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1.  Regulation of fear responses by striatal and extra-striatal adenosine A2A receptors in forebrain 
Biological psychiatry  2013;75(11):855-863.
Background
Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extra-striatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior.
Methods
We tested two brain region-specific A2AR knockout lines with A2ARs selectively inactivated either in the striatum only (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex, fb-A2AR KO) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of AAV5-Cre into conditional (floxed)-A2AR knockout mice.
Results
Selective deletion of striatal A2ARs in st-A2AR KO mice increased Pavlovian fear conditioning (both context and tone), but when the A2AR deletion was extended to include extra-striatal regions in fb-A2AR KO mice, context fear conditioning was normalized and tone fear conditioning was attenuated. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests and increased the startle response. These extra-striatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus.
Conclusions
This study provides the first evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning while inactivation of extra-striatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.
doi:10.1016/j.biopsych.2013.05.003
PMCID: PMC4058554  PMID: 23820821
Adenosine A2A receptor; Fear conditioning; Anxiety; Startle Response; Striatum; Hippocampus; Cortex; BDNF
2.  Deletion of striatal adenosine A2A receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning 
Behavioural brain research  2012;242:54-61.
Following early clinical leads, the adenosine A2AR receptor (A2AR) has continued to attract attention as a potential novel target for treating schizophrenia; especially against the negative and cognitive symptoms of the disease because of A2AR’s unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through the antagonistic interaction with the dopamine D2 receptor, and by regulating glutamate release and N-methyl-d-aspartate receptor function, striatal A2AR is ideally positioned to fine-tune the dopamine-glutamate balance whose disturbance is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A2ARsin the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A2AR knockout (st-A2AR-KO) on latent inhibition (LI) and prepulse inhibition (PPI) – behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A2AR-KO mice; although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning – conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A2ARs– a finding that may undermine the hypothesized importance of A2AR in the genesis and/or treatment of schizophrenia.
doi:10.1016/j.bbr.2012.12.024
PMCID: PMC3566338  PMID: 23276608
Adenosine; A2A receptor; latent inhibition; Prepulse inhibition; schizophrenia
3.  Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia  
The Journal of Clinical Investigation  2012;122(7):2567-2577.
An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the “adenosine hypothesis” of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.
doi:10.1172/JCI62378
PMCID: PMC3386823  PMID: 22706302
4.  MICROALBUMINURIA IS ASSOCIATED WITH ALL-CAUSE AND AIDS MORTALITY IN WOMEN WITH HIV INFECTION 
Prevalence of microalbuminuria is increased in patients with HIV. Microalbuminuria is associated with increased mortality in other populations, including diabetics, for whom microalbuminuria testing is standard of care. We investigated whether microalbuminuria is associated with mortality in HIV-infected women not receiving antiretroviral therapy.
Methods
Urinalysis for proteinuria and semi-quantitative testing for microalbuminuria were performed in specimens from two consecutive visits in 1,547 HIV-infected women enrolled in the Women’s Interagency HIV Study in 1994–1995. Time to death was modeled using proportional hazards analysis.
Results
Compared to women without albuminuria, the hazard ratio (HR) for all-cause mortality was increased in women with one (HR 3.4; 95% CI 2.2–5.2) or two specimens positive for either proteinuria or microalbuminuria (HR 3.9; 95% CI 2.1–7.0). The highest risk was observed in women with both specimens positive for proteinuria (HR 5.8; 95% CI 3.4–9.8). The association between albuminuria and all-cause mortality risk remained significant after adjustment for demographics, HIV disease severity, and related comorbidities. Similar results were obtained for AIDS death.
Conclusions
We identified a graded relationship between albuminuria and the risk of all-cause and AIDS mortality.
doi:10.1097/QAI.0b013e3181cc1070
PMCID: PMC2888617  PMID: 20098331
HIV; microalbuminuria; proteinuria; mortality
5.  The spectrum of kidney disease in patients with AIDS in the era of antiretroviral therapy 
Kidney international  2008;75(4):428-434.
With prolonged survival and aging of the HIV-infected population in the era of antiretroviral therapy, biopsy series have found a broad spectrum of HIV-related and co-morbid kidney disease in these patients. Our study describes the variety of renal pathology found in a prospective cohort of antiretroviral-experienced patients (the Manhattan HIV Brain Bank) who had consented to postmortem organ donation. Nearly one-third of 89 kidney tissue donors had chronic kidney disease, and evidence of some renal pathology was found in 75. The most common diagnoses were arterionephrosclerosis, HIV-associated nephropathy and glomerulonephritis. Other diagnoses included pyelonephritis, interstitial nephritis, diabetic nephropathy, fungal infection and amyloidosis. Excluding 2 instances of acute tubular necrosis, slightly over one-third of the cases would have been predicted using current diagnostic criteria for chronic kidney disease. Based on semi-quantitative analysis of stored specimens, pre-mortem microalbuminuria testing could have identified an additional 12 cases. Future studies are needed to evaluate the cost-effectiveness of more sensitive methods for defining chronic kidney disease, in order to identify HIV-infected patients with early kidney disease who may benefit from antiretroviral therapy and other interventions known to delay disease progression and prevent complications.
doi:10.1038/ki.2008.604
PMCID: PMC2704860  PMID: 19052538
AIDS; histopathology; HIV-associated nephropathy; kidney disease
6.  Prenatal Exposure to Lead, δ-Aminolevulinic Acid, and Schizophrenia: Further Evidence 
Environmental Health Perspectives  2008;116(11):1586-1590.
Background
A previously conducted study of prenatal lead exposure and schizophrenia using δ-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959–1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life.
Objectives
In the present study we extend these findings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959–1966). Using similar methods, in this study we found results that suggest a comparable association in this cohort.
Methods
We pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for matching and site structure as well as adjusting for maternal age at delivery and maternal education.
Results
The estimated odds ratio for schizophrenia associated with exposure corresponding to 15 μg/dL of blood Pb was 1.92 (95% confidence interval, 1.05–3.87; p = 0.03).
Conclusion
Although several limitations constrain generalizability, these results are consistent with previous findings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders.
doi:10.1289/ehp.10464
PMCID: PMC2592283  PMID: 19057716
δ-aminolevulinic acid; developmental; lead; Pb; prenatal; prospective; psychosis; schizophrenia

Results 1-6 (6)