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Biomedical subjects

M M McCarthy

Publications and source records attributed to M M McCarthy.

At least 55 records · Page 3Linked to original sources
PubMed1996

Hormonal and neurotransmitter regulation of GnRH gene expression and related reproductive behaviors.

Gonadotropin-releasing hormone (GnRH), having a highly conserved structure across mammalian species, plays a pivotal role in the control of the neuroendocrine events and the inherent sexual behaviors essential for reproductive function. Recent advances in molecular genetic technology have contributed greatly to the investigation of several aspects of GnRH physiology, particularly steroid hormone and neurotransmitter regulation of GnRH gene expression. Behavioral studies have focused on the actions of GnRH in steroid-sensitive brain regions to understand better its role in the facilitation of mating behavior. To date, however, there are no published reports which directly correlate GnRH gene expression and reproductive behavior. The intent of this article is to review the current understanding of the way in which changes in GnRH gene expression, and modifications of GnRH neuronal activity, may ultimately influence reproductive behavior.

Animals↗
PubMed1996

An anxiolytic action of oxytocin is enhanced by estrogen in the mouse.

The established role of oxytocin (OT) in facilitation of steroid-modulated reproductive and affiliative behaviors led to the speculation that it may have anxiolytic actions under certain hormonal conditions. NIH-Swiss mice were tested for responsiveness to OT in two behavioral tests of anxiety, the holeboard apparatus and elevated plus-maze. Dose-response assessment indicated that 3 mg/kg was the optimal dose for peripherally administered (IP) OT on the elevated plus-maze. There were no consistent effects at any dose on the holeboard apparatus. In ovariectomized mice pretreated with estradiol (E2), peripherally administered OT increased the number of entrances onto the open arms, as well as the amount of time on the open arms compared to other groups (ANOVA; p < 0.05). There was little to no effect of OT in ovariectomized animals not pretreated with E2. When OT was administered intracerebroventricularly (ICV), there was an increase in entrances and time on the open arms compared to that of females infused with arginine vasopressin (AVP). This increase was apparent in ovariectomized females, but was further enhanced in those pretreated with E2 (ANOVA; p < 0.05). In contrast, the combination of E2 pretreatment and ICV AVP decreased the number of entrances and time spent on the open arms of the elevated plus-maze compared to those receiving OT, suggesting an estrogen-modulated anxiogenic action of AVP. Analyses of [125]I-OVTA binding density indicated a significant increase in binding density in the lateral septum of E2-treated females compared to OIL-treated controls (ANOVA; p < 0.05). There was no effect of E2 treatment on [125]I-OVTA binding density in the amygdala or ventromedial nucleus of the hypothalamus. Taken together, these data indicate that OT exerts an anxiolytic action that is enhanced in the presence of circulating estrogen. This behavioral effect may be mediated by estrogen-induced increases in OT binding density in the lateral septum and may be important to the facilitation of social interactions.

Animals↗
PubMed1996

Antiandrogen microimplants into the rostral medial preoptic area decrease gamma-aminobutyric acidergic neuronal activity and increase luteinizing hormone secretion in the intact male rat.

gamma-Aminobutyric acid (GABA)ergic neurons terminating in the rostral hypothalamus are stimulated by testosterone. To investigate whether this action is mediated locally through androgen receptors in the rostral hypothalamus, bilateral microcannulas (28 gauge) containing the androgen receptor antagonist, hydroxyflutamide (HF), were stereotaxically implanted into the rostral medial preoptic area (rMPA) just dorsal to the major population of GnRH cell bodies. Two days later, blood samples were collected for assay of LH, and animals were killed for determination of GABAergic neuronal activity in tissue dissected from the site of the implanted cannulas. Animals were decapitated either without treatment or 60 min after inhibition of GABA degradation by aminooxyacetic acid (100 mg/kg, ip). The rate of GABA accumulation in the tissue after aminooxyacetic acid treatment was used as a measure of GABA turnover. Levels of messenger RNA for both forms of glutamic acid decarboxylase (GAD65 and GAD67), the rate-limiting enzyme responsible for GABA synthesis also were measured by a microlysate ribonuclease protection assay. LH levels were significantly increased (1.8-fold) in HF-treated animals compared with controls. In the MPA, beneath the implant cannulas, GABA turnover was significantly reduced in HF-treated rats. There was no effect of treatment in the frontal cortex, which was used as a control region. Surprisingly, levels of messenger RNA for both GAD65 and GAD67 were significantly increased in HF-treated rats. The results indicate that GABAergic neurons terminating in the rostral hypothalamus are tonically stimulated by testosterone acting by means of androgen receptors localized in this region. These findings support the working hypothesis that androgen-sensitive GABAergic neurons in the rMPA mediate the negative feedback action of testosterone on GnRH secretion in the male rat.

Androgen Antagonists↗
PubMed1995

Antisense oligonucleotide inhibition of tryptophan hydroxylase activity in mouse brain.

To examine in vivo effectiveness of antisense oligonucleotides against tryptophan hydroxylase (TPH) mRNA, adult male swiss-NIH mice were implanted with in-dwelling cannula into the 4th ventricle and after recovery infused with either antisense oligonucleotide to TPH, scrambled control oligo or saline vehicle for four consecutive days. An additional group of animals bearing cannula were injected a single time i.p. with the TPH inhibitor para-chlorophenylalanine (PCPA; 300 mg/kg). All animals were sacrificed on the afternoon of the 4th day of treatment. TPH activity was measured by enzymatic assay and HPLC quantification of end-product synthesis. There was a significant decrease (> 50%) in TPH activity in both the PCPA-treated and antisense-oligo infused animals compared to either scrambled-oligo or saline-infused subjects (ANOVA; P < 0.05). There was no difference between saline and scrambled oligo-infusion. In a separate group of animals treated in the same way, behavioral tests were conducted on the afternoon of the 4th day. Two tests of anxiety, the hole-board apparatus and the elevated plus-maze, indicated some significant effects of PCPA treatment and/or antisense oligo-infusion but confounding effects due to alterations in locomotion could not be ruled out. However, tests on a rotorod apparatus indicated that antisense oligo-infused animals retained good balance and coordination in that their performance significantly improved on the second test, as did that of scrambled-oligo infused animals. In contrast, PCPA-treated animals did not improve, suggesting that locomotor performance had been impaired. These data support the notion that antisense oligo blockade may offer advantages over pharmacological manipulations of enzyme activity.

Analysis of Variance↗
PubMed1995

Estrogen modulation of mRNA levels for the two forms of glutamic acid decarboxylase (GAD) in female rat brain.

Two separate forms of glutamic acid decarboxylase, now termed GAD65 and GAD67, are the rate limiting enzymes for synthesis of gamma-aminobutyric acid (GABA). Because of the significance of GABA to neuroendocrine processes, numerous attempts have been made to determine the impact of gonadal steroids on enzyme functioning with inconclusive results. Therefore, we attempted to determine the impact of estradiol on mRNA levels for each form of GAD by quantitative in situ hybridization histochemistry in various brain regions. Ovariectomized rats were treated with estradiol benzoate or oil vehicle on 2 consecutive days and the brains collected on the third day. DNA probes specific for GAD65 and GAD67 were radiolabeled with CTP32 using asymmetric polymerase chain reaction. Results of in situ hybridizations for each probe on alternate sections from the same animals were analyzed for magnocellular preoptic area (McPOA), dorsal medial nucleus of the hypothalamus (DMN), zona incerta (ZI), and midbrain central gray (MCG). In the McPOA, estradiol exerted opposite effects on the frequency distribution of pixels per cell for two GAD mRNA probes, significantly increasing GAD65 (P < .05) and decreasing GAD67 (P < .01; Kolmogorov-Smirnov). In the DMN, estradiol treatment significantly increased GAD67 by 60% (P < .05; two-way ANOVA) but decreased GAD65 mRNA by 73% (P < .01). Note the direction of effects are opposite between McPOA and DMN. In MCG, analysis showed no estradiol effect on GAD mRNA levels/cells, but the proportion of cells expressing detectable levels of GAD65 or GAD67 increased by 33-40% in estradiol-treated rats (chi 2, P < .001).

Animals↗
PubMed1995

Infusions of diazepam and allopregnanolone into the midbrain central gray facilitate open-field behavior and sexual receptivity in female rats.

We have previously shown that blocking GABAA receptors with bicuculline in the dorsal and lateral quadrants of the rostral two-thirds of the midbrain central gray (MCG) in rats reduces the lordosis quotient (LQ) and proceptive behaviors without increasing the defensive index (McCarthy, Pfaff, and Schwartz-Giblin, 1991b), indicating that tonic release of endogenous GABA in the MCG has a primary facilitatory effect on reproductive behaviors. The present study tests whether two modulators of the GABAA-benzodiazepine-receptor complex, diazepam and the progesterone metabolite, allopregnanolone, facilitate female receptivity as well as open-field behavior. Ovariectomized estradiol benzoate (EB)-treated rats were bilaterally infused in the MCG with vehicle, diazepam, or allopregnanolone and tested 20 min after diazepam and 12 min after allopregnanolone. Animals were tested once each for both receptive or open-field behavior with testing sessions being at least 1 week apart in a crossover design between vehicle and one of the two drugs. Both diazepam and allopregnanolone significantly increased the lordosis quotient in a dose-dependent manner, the lowest effective dose tested being 100 and 250 ng, respectively. In the open-field test, infusion of diazepam (100 ng) in EB-treated rats significantly increased the ratio of central squares entered to total squares entered (C/T) without a change in total activity. Rats without EB elicited comparable C/T ratios when tested with five times as much diazepam. Diazepam infusions at more dorsal sites in the midbrain and in overlying cortex were without effect on C/T ratios in EB-treated rats. Allopregnanolone (500 ng) infusions in MCG of EB-treated rats did not alter C/T ratios compared to animals without EB. Our results are consistent with diazepam and allopregnanolone acting through the GABAA receptors of the MCG to enhance female sexual receptivity and with estradiol potentiating the effect of diazepam in the MCG to increase open-field behavior.

Animals↗
PubMed1995

Estrogen modulation of oxytocin and its relation to behavior.

Establishment of the behavioral significance of oxytocin neurotransmission in the brain has been a leading component in the emerging concept of neuropeptide regulation of behavior. Elucidating the behavioral effects of oxytocin has been facilitated by its profound regulation by estrogen in discrete brain areas and its subsequent role in estrogen-dependent responses. For example, female sexual behavior is estrogen dependent, estrogen markedly increases oxytocin binding in the ventromedial nucleus of the hypothalamus and infusion of oxytocin in this brain area increases female sexual behavior. A similar correlation exists for the role of oxytocin and estrogen in the regulation of maternal behavior. A possible underlying cause of these behavioral effects is that by acting as an anxiolytic, oxytocin reduces the inhibition inherent in social encounters. Behavioral tests in the laboratory frequently involve the exposure of the animal to a novel environment, such as a pup-retrieval apparatus or mating arena, combined with exposure to an unfamiliar conspecific. These stimuli are likely to induce a stress response and perhaps this anxiety is reduced by oxytocin. Recent evidence in mice suggests that oxytocin has anxiolytic properties in estrogen-treated females (McCarthy and Goldman, 1994) and supports the hypothesis that a unifying principal in oxytocin action in the brain is to facilitate social encounters by reducing the associated anxiety.

Animals↗
PubMed1994

Intracerebral administration of antisense oligodeoxynucleotides to GAD65 and GAD67 mRNAs modulate reproductive behavior in the female rat.

Increased GABA activity in the medial hypothalamus (HYP) and midbrain central gray (MCG), but not the preoptic area (POA), facilitates sexual receptivity in the female rat [40]. In the current experiments, ovariectomized females were chronically treated with estrogen (via silastic capsules) to maintain a continuously high level of lordosis response. Administration of crystalline antisense oligodeoxynucleotide to the GABA synthetic enzyme, GAD67, into the HYP and MCG significantly and reversibly reduced lordosis response for 1-2 days, but did not inhibit lordosis when administered into the POA. Administration of a control oligonucleotide, consisting of the same nucleotide bases but in a scrambled sequence, did not significantly modulate behavior when infused into any brain areas. When oligodeoxynucleotide antisense to GAD67 was suspended in oil and then infused into the HYP or MCG it was more effective and resulted in less inter-animal variability. Subsequent experiments involving infusions into the MCG compared the effectiveness of antisense oligonucleotides to the two different forms of GAD, known as GAD65 and GAD67. Oligodeoxynucleotides antisense to the mRNA for either gene were effective at reducing lordosis behavior but with a different time course. Oligonucleotide antisense to GAD67 significantly reduced behavior within 24 h of infusion and there was full recovery by 4 days post-infusion. GAD65 antisense oligonucleotide did not significantly reduce behavior until 48 h post infusion and animals did not fully recover to pretest levels of lordosis until 5 days post-infusion. When antisense oligonucleotide for the two genes was administered simultaneously, the inhibition of lordosis was maximal at 24 h and stayed depressed for 4 days. There did not appear to be an additive effect of the two different antisense oligonucleotides when administered together. Tissue GABA levels in HYP and MCG of individual rats assayed by HPLC were no longer correlated with lordosis score after antisense oligonucleotide infusion but were after infusions of scrambled control oligos. Immunoblotting for the two forms of GAD revealed that GAD67 antisense oligonucleotide infusion led to significant decreases in both GAD67 and GAD65 protein levels as compared to infusions of scrambled control oligo. In addition, the levels of a neuronal marker, neuron-specific enolase, also decreased (although nonsignificantly) suggesting either a temporary shutdown of protein synthesis or a degeneration of GABAergic neurons after GAD67 antisense oligonucleotide infusion.

Animals↗
PubMed1994

Evidence for the involvement of prolactin in the maternal behavior of the hamster.

The hormonal basis of maternal behavior in the hamster has not been clearly established. Treatment of parturient females on the day of delivery with the prolactin release inhibitor, bromocriptine, resulted in a significant disruption of maternal responsiveness at doses as low as 0.5 mg When pregnant females were implanted with ectopic pituitary grafts under the kidney capsule on day 8 or 9 of gestation to elevate circulating prolactin levels, there was no disruption of maternal behavior after bromocriptine injection on the day of delivery. Taken together, these data indicate that prolactin may be an important modulator of the natural onset of maternal behavior at parturition in the hamster.

Animals↗
PubMed1994

Molecular aspects of sexual differentiation of the rodent brain.

The sexual differentiation of the brain is orchestrated by gonadal steroids during a restricted developmental period and results in permanent changes in the neural substrate including the capacity to support ovulation and expression of sex-specific reproductive behaviors. Sry gene-induced development of testes constitutes a binary switch directing all subsequent differentiation. Androgen produced by the testes of the embryonic male differentiates secondary sex characteristics but also acts in the brain to "masculinize" the neural substrate, many of the latter are the result of aromatization of testosterone to estrogen. Molecular characteristics of aromatase and 5 alpha-reductase enzymes are reviewed. It is assumed that estrogen binds to its receptor which then binds to DNA, inducing transcription of specific genes. Mutations in steroid receptor genes can markedly alter hormone-mediated differentiation. Two questions are addressed: (1), is the assumption correct that estrogen's effects on sexual differentiation are via the classic genomic action of steroids?; and (2) if so, what genes are transcribed as a result of the activated estrogen receptor complex? We have used antisense oligodeoxynucleotides designed to hybridize with and block the translation of mRNA for the estrogen receptor. Administration of antisense into brain of 3-day-old pups had permanent effects on estrogen-induced differentiation as indicated by behavioral and brain morphology differences in adulthood. These results demonstrate the effectiveness of antisense oligonucleotides if administered during a critical period and further confirm the widely accepted tenet that estrogen acts on the brain via its receptor. Subsequent experiments can now address the question of what genes are being activated by the estrogen receptor during development.

Animals↗
PubMed1994

Infusion of antisense oligodeoxynucleotides to the oxytocin receptor in the ventromedial hypothalamus reduces estrogen-induced sexual receptivity and oxytocin receptor binding in the female rat.

Exogenous administration of the neuropeptide oxytocin reliably facilitates sexual behavior in the female rat and exposure to estrogen increases oxytocin receptor (OTR) binding in the ventromedial nucleus (VMN) of the hypothalamus. We have used a novel approach to investigate the role of hypothalamic OTR in controlling behavior by infusing antisense oligodeoxynucleotides (oligo) to the 5'-region of the human OTR mRNA into the VMN of hormonally primed rats. Control infusions consisted of a scrambled-sequence oligo that had little or no homology to known mRNAs. OTR antisense oligo infusion significantly reduced lordosis frequency and intensity in females primed with estrogen. There was also a significantly greater number of rejection behaviors exhibited by antisense-oligo-infused estrogen-treated females versus controls and no evidence of decreased locomotion by either treatment. In contrast to the effects in estrogen-primed-females, when females were primed to be sexually receptive with estrogen plus progesterone, OTR antisense-oligo infusion had no effect on sexual behavior. The lack of effectiveness of OTR antisense oligo in females primed with progesterone may be the result of the action of this steroid on other neurotransmitter systems that also facilitate lordosis and thereby override a deficit in oxytocin binding. Alternatively, via previously described mechanisms, progesterone may enhance the effectiveness of oxytocin binding at its receptor. In vitro receptor autoradiography in estrogen-primed females indicated a 31% reduction in VMN OTR binding in the vicinity of the cannula tip in antisense-oligo-infused females compared to controls. There was no significant difference in the level of OTR binding in the central nucleus of the amygdala.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Nerve growth factor affects defense-related behaviors, but not lordosis, in ovariectomized, estrogen-treated rats.

Effects of NGF and anti-NGF on estrogen-sensitive behaviors were examined in ovariectomized, estrogen-treated rats. Intracerebroventricular (i.c.v.) administration of NGF resulted in a significant decrease in body weight. Daily treatment with low levels of estradiol resulted in a steady increase in lordosis behavior as reflected by average lordosis quotient and lordosis score. No effects of NGF or anti-NGF on lordosis behavior were detected. Estrogen treatment also resulted in a significant increase in the number of vocalizations elicited from female controls by male contact during sex behavior. NGF-treatment enhanced this effect, resulting in significantly more vocalizations elicited earlier in the course of estrogen treatment than were elicited from non-NGF-treated controls. These effects were blocked by progesterone. An increase in the number of rejections elicited by male contact during sex behavior was also observed in NGF-treated animals relative to controls. In addition, i.c.v. infusions of anti-NGF prevented the estrogen-mediated increase in elicited vocalizations, suggesting that NGF may have a physiological role in regulating this behavior. These data implicate NGF in the regulation of specific defense-related behaviors in estrogen-treated rats. Effects of NGF and anti-NGF on immunocytochemical staining for p75NGFR-, and ChAT-like immunoreactivity were also analyzed and are discussed.

Aggression↗
PubMed1993

Catalepsy induced by muscimol infused into the hypothalamus can be sensitized and is modulated by ovarian steroids.

Muscimol (25 ng), but not saline, infused into the region of the zona incerta and lateral hypothalamus induced significant catalepsy in female rats. Daily administration of muscimol for 5 days resulted in a sensitization of the cataleptic response such that there was a significantly greater response to the same dose of muscimol beginning on Day 3 and continuing to increase up to Day 5. It was determined that the increase in catalepsy across days was not the result of conditioning after an initial exposure to muscimol. The endocrine condition of the female affected the degree of catalepsy induced by the first exposure to intrahypothalamic muscimol. Ovariectomized rats pretreated with estradiol benzoate (EB) exhibited significantly greater catalepsy than did females untreated or treated with progesterone or combined EB and progesterone. Weekly administration of muscimol also produced significant sensitization of the behavioral response, and the degree of sensitization was again affected by endocrine condition. Specifically, although females treated with EB for 2 days before muscimol infusion showed a significantly greater catalepsy after the first infusion than did ovariectomized females, they failed to show any increase in catalepsy scores across the 4 weeks of treatment. The greater catalepsy induced by muscimol infusion in EB-treated females may be related to changes in dopaminergic transmission. In contrast, females pretreated with progesterone 4 hr before muscimol infusion (with or without prior EB) exhibited highly significant increases in cataleptic response across the 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Enduring consequences of neonatal treatment with antisense oligodeoxynucleotides to estrogen receptor messenger ribonucleic acid on sexual differentiation of rat brain.

Sexual differentiation of the mammalian brain is regulated by steroids during a critical developmental period, particularly by estradiol, which is believed to be aromatized in brain from gonadally derived testosterone. To ascertain the importance of neuronal estrogen receptor expression during sexual differentiation, we infused a 15-mer oligodeoxynucleotide antisense to the region of the translation start codon of estrogen receptor messenger RNA (mRNA), into the hypothalamus of 3-day-old rat pups. Two separate control treatments consisted of either a scrambled nucleotide sequence oligodeoxynucleotide, which had little homology to known mRNAs, or vehicle. Female pups either received a lightly androgenizing dose of testosterone 6 h after oligo infusion or were not hormone treated. Infusion of antisense oligo to estrogen receptor mRNA protected against many of the androgenizing effects of testosterone. Androgenized females infused with antisense oligo were significantly more likely to exhibit female sexual behavior in adulthood after treatment with estrogen plus progesterone and remained sensitive to the induction of wheel-running behavior by estrogen treatment seen in normal females, whereas the control androgenized females did not. Normal females did not exhibit any effects of antisense oligo treatment on sexual or locomotor behavior, but antisense oligo-treated normal females showed a trend (P = 0.09) toward disrupted estrous cyclicity and behaved differently in tests of open field behavior compared to controls. After killing, brains were processed for histology. Morphometric analysis of the sexually dimorphic nucleus of the preoptic area demonstrated a significantly smaller volume in antisense oligo-infused androgenized females compared with vehicle and scrambled oligo-infused controls. The sexually dimorphic nucleus volume was smaller still in normal females infused with antisense oligo, consistent with estrogen receptor activation playing an active role in sexual differentiation of the female brain. These results demonstrate the effectiveness of antisense oligodeoxynucleotides in permanently altering a developmental process if administered during a critical period.

Animals↗