age to approximately 0.15 pmol/ovary at 80 days; thereafter, the levels remained constant through 201 days of age. Hypophysectomy decreased both ovarian weight and the total content of immunoreactive β-endorphin, but the concentration per weight was not significantly altered. Most of the immunoreactive β-endorphin before puberty chromatographed like authentic β-endorphin, but after puberty most chromatographed like β-lipotropin. Hypophysectomy did not alter this chromatographic pattern.