Nigrostriatal and mesolimbic dopaminergic activities were modified throughout the ovarian cycle of female rats.
TL;DR: The results indicate the existence of physiological changes in the functional state of both dopaminergic systems during the ovarian cycle, which are partially different for each neuronal pathway, and supports the exist of a specific regulation, and not indiscriminate effects, by the hormones involved in this cycle.
Abstract: In this work, we have studied the changes in the functional state of nigrostriatal (NSDA) and mesolimbic (MLDA) dopaminergic neurons during the estrous cycle of the female rat. The activity of tyrosine hydroxylase (TH), the turnover rate (Kt) after inhibition of dopamine (DA) synthesis and the ratio between the contents of this amine and its metabolite, L-3,4 dihydroxyphenylacetic acid (DOPAC), were used as indices of neuronal activity. The neuronal activity of NSDA neurons rose during estrous and declined during proestrous, as reflected by the values of Kt and DOPAC/DA ratio measured during both phases. Interestingly, the course of variations in striatal TH activity was similar, although retarded in relation to the changes in neuronal activity. Thus, TH activity was high during diestrous, whereas it was low during estrous. The activity of MLDA neurons was reduced during proestrous. This can be concluded from the decreased Kt and DOPAC/DA ratio measured in this phase and it was accompanied by a low TH activity. Thereupon, both Kt and TH activity increased during estrous. These results indicate the existence of physiological changes in the functional state of both dopaminergic systems during the ovarian cycle, which are partially different for each neuronal pathway. This supports the existence of a specific regulation, and not indiscriminate effects, by the hormones involved in this cycle, mainly estradiol and progesterone.
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TL;DR: These findings show that although estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework.
Abstract: The prefrontal cortex (PFC) is exquisitely sensitive to its neurochemical environment. Minor fluctuations in cortical dopamine (DA) can profoundly alter working memory, a PFC-dependent cognitive function that supports an array of essential human behaviors. Dopamine's action in the PFC follows an inverted U-shaped curve, where an optimal DA level results in maximal function and insufficient or excessive DA impairs PFC function. In animals, 17β-estradiol (the major estrogen in most mammals, referred to henceforth as estradiol) has been shown to enhance DA activity, yet no human study has adequately addressed whether estradiol's impact on cognition occurs by way of modulating specific neurochemical systems. Here we examined the effects of endogenous fluctuations in estradiol on working memory in healthy young women as a function of baseline PFC DA [indexed by catechol-O-methyltransferase (COMT) Val(158)Met genotype and, at a finer scale, COMT enzyme activity]. The results demonstrate that estradiol status impacts working memory function and, crucially, the direction of the effect depends on indices of baseline DA. Moreover, consistent with a DA cortical efficiency hypothesis, functional MRI revealed that inferred optimal DA was associated with reduced PFC activity sustained across task blocks and selectively enhanced PFC activity on trials with the greatest demand for cognitive control. The magnitude of PFC activity during high control trials was predictive of an individual's performance. These findings show that although estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework. Given the clinical prevalence of dopaminergic drugs, understanding the relationship between estrogen and DA is essential for advancing women's health.
320 citations
TL;DR: There are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women, and it is anticipated that additional evidence will emerge for sexual dimorphisms not only in COMT but also in many other autosomal genes.
292 citations
Cites background from "Nigrostriatal and mesolimbic dopami..."
...…a significant confounder: rodent studies have shown marked fluctuations in multiple dopaminergic parameters in the striatum across the estrus cycle (Jori and Cecchetti, 1973; Favis et al, 1977; Crowley et al, 1978; Fernandez-Ruiz et al, 1991; Morissette and Di Paolo, 1993; Xiao and Becker, 1994)....
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TL;DR: Observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms of memory-impairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.
Abstract: There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinson's disease and dementia. These differences, as well as direct experimental data in rodents, suggest that gonadal hormones play a role in modulating this system. To determine whether circulating estrogen might have long-term effects by altering the number of dopamine neurons, the density of dopamine neurons was calculated in the compact zone of the substantia nigra of male and intact female short- (10 d) and longer-term (30 d) ovariectomized and short- and longer-term ovariectomized but estrogen-replaced nonhuman primates (African green monkeys). Furthermore, the number of tyrosine hydroxylase-expressing neurons, the total number of all types of neurons, and the volume of the compact zone of the substantia nigra were calculated in 30 d ovariectomized and in 30 d ovariectomized and estrogen-replaced monkeys. Unbiased stereological analyses demonstrated that a 30 d estrogen deprivation results in an apparently permanent loss of >30% of the total number of substantia nigra dopamine cells. Furthermore, the density calculations showed that brief estrogen replacement restores the density of tyrosine hydroxylase-immunoreactive cells after a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms of memory-impairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.
269 citations
TL;DR: The results confirm the age-related reduction of D2 receptor density and binding potential in both sexes in vivo and suggest an increased endogenous striatal dopamine concentration in women.
Abstract: OBJECTIVE: The authors investigated whether striatal dopamine D2 receptor binding characteristics in vivo are similar in men and women and whether there are sex-related differences in the decline in D2 receptor density due to aging. METHOD: Striatal D2 receptor density (Bmax), affinity (Kd), and binding potential (Bmax/Kd) were measured with positron emission tomography and [11C]raclopride in 54 healthy subjects (33 men and 21 women). RESULTS: Women had generally lower D2 receptor affinity than men, and this difference was statistically significant in the left striatum. Bmax and Bmax/Kd tended to decline with age twice as fast in men as in women, but the difference did not reach statistical significance. CONCLUSIONS: These results confirm the age-related reduction of D2 receptor density and binding potential in both sexes in vivo. The lower D2 receptor affinity suggests an increased endogenous striatal dopamine concentration in women. This may have implications for the differential vulnerability of men an...
244 citations
TL;DR: The results demonstrate that there are both acute and long-term effects of estrogen on the striatum that underlie the dynamic changes in stimulated DA release and amphetamine-induced behaviors during the reproductive cycle.
Abstract: There are estrous cycle-dependent differences in amphetamine-stimulated behaviors and striatal dopamine (DA) release; intact female rats exhibit a greater behavioral response to amphetamine on estrus than on other days of the cycle. Following ovariectomy amphetamine-induced behavior is attenuated, as is the striatal DA response to amphetamine in vitro. Repeated estrogen treatment in ovariectomized rats reinstates both of these responses to a level comparable to estrous females. In addition, 30 min after a single treatment with a physiological dose of estrogen there is enhanced amphetamine-induced behavior and increased amphetamine-induced striatal DA detected during microdialysis. This experiment was conducted to determine whether the acute effect of estradiol and the effect of repeated exposure to estrogen are functionally related. We report here that prior treatment with estrogen (three daily treatments of 5 μg estradiol benzoate) results in a significant enhancement of the effect of acute estrogen (5 μg estradiol benzoate) or progesterone (500 μg) on amphetamine-induced striatal DA release and stereotyped behaviors. Both the peak response and the duration of the response are greater in estrogen-primed animals treated with estrogen or progesterone 30 min prior to amphetamine, than in all other groups. Either prior treatment with estrogen (last dose 24 h before) or a single acute injection of estrogen result in an enhanced peak response to amphetamine, with no effect on the duration of amphetamine-induced striatal DA release. Treatment with progesterone in animals not primed with estrogen was not different from treatment with oil vehicle. These results demonstrate that there are both acute and long-term effects of estrogen on the striatum that underlie the dynamic changes in stimulated DA release and amphetamine-induced behaviors during the reproductive cycle.
182 citations
References
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TL;DR: It is revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system.
Abstract: NOREPINEPHRINE is found in appreciable amounts in mammalian brain tissue. VOGT (1954) showed that this amine was unequally distributed in various regions of the cat brain, the highest concentrations being found in the hypothalamus. Similar findings were reported for other animal species (BERTLER and ROSENGREN, 1959a; MCGEER, MCGEER and WADA, 1963) and man (SANO, GAMO, KAKIMOTO, TANAGUCHI, TAKE~ADA and NISHINUMA, 1959). Dopamine is also present in the brain in comparable amounts to norepinephrine (MONTAGU, 1957 ; CARLSSON, LINDQVIST, MAGNUSSON and WALDECK, 1958) but with a different regional distribution, the highest concentrations being in the corpus striatum of both animals and man (BERTLER and ROSENGREN, 1959a; SANO et al., 1959; EHRINGER and HORNYKIEWICZ, 1960; BERTLER, 1961). The anatomical distribution of these two catecholamines in the brain was confirmed by the use of fluorescent histochemical techniques which allow a precise description of the cellular localization of the amines in brain tissue (CARLSSON, FALK and HILLARP, 1962; DAHLSTROM and FUXE, 1964; FUXE, 1965). These techniques revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system. The metabolism of catecholamines in the rat brain was studied by introducing small amounts of radioactive norepinephrine or dopamine directly into the lateral ventricle (MILHAUD and GLOWINSKI, 1962, 1963; GLOWINSKI, KOPIN and AXELROD, 1965; GLOWINSKI, IVERSEN and AXELROD, 1966). By this approach the blood-brain barrier to catecholamines can be circumvented, penetration of the radioactive catecholamines into the brain being allowed. The disposition of PHInorepinephrine in the whole brain indicates that [3H]norepinephrine introduced into the lateral ventricle of the brain mixes with the endogenous amine and can be used as a tracer to study the biochemical behaviour of norepinephrine in the brain (GLOWINSKI and AXELROD, 1966). PHIDopamine, which is also taken up and retained in the brain, is rapidly metabolized and converted to norepinephrine (GLOWINSKI et a!., 1966). The unequal regional distribution of the endogeneous catecholamines in the brain led us to undertake a study of the disposition of radioactive norepinephrine and dopamine in various brain regions after intraventricular injection. The regional
5,385 citations
TL;DR: Groups of female rats were decapitated at 3-hr intervals throughout 4-day estrous cycles and the plasma of each rat was assayed for LH, FSH, prolactin, progesterone and estradiol-17β, which exhibited a peak concentration in plasma on the day of proestrus.
Abstract: Groups of female rats were decapitated at 3-hr intervals throughout 4-day estrous cycles and the plasma of each rat was assayed for LH, FSH, prolactin, progesterone and estradiol-17β. Radioimmunoassays were used to measure these hormones, except for progesterone which was determined by the competitive protein binding assay. All five hormones exhibited a peak concentration in plasma on the day of proestrus. In addition, progesterone was elevated from 0900 hr of metestrus to 0900 hr of diestrus, while plasma prolactin showed a brief rise at 1500 hr of estrus. The elevated level of estradiol on the day of proestrus followed a different pattern than the other four hormones. Estradiol concentration began to rise late on metestrus, reached a peak at noon of proestrus, and fell before peak levels of the other hormones were reached. The preovulatory elevation of LH, prolactin and progesterone occurred between noon and midnight of proestrus, while the peak of FSH lasted from noon of proestrus to noon of estrus. (E...
1,310 citations
Journal Article•
TL;DR: In the rabbit hypothalamus, NE is formed five times more rapidly than in the midbrain, though the turnover times are almost identical, which suggests that the rate of synthesis might be similar in each adrenergic unit and that variations in rates of synthesis in different brain areas are a function of the number of neurons per gram of tissue.
Abstract: A method of measuring the rate of synthesis of catecholamines in various tissues takes advantage of the steady state relationship in which the rate of catecholamine formation is equal to the rate of efflux. After tyrosine hydroxylase is blocked with α-methyltyrosine, the brain levels of norepinephrine (NE) and dopamine and the NE levels in various peripheral tissues of rats and rabbits decline exponentially. The rate of synthesis of the catecholamines is calculated from the product of the rate constant of amine decline and the normal catecholamine level. The value for heart NE yielded by this method is almost identical with that obtained from the decline in radioactivity after labeling with dl -H3-NE. The application of this method to studies in the rat shows that the turnover time for NE in heart, salivary gland and iris is about 12 hr, compared to 6 hr for brain NE, 3 hr for brain dopamine and 2 hr for NE in the cervical sympathetic ganglia. In the rabbit hypothalamus, NE is formed five times more rapidly than in the midbrain, though the turnover times are almost identical. This suggests that the rate of synthesis might be similar in each adrenergic unit and that variations in rates of synthesis in different brain areas are a function of the number of neurons per gram of tissue.
717 citations
TL;DR: Abnormalities in periodicity, onset, duration and magnitude of the preovulatory LH discharge during middLH secretion during pubertal life are studied.
Abstract: I. Introduction Essentially, two modalities of luteinizing hormone (LH) secretion have been identified in the rat. The basal mode is characterized by episodic bursts of pituitary LH discharge whose frequency and amplitude may vary considerably during the day in male (1, 2) and according to different phases of the estrous cycle in female rats (4). This low level of pulsatile LH secretion is established early in the juvenile period (5). With advancing age, subtle and progressive disintegration of several compo-nents of the LH episodes seems to account for the near cessation of rhythmicity in old rats (6). Additionally, in adult female rats, the periodic mode of LH secretion is interrupted on the afternoon of proestrus by fast, high amplitude pulses constituting the preovulatory LH surge lasting for 4–6 h (7–9). The cyclic pattern of LH secretion is fully established by the 5th week of pubertal life (5). Abnormalities in periodicity, onset, duration and magnitude of the preovulatory LH discharge during middl...
604 citations
"Nigrostriatal and mesolimbic dopami..." refers background in this paper
...There are many information about the neural events involved in the control of physiological variations in anterior pituitary and ovarian secretion during the sexual cycle of the female rat (for review see McEwen and Parsons, 1982; Kalra and Kalra, 1983)....
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TL;DR: It is found that prolonged electrical stimulation of the splanchnic nerves did not produce a pronounced depletion of the content of adrenal catecholamines, and Holland & Schumann ( 1956) later extended these findings by measuring directly the amount ofcatechol amines released during splan Schnic nerve stimulation and the content in the adrenal gland before and after the stimulation.
Abstract: Although stimulation of adrenergic nerves or adrenal chromaffin cells causes the release of catecholamines, in many cases it does not cause a decrease in the catecholamine content of these cells. One of the first reports of this phenomenon was made by T. R. Elliot ( 1 9 1 2) in a study designed to establish whether the release of catecholamines by the adrenal medulla was controlled by the splanchnic nerves. Although Elliot obtained con siderable data supporting this view, he also found that prolonged electrical stimulation of the splanchnic nerves did not produce a pronounced depletion of the content of adrenal catecholamines. In fact, Elliot wrote, "so slight is the change in the residual adrenalin caused by faradisation of the splanchnic nerves, that it would never have sufficed to convince me of the existence of the splanchnic control." Holland & Schumann ( 1956) later extended these findings by measuring directly the amount of catechol amines released during splanchnic nerve stimulation and the content of catecholamines in the adrenal gland before and after the stimulation. They observed that the output of catecholamines into the blood stream
524 citations
"Nigrostriatal and mesolimbic dopami..." refers background in this paper
...This could be related to the well known delayed mechanism that regulates the activity of this enzyme, by altering the enzyme level through induction of TH gene expression (Zigmond et al., 1989)....
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