Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry.

BACKGROUND: The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain obscure. Dopamine- and plasticity-related signalling in mesolimbic reward circuitry is implicated in the pathophysiology and aetiology of depression. OBJECTIVE: To determine the impact of a palatable high-fat diet (HFD) on depressive-like behaviour and biochemical alterations in brain reward circuitry in order to understand the neural processes that may contribute to the development of depression in the context of diet-induced obesity (DIO). METHODS: Adult male C57Bl6 mice were placed on a HFD or ingredient-matched, low-fat diet for 12 weeks. At the end of the diet regimen, we assessed anxiety and depressive-like behaviour, corticosterone levels and biochemical changes in the midbrain and limbic brain regions. Nucleus accumbens (NAc), dorsolateral striatum (DLS) and ventral tegmental area dissections were subjected to SDS-PAGE and immunoblotting using antibodies against D1A receptor, D2 receptor, brain-derived neurotrophic factor (BDNF), phospho-DARPP-32(thr75), phospho-CREB and ΔFosB. RESULTS: HFD mice showed significant decreases in open arm time and centre time activity in elevated plus maze and open field tasks, respectively, and increased immobility (behavioural despair) in the forced swim test. Corticosterone levels following acute restraint stress were substantially elevated in HFD mice. HFD mice had significantly higher D2R, BDNF and ΔFosB, but reduced D1R, protein expression in the NAc. Notably, the expression of BDNF in both the NAc and DLS and phospho-CREB in the DLS was positively correlated with behavioural despair. CONCLUSIONS: Our results demonstrate that chronic consumption of high-fat food and obesity induce plasticity-related changes in reward circuitry that are associated with a depressive-like phenotype. As increases in striatal BDNF and CREB activity are well implicated in depressive behaviour and reward, we suggest these signalling molecules may mediate the effects of high-fat feeding and DIO to promote negative emotional states and depressive-like symptomology.

Adaptations in brain reward circuitry underlie palatable food cravings and anxiety induced by high-fat diet withdrawal.

OBJECTIVE: To identify the emotional and motivational processes that reinstate palatable food intake following removal of high-fat diet (HFD) and associated neuroadaptations tied to neurochemical and behavioural changes underlying dopaminergic function. METHODS: Adult male C57Bl6 mice were placed on a HFD (58% kcal fat) or ingredient-matched, low-fat diet (LFD; 11% kcal fat) for 6 weeks. At the end of diet-regimen mice were either maintained on their respective diets, or HFD and LFD were replaced with normal chow (withdrawal). Effort-based operant responding for sucrose and high-fat food rewards was measured along with basal and stress-induced corticosterone levels and anxiety (elevated-plus maze). Protein levels for tyrosine hydroxylase (TH), corticosterone releasing factor type 1 receptor (CRF-R1), brain-derived neurotrophic factor (BDNF), phospho-CREB (pCREB) and ΔFosB (truncated splice variant of FosB) were assessed in the amygdala, nucleus accumbens (NAc) and ventral tegmental area (VTA) via western immunoblotting. RESULTS: Six weeks of HFD resulting in significant weight gain elicited sucrose anhedonia, anxiety-like behaviour and hypothalamic-pituitary-adrenocortical axis (HPA) hypersensitivity to stress. Withdrawal from HFD but not LFD-potentiated anxiety and basal corticosterone levels and enhanced motivation for sucrose and high-fat food rewards. Chronic high-fat feeding reduced CRF-R1 and increased BDNF and pCREB protein levels in the amygdala and reduced TH and increased ΔFosB protein in NAc and VTA. Heightened palatable food reward in mice withdrawn from HFD coincided with increased BDNF protein levels in NAc and decreased TH and pCREB expression in the amygdala. CONCLUSION: Anhedonia, anxiety and sensitivity to stressors develops during the course of HFD and may have a key role in a vicious cycle that perpetuates high-fat feeding and the development of obesity. Removal of HFD enhances stress responses and heightens vulnerability for palatable foods by increasing food-motivated behaviour. Lasting changes in dopamine and plasticity-related signals in reward circuitry may promote negative emotional states, overeating and palatable food relapse.

Training environment and Vitamin D status in athletes.

This study assessed the associations between gender, anthropometry, predominant training environment and Vitamin D status in 72 elite athletes. Additionally, any links between Vitamin D status and recent injury/health status, or sun protection practices were investigated. Athletes underwent an anthropometric assessment and provided venous blood samples for the determination of 25-hydroxyvitamin D (25(OH)D), the accepted biological marker of Vitamin D status. Finally, athletes completed a questionnaire relating to their recent training and injury history, and their sun protection practices. The athlete cohort were divided by predominant training environment as either indoor, outdoor, or mixed training environment athletes. The average ( ± SD) 25(OH)D levels of the group were 111 ± 37 nmol/L, with the indoor training group (90 ± 28 nmol/L) significantly lower than the outdoor (131 ± 35 nmol/L), and mixed (133 ± 29 nmol/L) training groups (p = 0.0001). Anthropometrical measures were positively associated with 25(OH)D levels; however, recent injury status or sun protection practice showed no association. Given the significant differences in 25(OH)D levels between the outdoor and indoor predominant training environments, coaches of indoor athletes may wish to monitor their athletes' Vitamin D levels throughout the year, in order to avoid any possibilities of a deficiency occurring.

Residence times of groundwater along a flow path in the Great Artesian Basin determined by 81Kr, 36Cl and 4He: Implications for palaeo hydrogeology.

Understanding the age distribution of groundwater can provide information on both the recharge history as well as the geochemical evolution of groundwater flow systems. Of the few candidates available that can be used to date old groundwater, 81Kr shows the most promise because its input function is constant through time and there are less sources and sinks to complicate the dating procedure in comparison to traditional tracers such as 36Cl and 4He. In this paper we use 81Kr in a large groundwater basin to obtain a better understanding of the residence time distribution of an unconfined-confined aquifer system. A suite of environmental tracers along a groundwater flow path in the south-west Great Artesian Basin of Australia have been sampled. All age tracers (85Kr, 39Ar 14C, 81Kr, 36Cl and 4He) display a consistent increase in groundwater age with distance from the recharge area indicating the presence of a connected flow path. Assuming that 81Kr is the most accurate dating technique the 36Cl/Cl systematics was unravelled to reveal information on recharge mechanism and chloride concentration at the time of recharge. Current-day recharge occurs via ephemeral river recharge beneath the Finke River, while diffuse recharge is minor in the young groundwaters. Towards the end of the transect the influence of ephemeral recharge is less while diffuse recharge and the initial chloride concentration at recharge were higher.

Subchronic JP-8 jet fuel exposure enhances vulnerability to noise-induced hearing loss in rats.

Both laboratory and epidemiological studies published over the past two decades have identified the risk of excess hearing loss when specific chemical contaminants are present along with noise. The objective of this study was to evaluate the potency of JP-8 jet fuel to enhance noise-induced hearing loss (NIHL) using inhalation exposure to fuel and simultaneous exposure to either continuous or intermittent noise exposure over a 4-wk exposure period using both male and female Fischer 344 rats. In the initial study, male (n = 5) and female (n = 5) rats received inhalation exposure to JP-8 fuel for 6 h/d, 5 d/wk for 4 wk at concentrations of 200, 750, or 1500 mg/m³. Parallel groups of rats also received nondamaging noise (constant octave band noise at 85 dB(lin)) in combination with the fuel, noise alone (75, 85, or 95 dB), or no exposure to fuel or noise. Significant concentration-related impairment of auditory function measured by distortion product otoacoustic emissions (DPOAE) and compound action potential (CAP) threshold was seen in rats exposed to combined JP-8 plus noise exposure when JP-8 levels of 1500 mg/m³ were presented with trends toward impairment seen with 750 mg/m³ JP-8 + noise. JP-8 alone exerted no significant effect on auditory function. In addition, noise was able to disrupt the DPOAE and increase auditory thresholds only when noise exposure was at 95 dB. In a subsequent study, male (n = 5 per group) and female (n = 5 per group) rats received 1000 mg/m³ JP-8 for 6 h/d, 5 d/wk for 4 wk with and without exposure to 102 dB octave band noise that was present for 15 min out of each hour (total noise duration 90 min). Comparisons were made to rats receiving only noise, and thosereceiving no experimental treatment. Significant impairment of auditory thresholds especially for high-frequency tones was identified in the male rats receiving combined treatment. This study provides a basis for estimating excessive hearing loss under conditions of subchronic JP-8 jet fuel exposure.

Neurosystems linking corticolimbic and hypothalamic pathways in energy balance: view from the Chair.

Recent work has advanced our knowledge of the neural pathways interfacing corticolimbic substrates of food motivation and reward with hypothalamic controls of food intake. As a neuroanatomical interface between limbic motivational processes, energy-sensing mechanisms in the mediobasal hypothalamus and motor output pathways, several studies draw attention to the lateral hypothalamus. Reviewed here are some highlights of the first session of the 11th International Symposium of the Merck-Frosst/CIHR Obesity Research Chair held in Quebec City on 5 November 2008 describing the neuroanatomical and neurochemical crosstalk between hypothalamic, midbrain and limbic sites and their role in energy balance.

Modulation of brain reward circuitry by leptin.

Leptin, a hormone secreted by fat cells, suppresses food intake and promotes weight loss. To assess the action of this hormone on brain reward circuitry, changes in the rewarding effect of lateral hypothalamic stimulation were measured after leptin administration. At five stimulation sites near the fornix, the effectiveness of the rewarding electrical stimulation was enhanced by chronic food restriction and attenuated by intracerebroventricular infusion of leptin. In contrast, the rewarding effect of stimulating neighboring sites was insensitive to chronic food restriction and was enhanced by leptin in three of four cases. These opposing effects of leptin may mirror complementary changes in the rewarding effects of feeding and of competing behaviors.

Reactance and elastance as measures of small airways response to bronchodilator in asthma.

Bronchodilation alters both respiratory system resistance (Rrs) and reactance (Xrs) in asthma, but how changes in Rrs and Xrs compare, and respond differently in health and asthma, in reflecting the contributions from the large and small airways has not been assessed. We assessed reversibility using spirometry and oscillometry in healthy and asthma subjects. Using a multibranch airway-tree model with the mechanics of upper airway shunt, we compared the effects of airway dilation and small airways recruitment to explain the changes in Rrs and Xrs. Bronchodilator decreased Rrs by 23.0 (19.0)% in 18 asthma subjects and by 13.5 (19.5)% in 18 healthy subjects. Estimated respiratory system elastance (Ers) decreased by 23.2 (21.4)% in asthma, with no significant decrease in healthy subjects. With the use of the model, airway recruitment of 15% across a generation of the small airways could explain the changes in Ers in asthma with no recruitment in healthy subjects. In asthma, recruitment accounted for 40% of the changes in Rrs, with the remaining explained by airway dilation of 6.8% attributable largely to the central airways. Interestingly, the same dilation magnitude explained the changes in Rrs in healthy subjects. Shunt only affected Rrs of the model. Ers was unaltered in health and unaffected by shunt in both groups. In asthma, Ers changed comparably to Rrs and could be attributed to small airways, while the change in Rrs was split between large and small airways. This implies that in asthma Ers sensed through Xrs may be a more effective measure of small airways obstruction and recruitment than Rrs.NEW & NOTEWORTHY This is the first study to quantify to relative contributions of small and large airways to bronchodilator response in healthy subjects and patients with asthma. The response of the central airways to bronchodilator was similar in magnitude in both study groups, whereas the response of the small airways was significant among patients with asthma. These results suggest that low-frequency reactance and derived elastance are both sensitive measures of small airway function in asthma.

Complete nucleotide sequence of a mouse VL30 retro-element.

The complete nucleotide sequence of a mouse retro-element is presented. The cloned element is composed of 4,834 base pairs (bp) with long terminal repeats of 568 bp separated by an internal region of 3,698 bp. The element did not appear to have any open reading frames that would be capable of encoding the functional proteins that are normally produced by retro-elements. However, some regions of the genome showed some homology to retroviral gag and pol open reading frames. There was no region in VL30 corresponding to a retroviral env gene. This implies that VL30 is related to retrotransposons rather than to retroviruses. The sequence also contained regions that were homologous to known reverse transcriptase priming sites and viral packaging sites. These observations, combined with the known transcriptional capacity of the VL30 promoter, suggest that VL30 relies on protein functions of other retro-elements, such as murine leukemia virus, while maintaining highly conserved cis-active promoter, packaging, and priming sites necessary for its replication and cell-to-cell transmission.

Gender differences in human immunodeficiency virus (HIV) RNA and CD4 cell counts among new entrants to HIV care.

Clinic database extraction identified 806 new entrants to human immunodeficiency virus (HIV) care in Cleveland, OH, USA. At entry, women had higher CD4 counts and lower HIV RNA levels than men (mean, 388 vs. 310 cells/microL, and 8.94 x 10(4) vs. 1.27 x 10(5) copies/mL, respectively), but the proportion of entrants with category C illnesses, category B conditions, sexually transmitted diseases and CD4 counts < 200 microL did not differ between genders. Hepatitis B seroprevalence was higher in men (8.7% vs. 0.6%), but there was no difference in hepatitis C prevalence. Whether women in Cleveland seek HIV care earlier, or whether early markers of HIV disease differ between the genders, remains to be determined.

National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000.

OBJECTIVE: Our goal was to provide health-care providers, patients, and the general public with an assessment of currently available data regarding the use of adjuvant therapy for breast cancer. PARTICIPANTS: The participants included a non-Federal, non-advocate, 14-member panel representing the fields of oncology, radiology, surgery, pathology, statistics, public health, and health policy as well as patient representatives. In addition, 30 experts in medical oncology, radiation oncology, biostatistics, epidemiology, surgical oncology, and clinical trials presented data to the panel and to a conference audience of 1000. EVIDENCE: The literature was searched with the use of MEDLINE(TM) for January 1995 through July 2000, and an extensive bibliography of 2230 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Evidence from randomized clinical trials and evidence from prospective studies were given precedence over clinical anecdotal experience. CONSENSUS PROCESS: The panel, answering predefined questions, developed its conclusions based on the evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov. CONCLUSIONS: The panel concludes that decisions regarding adjuvant hormonal therapy should be based on the presence of hormone receptor protein in tumor tissues. Adjuvant hormonal therapy should be offered only to women whose tumors express hormone receptor protein. Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status. The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. Available data are currently inconclusive regarding the use of taxanes in adjuvant treatment of lymph node-positive breast cancer. The use of adjuvant dose-intensive chemotherapy regimens in high-risk breast cancer and of taxanes in lymph node-negative breast cancer should be restricted to randomized trials. Ongoing studies evaluating these treatment strategies should be supported to determine if such strategies have a role in adjuvant treatment. Studies to date have included few patients older than 70 years. There is a critical need for trials to evaluate the role of adjuvant chemotherapy in these women. There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary cancer. Currently, the role of postmastectomy radiotherapy for patients with one to three positive lymph nodes remains uncertain and should be tested in a randomized controlled trial. Individual patients differ in the importance they place on the risks and benefits of adjuvant treatments. Quality of life needs to be evaluated in selected randomized clinical trials to examine the impact of the major acute and long-term side effects of adjuvant treatments, particularly premature menopause, weight gain, mild memory loss, and fatigue. Methods to support shared decision-making between patients and their physicians have been successful in trials; they need to be tailored for diverse populations and should be tested for broader dissemination.

Experiments and calculations concerning a thermal enzyme probe.

A simple device capable of measuring almost any reactant in an enzyme-catalyzed reaction is created when an enzyme is immobilized onto one thermal sensor of a differential thermometer. Experiments are described in which two thermistors, one bare and one coated with immobilized enzyme, are immersed in a well-stirred solution. The response of this device to increases in glucose-ATP concentration was observed using hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1), and to increases in glucose concentration using glucose oxidase (beta-D-glucose:oxygen 1-oxidoreductase, EC 1.1.3.4). A simple model is presented whose predictions are in reasonable agreement with the experimental results.

Large-scale processing of macromolecules.

Over the past year, a number of advances have been made in the large-scale purification of macromolecules, particularly proteins. Although refinements to individual unit operations have occurred, especially in improving the speed of operation and performance of large-scale chromatographic media, a major research thrust has been the development of processes in which steps are combined or eliminated to improve operability and reduce cost.

Preparative peptide purification by cation-exchange and reversed-phase perfusion chromatography.

Cation exchange was compared to reversed-phase chromatography for the preparative purification of a 28-residue peptide (vasoactive intestinal polypeptide) on the 100-mg scale. Optimized high-speed, high-resolution methods were developed for both chromatographic modes on POROS Perfusion Chromatography flow-through particle chromatography columns. While both methods appeared to provide similar purity, the cation exchange column had approximately ten times the loading capacity per unit column volume as the reversed-phase column. Five-minute methods for desalting the cation exchange-purified peptide and analysis of fractions were developed using small reversed-phase columns. The cation-exchange method was scaled up to process 95 mg of crude peptide in a 12-min run.

Antibody quantitation in seconds using affinity Perfusion Chromatography.

An extremely rapid assay technique for antibodies has been developed utilizing protein A or protein G bound to Perfusion Chromatography support matrices. Either dilute or concentrated samples are directly injected on a column that selectively binds antibody, which is quantitated directly by elution and UV absorbance. Due to the unique mass transport characteristics of the supports, total assay cycle times are typically 1 minute or less, with assays as short as 15 seconds possible. The assay system can accurately quantitate a 100,000:1 or greater dynamic range in sample concentration without sample dilution, is extremely repeatable and is easy to automate with conventional HPLC systems. Assay of antibodies in a wide range of sample types has been demonstrated.

Ultrafiltration vs equilibrium dialysis for determination of free fraction.

The analytical basis of membrane separation in determining plasma free drug concentrations is developed from consideration of the generalised ideal mass action and conservation laws applied to thermodynamic states of differing component volumes. The intuitively surprising theoretical independence of free drug concentration with changing fractional volume of protein predicts the equivalence of final free drug concentration after uniform pre-dilution with that after equilibrium dialysis against the same volume of buffer. Similarly, the ultrafiltrate free concentration of drugs in ideal plasma binding equilibrium is theoretically constant, regardless of the extent of reduction in fractional volume of binding protein during filtration. The pitfalls in calculating free and bound fraction and concentration from equilibrium dialysis are reviewed and expressions presented to correct the major artefacts. The dilution behaviour of drugs is predicted from the normalised mass action model. Practical aspects of validating ultrafiltration free drug levels using equilibrium dialysis are outlined.

Tumor necrosis factor-alpha affects in vitro hormone production by JEG-3 choriocarcinoma cell cultures.

Steroid hormones, produced by the placenta, appear to be critically important in maintaining the pregnancy of experimental animals and possibly humans. Previous studies in our laboratory have shown that macrophage-conditioned media, which are known to contain several cytokines including tumor necrosis factor-alpha (TNF-alpha), decreased the in vitro synthesis of progesterone (P) and increased the synthesis of estradiol (E2) by placental fragments. The present study was designed to further our understanding of the effect of cytokines on the synthesis of placental trophoblast hormones. The current study shows that TNF-alpha (1-20 ng/ml) decreases the in vitro synthesis of P and increases the synthesis of both E2 and human chorionic gonadotropin (hCG) by JEG-3 choriocarcinoma cells (a model for trophoblast hormone synthesis). The effects of TNF-alpha are independent of changes in formation of adenosine 3':5' cyclic-monophosphate, guanosine 3':5' cyclic-monophosphate, prostaglandin E2, and prostaglandin F2 alpha. However, the effect of TNF-alpha on P formation is blocked by cycloheximide (1 microgram/ml). These observations suggest TNF-alpha could have effects on placental hormone synthesis which might be important in the pathogenesis of both normal and preterm labor. At least some of these effects appear mediated through new protein synthesis.

Metastases to temporal bones from primary nonsystemic malignant neoplasms.

OBJECTIVES: To compare histopathological and clinical findings of metastasis to the temporal bone with previous reports and to determine the prevalence of these metastases in patients with nonsystemic cancer. STUDY DESIGN: Retrospective. METHODS: Autopsy records of 864 patients were screened to select those with primary nondisseminated malignant neoplasms. These were evaluated histopathologically for metastasis to and site of involvement within the temporal bone, and histological characteristics of the tumor. Clinical records and autopsy reports were reviewed for demographic data, clinical course, otologic and vestibular manifestations, site of primary and its histological features, extent of metastasis, and mode of spread. RESULTS: Of 212 patients with primary nondisseminated malignant neoplasms, 47 had metastases to the temporal bone (76 temporal bones). Twenty different primary tumors had metastasized, most commonly breast cancer. Hearing loss was the most common otologic symptom (seen in 19 patients [40%]), while 17 (36%) had no otologic or vestibular symptoms. Temporal bone involvement was bilateral in 29 patients (62%). Most metastases to the temporal bone demonstrated hematogenous spread in 58 temporal bones (76.7%), and petrous apex was the most common site of metastases in 63 temporal bones (82.9%). Temporal bone metastases were not observed in cases where the primary tumor was adequately treated. CONCLUSIONS: In the largest series to date, we found temporal bone metastases more frequently than previously reported. Absence of temporal bone involvement in cases in which the primary tumor was adequately treated stresses the need for early management of cancer. Metastatic disease must be considered as a cause of hearing loss in patients with a history of malignant neoplasm.

Turn-taking and speech act patterns in the discourse of senile dementia of the Alzheimer's type patients.

Conversational discourse patterns of 11 normal elderly and 11 senile dementia of the Alzheimer's type (SDAT) patients engaged in dyadic interaction with an examiner were examined. Differences in word usage, turn taking, and speech act production were investigated both for the two-subject groups and for the examiner's conversations with each group. Compensatory shifts in discourse by participants are identified. For the subject, differences were shown on words per turn with SDAT subjects speaking in shorter turns and in nonverbal responses with SDAT subjects using this strategy more frequently. Speech act categories of Requestives and Assertives also differed with SDAT subjects using more Requestives and fewer Assertives. The SDAT subjects had significantly more occurrences of unintelligible utterances. For the examiner, words per turn differed with the examiner using shorter turns with SDAT subjects. No differences were shown in the examiner's patterns of speech act usage, nonverbal responses, or intelligibility. In general, these results indicate significant discourse differences in the words per turn level for all participants and speech act levels of conversation for SDAT subjects. They also indicate generally maintained interaction patterns by speakers so that the discourse genre of conversation is sustained. The pattern of compensatory shifts in discourse suggests retained flexibility in the communication system of early and mid stage SDAT patients.

Hypothalamic-pituitary-ovarian interactions during reproductive senescence in the rat.

The neuroendocrine status of Long-Evans female rats was evaluated at several key stages of reproductive senescence. Young (4-8 mo), middle-aged (10-14 mo) and old (24-30 mo) animals were studied according to reproductive state. The reproductive states studied were (1) regularly cycling, (2) constant estrus and (3) pseudopregnant, as determined by vaginal smear cytology. Neuroendocrine parameters at the levels of the hypothalamus, pituitary and steroid-producing organs were compared between each group. DA3, E and NE concentrations in the median eminence of the hypothalamus were determined by a highly sensitive radioenzymatic assay. LRF content in the median eminence was measured by radioimmunoassay. Circulating levels of LH, FSH, PRL and six steroids were determined. Changes in hormone and neurotransmitter concentrations were deomonstrated in association with the various stages of reproductive senescence and with age advancement. These changes involved the hypothalamic, pitiutary and steroid systems. NE content in the median eminence, FSH in serum and circulating androstenedione were all significantly increased in middle-aged, cyclic rats prior to the onset of senescent anovulation. DA concentration in 24 mo. old constant estrous rats (30.7 +/- 7.7 pg/microgram, N = 6) and in 30 mo. old pseudopregnant rats (27.5 +/- 7.1 pg/microgram, N = 6) was significantly reduced compared to young (6 mo. old), cyclic controls on proestrous (55.0 +/- 4.7 pg/microgram, N = 12). This DA reduction was associated with a 3-fold increase in circulating prolactin. The results are discussed in terms of a regulatory cascade model of female reproductive senescence (Finch, 1976).