Augustus R. Lumia

Olfactory bulbectomy as a model for agitated hyposerotonergic depression.

Ablation of olfactory bulbs in rats reduced male sexual behavior, and altered the distribution of wheel-running activity between the light and dark phases of a 12:12 LD photoperiod. These effects were partially reversed by the tricyclic antidepressant amitriptyline. Olfactory bulbectomy also altered serotonin metabolism (5-HIAA/5-HT ratio) in the frontal cortex, nucleus accumbens, hippocampus and corpus striatum. These observations support the hypothesis that olfactory bulbectomy in rodents serves as a model of agitated hyposerotonergic depression.

Inhibition of male sex behavior by androgen receptor blockade in preoptic area or hypothalamus, but not amygdala or septum

Inhibition of masculine copulatory behavior was previously demonstrated following systemic injections of hydroxyflutamide (OHF). In the present study, we examined the localization of the effects of this androgen receptor blocker by direct intracranial implantation of OHF into the medial preoptic area (MPOA), ventromedial nucleus of hypothalamus (VMN), medial amygdala (AME), and lateral septum (SEPT). Animals were implanted intracranially with crystalline OHF or cholesterol, and at the same time received two 10-mm testosterone-filled Silastic capsules SC. Tests for restoration of copulatory behavior were initiated 3 days later, and conducted twice weekly for 2 weeks. Implants of OHF into the MPOA were effective in preventing restoration of male sexual behavior. However, the most effective site was the VMN. Implants of OHF into the AME were only partially effective in stimulating male sexual behavior, whereas implants into the SEPT had no effect. The OHF was discontinued and 1 week later males were retested for sexual behavior. The majority of these animals ejaculated, indicating, that the effects of OHF are reversible. The result of this study demonstrate that the functional integrity of androgen receptors in some, but not all, androgen-concentrating brain loci is necessary for the expression of the complete pattern of male sexual behavior. These data lend support to the view that androgen receptor populations in specific brain loci differentially express proteins involved in mediating the masculine copulatory response.

Effects of chronically high doses of the anabolic androgenic steroid, testosterone, on intermale aggression and sexual behavior in male rats

To determine if chronic exposure to high doses of anabolic androgenic steroids (AAS) increase aggression and sexual activity in gonadally intact rats, we administered SC injections of testosterone propionate (TP: 1 mg) or propylene glycol (PG: as a vehicle control) three times per week for 10 consecutive weeks. Weekly tests for male copulation were conducted by pairing each male with a sexually receptive female in a glass arena and recording various parameters of copulation. Chronic treatment with TP did not alter any parameter of male copulation including ejaculation and post ejaculatory interval. Sexually experienced males were tested once per week for intermale aggression in a neutral environment. For aggression tests, each experimental animal was placed into an arena with an opponent male for 15 min. The opponent, a gonadally intact male, was used only for the purpose of the aggression test. Frequencies of dominance, submissive, threat, and fight postures, as well as approaches were scored for each animal. TP-treated males did not differ in body weight from PG-treated males, suggesting that the increased aggression was not due to increased body mass. The results of this study show that chronic exposure to the anabolic androgenic steroid, testosterone, potentiates male aggressive response patterns but does not alter male sexual behavior or body weight.

The Effect of Anabolic-Androgenic Steroids on Sexual Behavior and Reproductive Tissues in Male Rats

This study assessed the effects of high doses of anabolic-androgenic steroids (AAS) and their withdrawal on male reproductive behavior and reproductive tissues during development. Prepubertal, peripubertal, and adult male Long Evans rats were divided into 4 groups: 1) Testosterone propionate for 16 weeks (TP), 2) TP for 3 weeks and withdrawn for 13 weeks (TPWL), 3) TP for 16 weeks and withdrawn for 3 weeks (TPWS), 4) propylene glycol (control vehicle) for 16 weeks (PG). As determined by sexual performance and sexual preference tests, administration of high doses of AAS to the peripubertal animals enhanced sexual performance and sexual motivation. There was no significant effect on sexual behavior of the prepubertal animals. High doses of anabolic-androgenic steroids depleted Leydig cell number in the prepubertal and adult rats, but had no effect on the Leydig cell number of the peripubertal animals. After long-term withdrawal from AAS no significant effects on sexual behavior were found. The depletion of Leydig cells that occurred in the prepubertal animals after withdrawal was reversible, while the depletion of the Leydig cells of the adult animals did not return to the control level suggesting a long lasting alteration.

Olfactory bulb control of circadian activity rhythm in mice.

Ablation of mouse olfactory bulbs lengthened the circadian period of wheel-running activity by 43 min and delayed the onset of entrained activity by 108 min. A transient increase in activity during the light phase of the 12:12 h light-dark photoperiod also occurred following surgery. These disruptions suggest that olfactory systems can modulate mammalian circadian rhythms.

Olfactory bulb removal decreases androgen receptor binding in amygdala and hypothalamus and disrupts masculine sexual behavior

In these experiments we examined the relationship between olfactory bulb removal, limbic system androgen receptor binding and male copulatory behavior. Sexually experienced male rats were castrated, and implanted with two 10 mm testosterone-filled silastic capsules. Animals then underwent either bilateral olfactory bulb removal (BOB) or sham surgery (Sham). Beginning 1-2 days postoperatively both BOB and Sham operates were given 4 tests for male copulation on alternate days. Less than 40% of BOB males ejaculated. In contrast, 80-100% of sham operates continued to ejaculate throughout the 4 postoperative tests. Cell nuclear androgen receptor binding was assessed in amygdala, hypothalamus, preoptic area and septum 1-2 and 8-9 days after either bulbectomy or sham surgery. We found that olfactory bulbectomy significantly reduces androgen receptor binding in amygdala and hypothalamus. The reduction in androgen receptor binding in amygdala occurs within 1-2 days following olfactory bulb removal and is correlated with the disruption of ejaculatory activity. These data suggest that the neuromodulation by olfactory bulb input to androgen-concentrating neurons in the amygdala and hypothalamus is necessary for effective copulation in male rats.

Effects of anabolic androgenic steroids on the development and expression of running wheel activity and circadian rhythms in male rats

In humans, anabolic androgenic steroid (AAS) use has been associated with hyperactivity and disruption of circadian rhythmicity. We used an animal model to determine the impact of AAS on the development and expression of circadian function. Beginning on day 68 gonadally intact male rats received testosterone, nandrolone, or stanozolol via constant release pellets for 60 days; gonadally intact controls received vehicle pellets. Wheel running was recorded in a 12:12 LD cycle and constant dim red light (RR) before and after AAS implants. Post-AAS implant, circadian activity phase, period and mean level of wheel running wheel activity were compared to baseline measures. Post-AAS phase response to a light pulse at circadian time 15 h was also tested. To determine if AAS differentially affects steroid receptor coactivator (SRC) expression we measured SRC-1 and SRC-2 protein in brain. Running wheel activity was significantly elevated by testosterone, significantly depressed by nandrolone, and unaffected by stanozolol. None of the AAS altered measures of circadian rhythmicity or phase response. While SRC-1 was unaffected by AAS exposure, SRC-2 was decreased by testosterone in the hypothalamus. Activity levels, phase of peak activity and circadian period all changed over the course of development from puberty to adulthood. Development of activity was clearly modified by AAS exposure as testosterone significantly elevated activity levels and nandrolone significantly suppressed activity relative to controls. Thus, AAS exposure differentially affects both the magnitude and direction of developmental changes in activity levels depending in part on the chemical composition of the AAS.

Effects of withdrawal from anabolic androgenic steroids on aggression in adult male rats

In gonadally intact male rats, chronic exposure to high levels of testosterone propionate (TP) increases aggression, nandrolone (ND) has little effect and stanozolol (ST) suppresses aggression. The present experiment tested whether the effects of TP, ND and ST on aggression and reproductive tissues are reversed following anabolic androgenic steroid (AAS) withdrawal. Gonadally intact males received TP, ND, ST or vehicle for 12 weeks. Injections were then discontinued. Aggression was tested 3 weeks (short term) and 12 weeks (long term) after withdrawal of AAS treatment, with either a gonadally intact or a castrated opponent in three different environments (home, opponents and neutral cage). After short-term withdrawal, some parameters of aggression were significantly above control levels in TP males. There were no significant differences between ND or ST males and controls, though ST males showed the lowest levels of aggression. No significant differences between any of the groups were found after long-term withdrawal. Eighteen weeks after AAS withdrawal, serum testosterone (T) and LH levels were comparable to controls in all groups. Testes weights were at control levels in ST males, but significantly higher than controls in TP and ND males. Seminal vesicle weights were significantly elevated in TP males, but similar to controls in both ND and ST males. None of the prostate weights were significantly different from controls. These results suggest that aggression gradually returns to normal following withdrawal from AAS. Some, if not all, hormone levels and tissue weights return to normal, suggesting possible long-lasting effects of chronic AAS exposure.

Effects of fluoxetine and olfactory bulbectomy on mouse circadian activity rhythms

Olfactory bulbectomy (OBX) in SWR outbred male mice lengthened the free-running period and delayed the phase of a circadian rhythm for wheel-running activity. OBX also increased mean levels of activity. Two weeks of daily intraperitoneal injections of Fluoxetine (8 mg/kg), a serotonin re-uptake inhibitor, reversed the effects of bulbectomy on the mean level of activity and significantly shortened the free-running period of the activity rhythm. The phase of the activity rhythm was not significantly affected by the Fluoxetine treatment. These results are consistent with a hyposerotonergic mediation of the effects of OBX on circadian period and activity level.

Increased estrogen receptor binding in amygdala correlates with facilitation of feminine sexual behavior induced by olfactory bulbectomy.

In this experiment we tested the hypothesis that the potentiation of feminine sexual behavior following olfactory bulb removal in female rats would be associated with increased ovarian steroid receptor binding in brain. Ovariectomized adult female rats underwent either bilateral olfactory bulb removal (BOB) or a sham operation and were exposed to 100% estradiol (E2) in silastic capsules for 4 or 6 h. Following behavior testing, either cell nuclear estrogen receptor levels were measured in amygdala, hypothalamus, preoptic area and pituitary, or cytosol progestin receptors levels were determined in cortex, preoptic area and hypothalamus. After 6 h E2 exposure, BOB females showed increasing lordosis responding with increasing progesterone (P) doses, at levels significantly higher than those of sham-operated rats. After 4 h E2 exposure bulbectomized rats showed both a facilitation of lordosis and elevated estrogen receptor levels in amygdala. Sham-operates showed neither response to the 4 h E2 stimulus. For both BOB and sham groups, progestin receptors were induced after 6 h E2 exposure, but were uninduced after 4 h E2 exposure. Additional rats were exposed to 5% E2 for 24 or 48 h, followed by P. Lordosis was potentiated in BOB rats at 24 h; sham-operates showed high levels of lordosis only after 48 h of 5% E2 exposure. Proceptivity was enhanced in BOB rats after both 24 and 48 h of 5% E2 exposure. In contrast, proceptivity was rarely observed in sham-operates, or in either group after 4 or 6 h E2 exposure. We propose that increased estrogen receptor binding in the amygdala may provide a biochemical basis for the increased estrogen sensitivity found in olfactory bulbectomized female rats.