Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio-molecular substrates and genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict the occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4-methylenedioxymethamphetamine; “ecstasy” (MDMA), morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity and sleep/wake cycles. All traits have been measured in both sexes in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.

Termination of serotonergic transmission is the function of the plasma membrane 5-hydroxytryptamine (serotonin, 5-HT) transporter (SERT), which is also a high-affinity target in vivo for antidepressants, amphetamines, and cocaine. Studies show that SERT is regulated by protein kinase-and phosphataselinked pathways. In contrast, receptor-linked modulation of SERT is only minimally defined. Because noradrenergic stimulation is reported to influence 5-HT release, we explored possible presynaptic adrenoceptor-mediated regulation of SERT. In mouse forebrain synaptosomes, ␣ 2 -adrenoceptor agonists, particularly 5-bromo-N-[4,5-dihydro-1H-imidazol-2-yl]-6-quinoxalinamine (UK14304), triggered a concentration-and timedependent decrease in 5-HT transport. In contrast, 5-HT uptake was unaffected by pharmacological ␣ 1 -adrenoceptor activation. Kinetically, UK14304 significantly decreased the apparent substrate affinity, K m without altering transport capacity, V max . At concentrations of UK14304 supporting maximal inhibition of SERT in synaptosomes, no effect on SERT in transfected cells was observed, suggesting that UK14304 acts indirectly to reduce SERT activity. The effect of UK14304 on 5-HT uptake was not shared by other Na ϩ and Cl Ϫ -dependent transporters. UK14304-mediated inhibition of SERT function was yohimbine-sensitive, as was inhibition triggered by norepinephrine, and was abolished in the absence of added Ca 2ϩ . Moreover, UK14304 effects were attenuated by voltage-sensitive Ca 2ϩ channel antagonists, consistent with a role for Ca 2ϩ in UK14304 effects. In agreement with altered 5-HT transport activity in vitro, in vivo chronoamperometry studies revealed that UK14304 significantly prolonged 5-HT clearance. Our findings suggest that UK14304 modulates SERT function in vitro and in vivo via signaling pathways, possibly supported by an influx of Ca 2ϩ through voltage-sensitive Ca 2ϩ channels.It is well established that perturbation in monoaminergic transmission is a contributing factor in depression (Malison et al., 1998;Frazer, 2000). Consistent with these findings, the therapeutic actions of the first generation of antidepressants, the tricyclics, most likely exert their therapeutic actions by blocking the neuronal uptake of 5-hydroxytryptamine (serotonin, 5-HT) and/or norepinephrine (NE) (Barker and Blakely, 1995). In the central nervous system (CNS), 5-HT, and NE systems are themselves intimately connected. Electron microscopic autoradiography studies have provided evidence that serotonergic neurons in the rat dorsal raphe receive direct input from noradrenergic neurons (Baraban and Aghajanian, 1981). In addition, in vivo microdialysis studies (Numazawa et al., 1995;Gobert et al., 1998) and release experiments in brain slices (Scheibner et al., 2001) and synaptosomes (Maura et al., 1992;Gobbi et al., 1993a) have demonstrated that 5-HT release is modulated by the activation of presynaptic ␣ 2 -adrenoceptors. Such an interaction suggests a functional cross talk between the noradrenergic and the seroton...

We recently reported that epicatechin, a bioactive compound that occurs naturally in various common foods, promoted general health and survival of obese diabetic mice. It remains to be determined whether epicatechin extends health span and delays the process of aging. In the present study, epicatechin or its analogue epigallocatechin gallate (EGCG) (0.25% w/v in drinking water) was administered to 20-mo-old male C57BL mice fed a standard chow. The goal was to determine the antiaging effect. The results showed that supplementation with epicatechin for 37 wk strikingly increased the survival rate from 39 to 69%, whereas EGCG had no significant effect. Consistently, epicatechin improved physical activity, delayed degeneration of skeletal muscle (quadriceps), and shifted the profiles of the serum metabolites and skeletal muscle general mRNA expressions in aging mice toward the profiles observed in young mice. In particular, we found that dietary epicatechin significantly reversed age-altered mRNA and protein expressions of extracellular matrix and peroxisome proliferator-activated receptor pathways in skeletal muscle, and reversed the age-induced declines of the nicotinate and nicotinamide pathway both in serum and skeletal muscle. The present study provides evidence that epicatechin supplementation can exert an antiaging effect, including an increase in survival, an attenuation of the aging-related deterioration of skeletal muscles, and a protection against the aging-related decline in nicotinate and nicotinamide metabolism.-Si, H., Wang, X., Zhang, L., Parnell, L. D., Admed, B., LeRoith, T., Ansah, T.-A., Zhang, L., Li, J., Ordovás, J. M., Si, H., Liu, D., Lai, C.-Q. Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

Parkinson’s Disease (PD) is marked by prominent motor symptoms that reflect striatal dopamine insufficiency. However, non-motor symptoms, including depression, are common in PD. These changes have been suggested to reflect pathological involvement of non-dopaminergic systems. We examined regional changes in serotonin and norepinephrine systems in mice treated with two different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment paradigms and that survived for 3 or 16 weeks after the last MPTP injection. MPTP caused a decrease in striatal dopamine concentration, the magnitude of which depended on the treatment regimen and survival interval after MPTP treatment. There was significant involvement of other subcortical areas receiving a dopamine innervation, but no consistent changes in serotonin or norepinephrine levels in subcortical sites. In contrast, we observed an enduring decrease in serotonin and norepinephrine concentrations in both the somatosensory and medial prefrontal (PFC) cortex. Immunohistochemical studies also revealed a decrease in the density of PFC norepinephrine and serotonin axons. The decrease in the cortical serotonergic innervation preferentially involved the thick beaded but not smooth fine serotonin axons. Similar changes in the serotonin innervation of postmortem samples of the prefrontal cortex from idiopathic PD cases were seen. Our findings point to a major loss of the serotonin and norepinephrine innervations of the cortex in MPTP-induced parkinsonism, and suggest that loss of the beaded cortical serotonin innervation is associated with a predisposition to the development of depression in PD.

Clinical observations have suggested that ritanserin, a 5-HT 2A/C receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT 2A receptor antagonist M100907 and the selective 5-HT 2C receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT 2A/C antagonist ritanserin and the selective 5-HT 2A antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT 2A receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease. KeywordsM100907; motor deficits; MPTP; ritanserin; SB 206553; serotonin Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor impairments, including rigidity, tremor, bradykinesia, and postural instability. These motor symptoms have been primarily attributed to the progressive degeneration of dopamine (DA) neurons in the substantia nigra and a concomitant loss of striatal DA (Lang and Luzano, 1998;Dauer and Przedborski, 2003;Fahn, 2003;Nutt and Wooten, 2005).The motor symptoms of PD are treated by dopamine replacement therapy (DRT) with administration of either L-3,4-dihydroxyphenylalanine (levodopa) or direct dopamine agonists. Unfortunately, most patients so treated develop motor fluctuations and abnormal involuntary movements (dyskinesias) after several years (Lang and Luzano, 1998;Obeso et al., 2000;Dauer and Przedborski, 2003;Fahn, 2003;Nutt and Wooten, 2005). There is a clear need to identify non-dopaminergic drug targets to provide fewer side effects while maintaining therapeutic efficacy.* Correspondence: Department of Neuroscience and Pharmacology, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208, Tel (615) 327-6295, Fax (615) 327-6632, tansah@mmc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuropharmacology. Author manuscript; available in PMC 2011 July 1. Clinical studies have suggested that serotonin-2 (5-HT2) receptor antagonists may be useful in the treatment of the motor symptoms of PD. For example, ritanserin, a mixed 5-HT 2A/C receptor antagonist...