Reduced levels of Cacna1c attenuate mesolimbic dopamine system function.

Genetic variation in CACNA1C, which codes for the L-type calcium channel (LTCC) Cav 1.2, is associated with clinical diagnoses of bipolar disorder, depression and schizophrenia. Dysregulation of the mesolimbic-dopamine (ML-DA) system is linked to these syndromes and LTCCs are required for normal DAergic neurotransmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc). It is unclear, however, how variations in CACNA1C genotype, and potential subsequent changes in expression levels in these regions, modify risk. Using constitutive and conditional knockout mice, and treatment with the LTCC antagonist nimodipine, we examined the role of Cacna1c in DA-mediated behaviors elicited by psychomotor stimulants. Using fast-scan cyclic voltammetry, DA release and reuptake in the NAc were measured. We find that subsecond DA release in Cacna1c haploinsufficient mice lacks normal sensitivity to inhibition of the DA transporter (DAT). Constitutive haploinsufficiency of Cacna1c led to attenuation of hyperlocomotion following acute administration of stimulants specific to DAT, and locomotor sensitization of these mice to the DAT antagonist GBR12909 did not reach the same level as wild-type mice. The maintenance of sensitization to GBR12909 was attenuated by administration of nimodipine. Sensitization to GBR12909 was attenuated in mice with reduced Cacna1c selectively in the VTA but not in the NAc. Our findings show that Cacna1c is crucial for normal behavioral responses to DA stimulants and that its activity in the VTA is required for behavioral sensitization. Cacna1c likely exerts these effects through modifications to presynaptic ML-DA system function.

Evaluation of the vaccination efficacy against H5N1 in domestic poultry in the Red River Delta in Vietnam.

The domestic poultry population in Vietnam has been vaccinated against highly pathogenic avian influenza (HPAI) H5N1 since 2005. Since then, outbreaks have continued to occur without a clear understanding of the mechanisms involved. The general objective of this study was to understand the epidemiology of the disease in the context of vaccination and to draw some conclusions about vaccination efficacy in the domestic poultry population of the Red River Delta area. Five cross-sectional surveys to measure the serological and virological prevalence in vaccinated and unvaccinated poultry were performed from the end of 2008 to June 2010. The global seroprevalence was 24% (95% confidence interval 19·9-28·2). Determinants of vaccine immunogenicity were identified separately in chickens and ducks as well as determinants of the seroconversion in unvaccinated birds. The results highlight the difficulties in maintaining good flock immunity in poultry populations using inactivated vaccine in the field with two vaccination rounds per year, and in preventing circulation of virus in co-existing unvaccinated poultry.

Antidepressant-like responses to lithium in genetically diverse mouse strains.

A mood stabilizing and antidepressant response to lithium is only found in a subgroup of patients with bipolar disorder and depression. Identifying strains of mice that manifest differential behavioral responses to lithium may assist in the identification of genomic and other biologic factors that play a role in lithium responsiveness. Mouse strains were tested in the forced swim test (FST), tail suspension test (TST) and open-field test after acute and chronic systemic and intracerebroventricular (ICV) lithium treatments. Serum and brain lithium levels were measured. Three (129S6/SvEvTac, C3H/HeNHsd and C57BL/6J) of the eight inbred strains tested, and one (CD-1) of the three outbred strains, showed an antidepressant-like response in the FST following acute systemic administration of lithium. The three responsive inbred strains, as well as the DBA/2J strain, displayed antidepressant-like responses to lithium in the FST after chronic administration of lithium. However, in the TST, acute lithium resulted in an antidepressant-like effect only in C3H/HeNHsd mice. Only C57BL/6J and DBA/2J showed an antidepressant-like response to lithium in the TST after chronic administration. ICV lithium administration resulted in a similar response profile in BALB/cJ (non-responsive) and C57BL/6J (responsive) strains. Serum and brain lithium concentrations showed that behavioral results were not because of differential pharmacokinetics of lithium in individual strains, suggesting that genetic factors likely regulate these behavioral responses to lithium. Our results indicate that antidepressant-like responses to lithium in tests of antidepressant efficacy varies among genetically diverse mouse strains. These results will assist in identifying genomic factors associated with lithium responsiveness and the mechanisms of lithium action.

Ultrastructure of hypertensive rat aorta. Increased basement membrane-like material.

To determine the effect of elevated blood pressure on the ultrastructure of rat aorta, hypertension (average mean pressure 163 +/- 17 mm Hg) was produced by suprarenal aortic coarctation. After 3 weeks, the subendothelium of the hypertensive thoracic aorta showed significantly increased volume measurements for mononuclear leukocytes and basement membrane-like material compared with the sham-operated control group. Focal areas of rarefaction of the subendothelial extracellular material were associated with the nearby presence of mononuclear leukocytes. None of these alterations were found in the normotensive abdominal aorta. The tunica media of hypertensive thoracic aorta also contained significantly increased basement membrane-like material. This new finding in an animal hypertension model is the direct result of the quantitative morphological approach employed in this study. In some rats, the partially constricting aortic ligature compromised the right renal artery leading to ischemic atrophy of the right kidney and hyperreninemia in addition to hypertension. In this group, excluded from the previous analysis and evaluated separately, subendothelial thickening and accumulation of basement membrane-like material in the thoracic aorta were greatly increased compared with the control group and other hypertensive rats. This result could not be attributed to an effect of blood pressure alone and might have been caused in part by humoral factors. Basement membrane accumulation appears to be an important early response of the arterial wall to hypertension or other factors in this rat model.

Endothelial denudation and myointimal thickening in the rat carotid artery induced by the passage of bubbles.

A new technique for the selective removal of endothelium in the rat carotid artery has been developed, and subsequent events in the vascular wall have been examined. To achieve de-endothelialization, more than 2,000 bubbles of nitrogen in phosphate-buffered saline are passed through a temporarily isolated segment of rat carotid over a period of 3 min. Bubbles are generated by a simple apparatus, consisting of a pressurized tilting chamber and catheter. Endothelium is removed while subendothelial basement membrane and other subjacent structures remain intact. Platelets attach to the denuded surface within minutes after re-establishment of blood flow. Myointimal thickening is found at 5 weeks and 4 months after de-endothelialization. The method is quite reliable and will facilitate further studies of reactions to carotid endothelial injury in young adult rats.

Comparison of aortic intima and inner media in young adult versus aging rats. Stereology in a polarized system.

Age-related ultrastructural changes in the intima and inner media of rat thoracic aorta were examined by new morphometric techniques. Young adult male rats, 10 weeks old, were compared with 1-year-old male rats. The most marked changes were found in the sub-endothelium, which increased in thickness more than five-fold. Basement-membrane-like and granular material accounted for the bulk of this thickening. Certain other structures were increased sevenfold or more in subendothelium. These structures and the volume fractions they occupied in 1-year-old rats were as follows: banded collagen, 4.3%; mononuclear leukocytes, 4.5%; cystic structures, 3.3%; and fibrillar elastin, 1.0%. Changes were also demonstrated in the fenestrae of and at selected depth levels below the innermost, or alternatively the internal, elastic lamina. Collagen increased strikingly within fenestrae and just below the elastic lamina. This was associated with a 28% increase in the thickness of the elastic lamina and a recession of smooth muscle cytoplasm to a deeper position within the first musculoelastic medial layer. The alterations in subendothelial tissues imply an altered basis for mechanical support for aortic endothelium in aging rats. These results mark the successful application of micro-computer-based stereology to a situation of polarized geometry.