CIRCUIT AND PHARMACOLOGICAL APPROACHES FOR COUNTERACTING STRESS EFFECTS ON THE DOPAMINE SYSTEM: IMPLICATIONS FOR MAJOR DEPRESSION

Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Evidence from clinical and preclinical models suggests that an important component to MDD is dysfunction in the mesolimbic dopamine reward system. This thesis focused on better understanding the brain circuits potentially involved in driving this dopamine system dysfunction, as well as mechanisms of an antidepressant therapy that directly acts on the dopamine system. We used the chronic mild stress (CMS) rodent model of depression, which features a prominent hypodopaminergic phenotype, to answer two specific questions: 1) How do brain regions with identified involvement in MDD based on clinical literature regulate the dopamine system in normal and CMS-exposed rats; and 2) What effect does the atypical antipsychotic agent quetiapine have on normal and CMS-exposed rats with acute and repeated administration? In each case, we performed single-unit recordings of identified ventral tegmental area (VTA) dopamine neurons to assess the dopamine system’s functional status. For question 1, we found that activation of the Infralimbic Prefrontal Cortex (ILPFC; rodent homologue of human Brodmann Area 25) and Lateral Habenula (LHb) in normal rodents each inhibits a distinct subset of dopamine neurons based on their location in the VTA, that those inhibited by the ILPFC have greater overlap with those inhibited by CMS than do those inhibited by the LHb, and that ILPFC but not LHb inactivation following CMS restores dopamine system function to normal levels. For question 2, we found that quetiapine has distinct effects on the dopamine system based on duration of administration and history of exposure to CMS, with only repeated quetiapine administration restoring dopamine system function in CMS-exposed rats. Together, these results offer insight to clinically relevant questions regarding interactions among brain regions mediating hedonic and affective processes, as well as highlight potential dopaminergic mechanisms of novel antidepressant therapies

Divergent effects of acute and repeated quetiapine treatment on dopamine neuron activity in normal vs. chronic mild stress induced hypodopaminergic states

Abstract Clinical evidence supports the use of second-generation dopamine D2 receptor antagonists (D2RAs) as adjunctive therapy or in some cases monotherapy in patients with depression. However, the mechanism for the clinical antidepressant effect of D2RAs remains unclear. Specifically, given accumulating evidence for decreased ventral tegmental area (VTA) dopamine system function in depression, an antidepressant effect of a medication that is expected to further reduce dopamine system activity seems paradoxical. In the present paper we used electrophysiological single unit recordings of identified VTA dopamine neurons to characterize the impact of acute and repeated administration of the D2RA quetiapine at antidepressant doses in non-stressed rats and those exposed to the chronic mild stress (CMS) rodent depression model, the latter modeling the hypodopaminergic state observed in patients with depression. We found that acute quetiapine increased dopamine neuron population activity in non-stressed rats, but not in CMS-exposed rats. Conversely, repeated quetiapine increased VTA dopamine neuron population activity to normal levels in CMS-exposed rats, but had no persisting effects in non-stressed rats. These data suggest that D2RAs may exert their antidepressant actions via differential effects on the dopamine system in a normal vs. hypoactive state. This explanation is supported by prior studies showing that D2RAs differentially impact the dopamine system in animal models of schizophrenia and normal rats; the present results extend this phenomenon to an animal model of depression. These data highlight the importance of studying medications in the context of animal models of psychiatric disorders as well as normal conditions

Progesterone: Examination of its postulated inhibitory actions on lordosis during the rat estrous cycle

Three experiments tested whether the inhibitory effects of progesterone could be of physiological significance in regulating the duration of behavioral estrus in female rats. In animals displaying 5 day estrous cycles, a second period of sexual receptivity, one day following the occurrence of spontaneous estrus, could be induced by exogenous hormone administration, regardless of whether the ovaries were intact or were removed during the period over which the exogenous hormones were acting. In a second experiment, acute ovariectomy at various times during the progesterone surge acted only to degrade the quality of receptive behavior subsequently observed, never to enhance it by removing a postulated inhibitory influence. In the final experiment there was some suggestion that progesterone's facilitating effect on lordosis during the later portions of spontaneous estrus were attenuated by prior exposure to ovarian secretions during the early period of behavioral estrus. Our results are consistent with the hypothesis that the duration of receptive behavior under physiological conditions is not primarily regulated by inhibitory actions of progesterone, but rather by the quantity and duration of estrogen secretions during the conditioning period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21689/1/0000080.pd

A Consideration of Biomarkers to be Used for Evaluation of Inflammation in Human Nutritional Studies

To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammatio

Brain imaging and human nutrition: which measures to use in intervention studies?

The present review describes brain imaging technologies that can be used to assess the effects of nutritional interventions in human subjects. Specifically, we summarise the biological relevance of their outcome measures, practical use and feasibility, and recommended use in short- and long-term nutritional studies. The brain imaging technologies described consist of MRI, including diffusion tensor imaging, magnetic resonance spectroscopy and functional MRI, as well as electroencephalography/magnetoencephalography, near-IR spectroscopy, positron emission tomography and single-photon emission computerised tomography. In nutritional interventions and across the lifespan, brain imaging can detect macro- and microstructural, functional, electrophysiological and metabolic changes linked to broader functional outcomes, such as cognition. Imaging markers can be considered as specific for one or several brain processes and as surrogate instrumental endpoints that may provide sensitive measures of short- and long-term effects. For the majority of imaging measures, little information is available regarding their correlation with functional endpoints in healthy subjects; therefore, imaging markers generally cannot replace clinical endpoints that reflect the overall capacity of the brain to behaviourally respond to specific situations and stimuli. The principal added value of brain imaging measures for human nutritional intervention studies is their ability to provide unique in vivo information on the working mechanism of an intervention in hypothesis-driven research. Selection of brain imaging techniques and target markers within a given technique should mainly depend on the hypothesis regarding the mechanism of action of the intervention, level (structural, metabolic or functional) and anticipated timescale of the intervention's effects, target population, availability and costs of the technique

Randomised Controlled Trial of Antiglucocorticoid Augmentation (Metyrapone) of Antidepressants in Depression (Add Study)

Background: Depressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of antiDepressants in Depression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD. Objective: To determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD. Methods: A total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants. Results: The estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 [95% confidence interval (CI) –3.48 to 2.46]; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures. Discussion: The inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes. Conclusions: The results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia. Trial registration: Current Controlled Trials ISRCTN45338259. Funding details: This study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership

Ovarian Estradiol And Progesterone Regulation Of Sexual Receptivity Of Female Rats.

Ph.D.PsychobiologyPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127563/2/8106195.pd

Vitamin K supplementation does not prevent bone loss in ovariectomized Norway rats

Abstract Background Despite plausible biological mechanisms, the differential abilities of phylloquinone (PK) and menaquinones (MKn) to prevent bone loss remain controversial. The objective of the current study was to compare the effects of PK, menaquinone-4 (MK-4) and menaquinone-7 (MK-7) on the rate of bone loss in ovariectomized (OVX) Norway rats. A secondary aim was to compare the effects of vitamin K with those of bisphosphonates (BP) on bone loss. Methods Rats (n = 96) were randomized to 6 dosing groups [n = 16/group; Sham; OVX; OVX + BP (100 μg/kg/100 μg/mL saline sc); OVX + PK; OVX + MK-4; and OVX + MK-7] for 6 wk. Equimolar daily doses of 107 mg PK/kg, 147 mg MK-4/kg, and 201 mg MK-7/kg diet were provided. Results BP significantly increased bone strength and bone mineral density (BMD) vs. OVX (P Conclusion PK, MK-4, and MK-7 do not appear to prevent bone loss in OVX rats when administered concurrent with adequate intake of other nutrients.</p

Effects of acute ovariectomy on the lordosis response of female rats

The sexual receptivity of intact females with 4- or 5-day estrous cycles was compared to that of other females which had been ovariectomized at particular times during their cycles. The quality and frequency of lordosis responding were more degraded the earlier during the cycle ovariectomy was performed. This effect was more pronounced in 4-day than in 5-day cyclic females. Because exogenous progesterone was administered to all ovariectomized females, these behavioral deficits were attributed to removal of ovarian estradiol. Ovariectomy 6 hr before the critical period for luteinizing hormone release significantly shortened the duration of behavioral estrus, even though it had no effect when lordosis was tested at the time intact estrous females are maximally receptive. These findings are consistent with the hypothesis that the continual availability of estradiol throughout the 18-24 hr interval prior to the onset of behavioral estrus is essential for optimal conditioning of sexual receptivity to occur under physiological conditions. The relevance of triggering and maintenance functions of estradiol to these results is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22863/1/0000425.pd