Relationships among gender,age, time,and temperature in methamphetamine-induced striatal dopaminergic neurotoxicity

A neurotoxic regimen of methamphetamine (MA—40 mg/kg ip) administered at 0 (control—MA vehicle), 0.5 and 72 h prior to determinations of striatal dopamine (DA) and DOPAC (3,4-dihydroxyphenylacetic acid)/DA ratios were compared among juvenile and adult female and male mice. Adult females and males showed similar depletions in striatal DA at 0.5 h post-MA, but males showed greater DA depletions and DOPAC/DA ratios at 72 h post-MA. Juvenile mice showed neither sex differences, nor any MA neurotoxicity upon striatal DA or DOPAC/DA ratios. Following MA, body temperatures increased in all mice, but increases in adult males were greater than adult females; juveniles showed no sex differences and body temperature increases were similar to that of adult males. MA-evoked DA output was greater in adult compared to juvenile males and a biologically effective regimen of testosterone to juvenile males neither increased MA-evoked DA output nor decreased MA-induced striatal DA like that observed in adult males. These results demonstrate: (1) Unlike adults, juvenile mice show neither a sex difference for MA-induced neurotoxicity or body temperature increases, nor MA neurotoxicity, (2) Initial effects of MA (0.5 h) in adult females and males are similar, but at 72 h post-MA females show no further striatal DA depletion, (3) Increased striatal DA depletion within adult versus juvenile males may be related to initially higher MA-evoked DA responses, and (4) Testosterone fails to convert juvenile males into adults with regard to MA effects.     

Cold restraint alters dopamine metabolism in frontal cortex, nucleus accumbens and neostriatum

The concentrations of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) were assayed in the striatum, nucleus accumbens and frontal cortex of rats following 2 hours of cold restraint. The concentration of DA was significantly decreased in both the striatum (-16%) and nucleus accumbens (-41%) relative to unstressed controls. The content of DOPAC was significantly increased in both striatum (+56%) and frontal cortex (+76%), but not in nucleus accumbens. The DOPAC/DA ratio was increased in all three regions, that in frontal cortex approaching three-fold. These results extend earlier findings of an activation by acute stressors of frontal cortex DA metabolism, but suggest an involvement of other DA systems as well. The finding of the greatest response in frontal cortex, and the previous observations that this was the only region to show significant changes, may be ascribed to the suggested lack of presynaptic autoreceptors in this region.     

Aging and sex differences in striatal dopaminergic function

In this report the potassium- (30 mM) and amphetamine- (10 microM) stimulated responses of dopamine (DA) and 3,4-dihydroxy phenylacetic acid (DOPAC) from superfused striatal tissue of female and male mice as sampled at 2, 6, 18 and 24 months of age were compared. When assessed relative to responses obtained from 2-month-old female mice, potassium-stimulated DA output of female mice was significantly decreased at 18 months of age and significantly increased at 24 months of age. In male mice, the only statistically significant change was an increase in potassium-stimulated DA in the 24 versus 2-month-old mice. In response to amphetamine-stimulation, DA responses from striatal tissue of 18-month-old females were significantly decreased and that of 24-month-old mice significantly increased relative to that of the 2-month-old females. In the case of male mice, amphetamine-stimulated DA responses of 6- and 18-month-old mice were significantly decreased compared with responses observed in the 2-month-old males.In addition, amphetamine-stimulated DA responses of the 24-month-old females were significantly greater than the 24-month-old males. In general, the response profiles for DOPAC to potassium and amphetamine stimulation were similar to that of DA for male, but not female, mice. These results demonstrate that sex differences in striatal dopaminergic function are differentially affected by age. Overall, striatal DA responsiveness of female mice shows more extreme age-related changes, particularly between the 2- and 6-month versus the 18- and 24-month-old mice and a discord between DA and DOPAC responses. Such extreme changes may be related to the presence (at 2 and 6 months) versus absence (at 18 and 24 months) of estrous cycles/gonadal steroid hormonal functions in female mice.     

Nomifensine reveals age-related changes in K(+)-evoked striatal DA overflow in F344 rats

To investigate the influence of age-associated changes in DA uptake on measures of potassium-stimulated DA overflow in the striatum, microdialysis was conducted in anesthetized young (6-month-old) versus aged (24-month-old) F344 rats. Extracellular levels of DA, DOPAC, and HVA were measured under basal and potassium-stimulated (10, 25, 50, & 100 mM) conditions. Basal levels of DA and metabolites did not differ significantly between the two age groups. At the 50 and 100 mM concentrations, potassium stimuli significantly increased DA overflow and decreased DOPAC and HVA--effects that did not differ with age. The addition of the DA uptake inhibitor nomifensine (100 microM) to the perfusion solutions revealed differences between the two age groups. Nomifensine augmented potassium-evoked DA overflow at the 50 mM concentration in both groups, but only amplified the effect of the 100 mM concentration in the young animals. The results demonstrate that decreased DA transporter function in aged rats masks age-related differences in K(+)-evoked striatal DA release when microdialysis methods are used, resulting in net equalization of K(+)-evoked striatal DA overflow in young versus aged F344 rats.     

Aging and haloperidol-induced dopamine turnover in the nigro-striatal pathway of C57BL/6J mice

The responsiveness of male C57BL/6J mice to acute haloperidol (2.5 mg/kg, IP) was studied throughout the average adult lifespan (4, 8, 12, 21, 28 months) by effects on dopamine (DA) turnover, as estimated by DA loss after α-methyl-p-tyrosine (AMPT). Previously, striatal receptors for spiroperidol (a related butyrophenone) decreased progressively after 3 months to a loss of 40% by 28 months [29]. Haloperidol treatment (2 hours) accelerated striatal DA turnover similarly in all age groups, by about 100%. The haloperidol-induced accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC) was not significantly impaired in AMPT treated mice with age. These results suggest that the age-related loss of butyrophenone binding sites may not limit acute compensatory responses to blockade of the remaining sites by a large dose of haloperidol. Regional differences in DA metabolism were detected between the substantia nigra (cell bodies and dendrites) and striatum (axonal terminals). Dopamine turnover and DOPAC levels were less in striatum than in substantia nigra; each region had a characteristic DOPAC/DA ratio (nigra, 38%; striatum, 7%); and, DOPAC levels did not precisely covary with DA turnover between regions. The constancy of DOPAC/DA ratios in conrols and after AMPT treatment, in all ages suggests that a constant fraction of DA continued to be released and catabolized to DOPAC despite major decrease of DA after blockade of synthesis of DA.     

Sexual behavior increases dopamine transmission in the nucleus accumbens and striatum of male rats: comparison with novelty and locomotion.

Extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were examined concurrently, using in vivo microdialysis, in the nucleus accumbens and dorsal striatum of sexually active male rats during tests of locomotor activity, exposure to a novel chamber, exposure to sex odors, the presentation of a sexually receptive female, and copulation. DA increased significantly in the nucleus accumbens when the males were presented with a sexually receptive female behind a screen and increased further during copulation. Although DA also increased significantly in the dorsal striatum during copulation, the magnitude of the effect was significantly lower than that observed in the nucleus accumbens. In contrast, forced locomotion on a rotating drum, exposure to a novel chamber, and exposure to sex odors did not increase DA significantly in either region, although both DOPAC and HVA increased significantly in both regions during the locomotion test. These results indicate that novelty or locomotor activity alone cannot account for the increased extracellular DA concentrations observed in the nucleus accumbens of male rats during the presentation of a sexually receptive female behind a screen, nor can they account for the increased DA concentrations observed in both the nucleus accumbens and dorsal striatum of male rats during copulation. The preferential increase in DA transmission in the nucleus accumbens, compared with that in the striatum, suggests that anticipatory and consummatory aspects of sexual activity may belong to a class of naturally occurring events with reward values that are mediated by DA release in the nucleus accumbens.     

Decreased tuberoinfundibular and pituitary dopamine and dihydroxyphenylacetic acid concentrations in rats with estrogen-induced pituitary tumors

The majority of pituitary adenomas are prolactin (PRL)-secreting, but it is still uncertain whether their pathogenesis results from a central nervous system (CNS) disturbance or autonomous lactotroph growth and function. We have measured dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations in rats bearing estradiol-induced PRL-secreting pituitary tumors. Female rats, injected at 3-week intervals with 2 mg estradiol valerate (EV), had increased plasma prolactin concentrations, up to 3 micrograms/ml, at 31 weeks. Inversely, there was a reduction of DA and DOPAC in the median eminence and arcuate nucleus as well as a decreased DOPAC/DA ratio in the arcuate nucleus. DA-containing nuclei in the other parts of the brain were not affected. Anterior pituitary weight increased while its DA concentration decreased during estradiol treatment. In the neurohypophysis, DA concentrations were unchanged while DOPAC and the ratio DOPAC/DA decreased following the estrogen treatment. Our data suggest that rats with primary estrogen-induced PRL-secreting tumors have a defect in the CNS-DA neurotransmission.     

Increased dopamine synthesis in aging substantia nigra neurons.

Striatal dopamine (DA) and metabolite (DOPAC) levels in 8-, 21-, 52- and 104-week-old C57BL mice were compared with those in 11-week-old mice, 20 days after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. DA and DOPAC concentrations expressed relative to striatal wet weight did not change with age. In contrast, DA and DOPAC levels increased almost linearly when values were expressed relative to the proportion of remaining tyrosine hydroxylase-positive (TH+) SNc neurons, reaching a 5-7-fold increase per average remaining TH+ neuron by 104 weeks of age (corresponding to neuronal loss of 70%) relative to that found per average neuron in 8-week-old mice. DA and DOPAC levels per average remaining TH+ SNc neuron following MPTP increased for low doses (neuronal losses less than 42%) but decreased for higher doses (55 and 70% losses) but the DOPAC/DA ratio per SNc neuron increased and was 9-fold higher in the 300 mg/kg MPTP-treated animals in comparison to saline controls. Cytoplasmic TH protein (estimated by somal TH immunodensity) was increased by 45% in SNc somata from mice treated with 150 mg/kg MPTP in comparison to saline controls, and by 63% in 104-week-old mice in comparison to 8-week-old animals. This study provides evidence that an average surviving TH+ SNc neuron compensates for the age-related loss of other SNc neurons by increasing dopamine synthesis similar to younger SNc neurons surviving low levels of toxically induced damage and that the compensation may be in part mediated by increased synthesis of TH.     

Pharmacological investigation on the role of dopamine in the rat locus coeruleus

The role of dopamine (DA) in the rat locus coeruleus (LC) was investigated by determining the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), DA and noradrenaline (NA) in the LC after pharmacological treatments by pargyline, haloperidol, 6-hydroxydopamine (6-OHDA) and desmethylimipramine (DMI). The DA, DOPAC and NA contents of the LC were determined by high pressure liquid chromatography. Fifteen days after 6-OHDA, the DOPAC and NA levels were reduced by 60%, but they remained constant after 6-OHDA + DMI. Pargyline provoked highly significant increases in DA and NA but reduced DOPAC to non-measurable amounts. Haloperidol caused a 54% decrease in the DOPAC levels. Pargyline and haloperidol administered to rats having received 6-OHDA + DMI 15 days before, caused similar effects on DA, DOPAC and NA levels as those in non-treated rats. It is suggested that DOPAC is mainly located in noradrenergic neurons, thus eliminating the possibility of a significant DA cell body population in the rat LC.     

Increased utilization of dopamine in the nucleus accumbens but not in the cerebral cortex after dorsal raphe lesion in the rat

Dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels were estimated in the frontal cortex, the nucleus accumbens and the striatum of the rat after electrolytical lesion of the dorsal raphe nucleus. The efficiency of this lesion was tested by measuring the decline in serotonin (5-HT) levels in the striatum. 5-HT levels were reduced by 90% when compared to those of sham-operated rats 11 days after the lesion. As revealed both by the increase in DOPAC levels and in the DOPAC/DA ratio, the rate of DA utilization was markedly increased in the nucleus accumbens, slightly enhanced in the striatum and in contrast remained unaffected in the frontal cerebral cortex 4 days after the lesion. Changes in DOPAC levels in the nucleus accumbens were also seen 11 and 30 days after the lesion but they were less pronounced than those observed at 4 days. These results suggest that neurons originating from the dorsal raphe and projecting to the ventro-tegmental area are regulating the activity of the meso-nucleus accumbens dopaminergic neurons but not that of the meso-cortical dopaminergic neurons.     

Heterosis for concentrations of dopamine,norepinephrine, their metabolites,and epinephrine in the chick hyperstriatum ventrale,hypothalamus, and optic tectum

A complete diallel cross using both sexes was derived from four parental populations of chickens having divergent developmental rates. This paradigm was used to investigate the genetic architecture of the neurochemicals, norepinephrine (NE), epinephrine (EPI), 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). No sex differences were found for any genetic parameter investigated. Estimates of average line effects, maternal effects, and additive sex linkage were not significant. Highly significant heterosis, in the form of overdominance, was observed for catecholamine and metabolite concentrations. Hybrids exhibited significant line heterosis in the positive direction for NE, while heterosis for MHPG was observed in the negative direction for all crosses. Heterosis for EPI was both line and brain area specific with the hypothalamus showing greatest heterotic effects. DOPAC showed significant heterosis for all lines only in the optic tectum, and DA showed little heterosis specific to any line, cross, or brain area.This research was supported, in part, by a grant from the Pennsylvania Department of Agriculture to GFB (Contract Number ME48005).To whom corrspondence should be addressed at 201 Henning Bldg., Department of Poultry Sciences, The Pennsylvania State University Park, Pennsylvania 16802.     

Effect of sex and age on brain monoamines and spatial learning in rats

The concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites were measured in the prefrontal cortex, caudate-putamen, and hippocampus in young (3 months) and aged (27–31 months) Wistar rats of both sexes. Age-related changes were found in prefrontal NA and HVA/DA ratio, striatal DA and DOPAC/DA ratio, and striatal and hippocampal 5-HT and 5-HIAA/5-HT ratio. Age and sex dependent changes were found in striatal DA and DOPAC/DA ratio, and hippocampal MHPG-SO₄/NA ratio. The aged rats were tested in spatial discrimination and reversal tasks in a T maze. The effects of α₂-agonist medetomidine (3 μg/kg) on the task performance were assessed in relation to individual variation in monoamine metabolism. Medetomidine impaired spatial discrimination learning of the aged rats by interacting with the hippocampal 5-HT turnover. Medetomidine improved reversal learning through an interaction with the striatal DA turnover and reduced the number of perseverative errors after reversal, mainly due to its interaction with the prefrontal NA turnover. It is concluded that the memory enhancing effect of drugs acting through the brain monoamine systems is highly dependent on the stage of degeneration of these systems that show considerable individual variation in aged animals.     

Neurotransmitter levels in two populations of larval Fundulus heteroclitus after methylmercury exposure

The effects of methylmercury (MeHg) exposure on neurotransmitter (NT) levels in larval mummichogs (Fundulus heteroclitus) obtained from a mercury-polluted site (Piles Creek (PC), NJ) and a reference site (Tuckerton (TK), NJ) were examined. Population differences between PC and TK larvae in neurochemical composition and in neurochemical changes in response to MeHg intoxication were found. Heads of untreated PC larvae (7 days posthatch (dph)) contained considerably higher levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) than TK. However, they had comparable levels of serotonin (5-hydroxytryptamine (5-HT)) and 5-hyroxy-3-indoleacetic acid (5-HIAA)/5-HT ratios. Changes in NTs with age were noticed, especially in PC larvae. Exposure of larvae to 10 microg/l MeHg induced neurochemical alterations. A significant increase in DA and 5-HT, as well as depressed dopaminergic and serotonergic activity (i.e. decreased DOPAC/DA, HVA/DA and 5-HIAA/5-HT ratios) were seen in TK larvae. Exposure of PC larvae to 10 microg/l MeHg reduced 5-HT at 14 dph, increased serotonergic activity at 7 dph, and altered dopaminergic activity (i.e. increased DOPAC/DA ratios, but decreased HVA/DA ratios). Changes in DA levels were inconsistent over time. The DA level, which was considerably higher than the control at 7 dph, was significantly lower than the control at 14 dph. For the two populations, the level of 5-HT and serotonergic activity, as well as DOPAC and HVA levels, were correlated with previously noted spontaneous activity. The changes in NT levels after exposure to MeHg are an indication of neurological dysfunction in larvae.     

Comparisons between brain dopaminergic neurons of juvenile and aged rats: sex-related differences.

It is known that several aspects of dopaminergic neurotransmission deteriorate with advanced age. In the present report, we have studied the possible existence of sexual differences in these aging-induced changes. Thus, we measured several pre- and postsynaptic biochemical parameters, indicative of the activity of dopaminergic neurons, in striatum, limbic forebrain and hypothalamic-anterior pituitary area of aged (24-26 months) and young (2 months) rats of both sexes. Tyrosine hydroxylase (TH) activity, as well as the number of D2-dopaminergic receptors, decreased in the striatum of aged rats, especially in the males in which the decrease in the number of receptors was associated with an increase in their affinity. In addition, the ratio between dopamine (DA) and its intraneuronal metabolite, L-3,4-dihydroxyphenyl-acetic acid (DOPAC), which can be used as an index of neurotransmitter turnover, was increased in aged females in parallel with a decreased DA content. In the limbic forebrain, TH activity was also decreased during aging, but only in males, whereas the DOPAC/DA ratio was increased in females, although in parallel with an increased DOPAC production. Finally, in the hypothalamic-anterior pituitary area, aging only affected the females, in which increased plasma prolactin levels were observed. This effect might be the result of a low responsiveness of pituitary lactotrophs to DA released from hypothalamic neurons, in spite of high prolactin levels producing a constant, although ineffective, stimulation of the activity of these neurons, as reflected by the high DOPAC content and DOPAC/DA ratio observed in the medial basal hypothalamus. In summary, these data allow us to suggest that the activity of brain dopaminergic neurons is modified with aging and there are significant differences as a function of sex and brain area.     

Changes in monoamines and their metabolite levels in some brain regions of aged rats

The concentrations of dopamine (DA) norepinephrine (NE), serotonin (5HT) and their metabolites, HVA, DOPAC, MHPG-SO4 and 5HIAA were measured in several brain areas of rats aged 4, 18 and 29 months. Dopamine and its metabolites showed a decline, statistically correlated with age, in all the dopaminergic areas considered, indicating that this system is profoundly affected in the senescent rat. The changes in the noradrenergic system were more complex. This neurotransmitter was reduced in spinal cord and in limbic area, but was not modified in hippocampus, cerebellum, striatum and s. nigra. In cortex, MHPG-SO4, the main NE metabolite, showed a significantly age-related increase. Tyrosine hydroxylase (TH) activity was low in striatum, and brainstem but not in hypothalamus of aged rats. Neither 5HT nor its metabolites was affected by age. The results indicate that central catecholaminergic systems are markedly affected in senescent rats.     

Age-related changes in nigrostriatal dopaminergic function in heterozygous mutant dopamine transporter knock-out mice

In this report we compared three different parameters of nigrostriatal dopaminergic (NSDA) function – locomotor activity, striatal dopamine (DA) levels and 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratios between heterozygous mutant dopamine transporter mice (+/− DAT) and their wild type controls (+/+ DAT) at three different age range periods: 4–10, 11–17 and 18–24 months of age. Locomotor activity of the +/− DAT mice failed to differ over the three age periods sampled. In +/+ DAT mice a significant decrease in locomotor activity was obtained at the 18–24-month old period compared with scores at the two earlier age periods. In addition, locomotor scores of +/+ DAT mice at 18–24 months of age were significantly decreased as compared with scores of the +/− DAT mice at this age. Striatal DA concentrations of +/− DAT mice also failed to differ over the three age periods sampled, while that of +/+ DAT mice showed significant decreases in striatal DA at 11–17 and 18–24 months of age as compared to their 4–10-month old cohorts. Striatal DOPAC/DA ratios were significantly increased in both +/+ and +/− DAT mice at the 11–17 and 18–24 month age periods as compared with their respective 4–10-month old groups. Striatal DOPAC/DA ratios of +/− DAT mice were significantly greater than that of the +/+ DAT mice at 18–24 months of age. These findings reveal the significance of interactions between a mutation of the dopamine transporter and aging upon NSDA function and the importance of isolating such variables when using knock-out models.     

Regional changes in monoamine metabolism in the aging constant estrous rat

Studies were undertaken to determine levels of monoamines and their metabolites in brain regions in young (3–4 months) normally cycling and old (25–26 month) constant estrous female rats. Dopamine (DA) concentrations were reduced in old rats in the median eminence (ME), medial basal hypothalamus (MBH), preoptic area-anterior hypothalamus (POA-AH) and the striatum. Similarly, concentrations of dihydroxyphenylacetic acid (DOPAC), the major acid metabolite of DA, were reduced significantly in all 4 regions. In the ME, a strong positive correlation was observed between DA and DOPAC concentrations in both young and old rats. Concentrations of norepinephrine (NE) were reduced in old rats in the MBH and POA-AH but not in the ME or striatum. Concentrations of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA) were generally unchanged with age in all of the regions examined. These studies indicate the age-related regional alterations in DA and 5HT metabolism can be monitored by methods which quantitate monoamines and their metabolites.     

Regional changes in monoamine metabolism in the aging constant estrous rat

Studies were undertaken to determine levels of monoamines and their metabolites in brain regions in young (3–4 months) normally cycling and old (25–26 month) constant estrous female rats. Dopamine (DA) concentrations were reduced in old rats in the median eminence (ME), medial basal hypothalamus (MBH), preoptic area-anterior hypothalamus (POA-AH) and the striatum. Similarly, concentrations of dihydroxyphenylacetic acid (DOPAC), the major acid metabolite of DA, were reduced significantly in all 4 regions. In the ME, a strong positive correlation was observed between DA and DOPAC concentrations in both young and old rats. Concentrations of norepinephrine (NE) were reduced in old rats in the MBH and POA-AH but not in the ME or striatum. Concentrations of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA) were generally unchanged with age in all of the regions examined. These studies indicate the age-related regional alterations in DA and 5HT metabolism can be monitored by methods which quantitate monoamines and their metabolites.     

In vivo basal and amphetamine-induced striatal dopamine and metabolite levels are similar in the spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male rats

Nigrostriatal alterations are proposed to partially underlie the hypertension and hyperactivity exhibited by the spontaneously hypertensive rat (SHR). Here, in vivo microdialysis was used to measure baseline and d-amphetamine (AMPH)-stimulated striatal dopamine (DA) and metabolite levels in adult male SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. At approximately 19 weeks of age, baseline levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured after which time, each rat was injected intraperitoneally with 2 mg/kg AMPH and samples were collected for the subsequent 200 min. There were no significant strain differences in baseline levels of DA, HVA, and 5-HIAA. The baseline level of DOPAC was decreased in the WKY relative to the SD. AMPH treatment altered DA, DOPAC, HVA, and 5-HIAA to a similar extent in all strains; thus, there were no significant strain differences, nor did the area under the curve (AUC) for DA levels differ between strains. AUC for DOPAC was significantly smaller for the WKY relative to the SD strain, likely due to the lower baseline level. At the single dose of amphetamine used here, the results indicate that in vivo DA levels in the SHR are similar to the WKY and SD strains.     

Sexual refractoriness and locomotion effects on brain monoamines in the male rat

Serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and norepinephrine (NE) concentrations in seven brain regions were compared in sexually refractory, physically active, and inactive male rats. Also examined were 5-HIAA/5-HT and DOPAC/DA concentration ratios. Sexually refractory males were permitted uninterrupted copulation with successive receptive females until they failed to mount or ejaculate in a set period. Physically active males ran in motor-driven activity wheels except during the postejaculatory refractory periods of experimental animals, and inactive males remained alone in testing arenas. Significant group differences were found only in monoamine concentrations in the medial preoptic area (MPOA) and the medial forebrain bundle (MFB). In the MPOA, 5-HT concentration was elevated in sexually refractory males, as was DA in both refractory and active animals. In the MFB, 5-HT concentration was increased in active males. MFB DOPAC levels of sexually refractory rats significantly correlated inversely with their ejaculation totals, as did MFB and dorsal raphe (DR) NE levels. The results suggest that the MPOA is a forebrain target for inhibitory influences on male rat sexual behavior of ascending serotonergic fibers and that increased MFB 5-HT and MPOA DA may be associated with general activity.