Effects of RU 486 and tamoxifen on cocaine-induced behavioral and endocrinologic activations in male and female Fischer rats.

Evidence suggests that sex differences in response to cocaine administration may be regulated by activation of progesterone and estrogen receptors. To test this hypothesis, rats were pretreated with either RU 486 (progesterone antagonist; 0, 3, or 25 mg/kg), tamoxifen (estrogen antagonist; 0, 1, or 3 mg/kg), or vehicle followed by saline or cocaine administration (15 mg/kg). Although RU 486 did not affect cocaine-induced locomotor activity in female rats, it dose-dependently decreased such activity in males (3 mg/kg significantly attenuated locomotor responses in cocaine-treated rats as compared with vehicle treatment or 25 mg/kg of RU 486). RU 486 also affected baseline serum levels of corticosterone. Males treated with 3 mg/kg of RU 486 plus cocaine had higher progesterone and corticosterone serum levels than vehicle-treated groups. In females, both doses (3 and 25 mg/kg) of RU 486 significantly attenuated corticosterone serum levels compared with vehicle treatment. For both sexes overall, tamoxifen neither significantly influenced cocaine-induced ambulatory and rearing responses nor altered cocaine-induced progesterone and corticosterone serum levels. Taken together, our results suggest that progesterone receptors have a sexually dimorphic role in cocaine-induced effects, but estrogen receptors have only a limited role. Moreover, both receptor antagonists modulate neurochemical responses differentially.

Cocaine-induced sex differences in D1 receptor activation and binding levels after acute cocaine administration.

Although it is established that female rats have a more robust behavioral response to acute cocaine administration than male rats, the neurobiological mechanisms underlying these differences remain unclear. The purpose of the present study was to determine whether dopamine (DA) receptor activation influences sex differences in cocaine-induced behaviors. A second study was performed to determine sex differences in D1/D2 receptor levels prior to and post-cocaine administration. Male and female Fischer rats were pre-treated with the D1 antagonist SCH-23390 (0.05, 0.1, and 0.25 mg/kg, i.p.), the D2 antagonist eticlopride (0.03, 0.1 mg/kg, i.p.), or vehicle (saline) 15 min before acute cocaine (20 mg/kg, i.p.) or saline administration. Cocaine-induced ambulatory and rearing activity was greater in female than male rats. Pre-treatment with SCH-23390 affected cocaine-induced ambulatory, rearing, and stereotypic activity in a sex-dependent manner; cocaine-induced ambulatory and stereotypic behavior in female rats was reduced by the lowest dose of SCH-23390. Eticlopride did not alter behavioral responses to cocaine in male or female rats. These results suggest that in both male and female rats, activation of the D1, but not the D2, receptor modulates cocaine's motor effects. There were no sex differences in baseline levels of D1, D2, and DA transporter binding in the caudate putamen (CPu) and the nucleus accumbens (NAc). Cocaine administration reduced D1 binding levels in the CPu only in male rats. Our findings suggest that the regulation of striatal D1 binding levels after acute cocaine administration is a sexually dimorphic process. We also hypothesize that the greater sensitivity to D1 receptor blockade in female rats, as compared to male rats, may contribute to their overall increased hyperactivity in response to acute cocaine. Taken together, the D1 receptor may be an important substrate in the regulation of sex differences to cocaine-induced locomotor activity.

Sex differences in behavioral and PKA cascade responses to repeated cocaine administration.

Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point. Our results showed that females exhibited higher cocaine-induced behavioral responses and developed behavioral sensitization and tolerance faster than males. Whereas females developed behavioral sensitization to cocaine after 2 days and tolerance after 14 days, male rats developed sensitization after 5 days. In addition, cocaine induced a sexual dimorphic pattern in the progression of neuronal adaptations on the PKA cascade signaling in region (NAc vs. CPu) and time (days of cocaine administration)-dependent manners. In general, more PKA signaling cascade changes were found in the NAc of males on day 5 and in the CPu of females with repeated cocaine injection. In addition, in females, behavioral activities positively correlated with FosB levels in the NAc and CPu and negatively correlated with Cdk5 and p35 in the CPu, while no correlation was observed in males. Our studies suggest that repeated cocaine administration induced different patterns of behavioral and molecular responses in the PKA cascade in male and female rats.

Welding and ischemic heart disease.

Metal welding and cutting are associated with inhalation of gases and respirable particles. The purpose of this study was to compare the mortality of male welders with that of all gainfully employed men in Sweden regarding ischemic heart disease (IHD). Male welders and gas cutters were identified in the Swedish National Censuses of 1970 and 1990. Two cohorts were established and followed until the end of 1995. The IHD mortality among the welders was compared with that of all gainfully employed men. An increased mortality due to IHD was observed among welders identified in the 1990 Census, SMR = 1.35, 95% confidence limits 1.1-1.6. The observed increased mortality due to IHD was unlikely to be explained by different smoking habits. A general hypothesis linking inhalation of particles to the occurrence of IHD via an inflammatory process is discussed.

Ischemic heart disease in female cleaners.

Review of the literature regarding ischemic heart disease (IHD) among female cleaners in Medline and NIOSHTIC for 1990-2001 yielded one specifically relevant study, three surveys of several occupations, and one case-referent study. All showed minor increases of standardized mortality ratios or relative risks regarding diseases of the circulatory system, IHD, or myocardial infarction among female cleaners. Many determinants might explain the female cleaners' increased risk for IHD, e.g., imbalances regarding job strain and effort-reward, anxiety and depression, periodontal disease, smoking habits and air pollutants. These factors need further exploration.

Ischemic heart disease mortality among miners and other potentially silica-exposed workers.

BACKGROUND: Some previous studies have observed an increased mortality regarding ischemic heart disease (IHD) among miners and industrial sand workers. The purpose was to study the occurrence of IHD mortality among silica-exposed workers. METHODS: Male miners, well borers, dressing plant workers, and other mine and stone workers were identified in the Swedish National Census of 1970. The total cohort (n = 11,896) was followed from 1970 until December 31, 1995 and linked to the Cause of Death Register. The referent group comprised all gainfully employed men identified in the same census. The Standardized Mortality Ratio was calculated as the ratio between observed and expected numbers of deaths. RESULT: An increased risk due to IHD mortality was observed among miners, well borers, dressing plant workers, and other mine and stone workers. CONCLUSION: These results indicate a possible relation between silica-dust exposure and IHD. The increased risk of IHD mortality is unlikely explained by smoking habits. Shift work might explain some of the increased risk. A low-grade inflammation in the lungs as a result of dust exposure is discussed as a possible cause. However, the key message is that better dose estimates and better confounding control is needed to study the possible relation between silica-dust exposure and IHD.