Cyclic Adenosine Monophosphate Phosphodiesterase in Brain: Effect on Anxiety

Beer, Bernard; Chasin, Mark; Clody, Donald E.; Vogel, John R.; Horovitz, Zola P.

doi:10.1126/science.176.4033.428

Cited by 201 publications

(45 citation statements)

References 18 publications

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“…Diazepam, an anxiolytic benzodiazepine, and rolipram, a pyrrolidinone antidepressant with anxiolytic properties, mediate their anxiolytic effect through PDE inhibition, as do the methyl xanthines like caffeine. In vitro potency of several PDE inhibitors show a positive correlation with the anxiolytic efficacy of rat performance on the Vomer conflict task (Beer, Chasin et al 1972). In vivo anxiolytic pharmacologic studies show a similar PDE inhibition mechanism.…”

Section: Camp In Stress and Anxietymentioning

confidence: 72%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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Section: Camp In Stress and Anxietymentioning

confidence: 72%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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“…Phosphodiesterase-4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cyclic AMP (cAMP) and is critical in controlling its intracellular concentration, is involved in various central nervous system (CNS) processes, including depression , learning and memory (Barad et al, 1998), anxiety (Beer et al, 1972), and analgesia (Bradaia et al, 2005). Administration of PDE4 inhibitors such as rolipram produces antidepressant-like effects (Zhang et al, 2002(Zhang et al, , 2006, reverses memory deficits induced pharmacologically, physically, or genetically (Bourtchouladze et al, 2003;Imanishi et al, 1997;Zhang et al, 2000Zhang et al, , 2004, alters anxiogenic-like behavior (Imaizumi et al, 1994;Silvestre et al, 1999a), and induces analgesia in rodents (Kumar et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

157

143

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Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression-and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4BÀ/À). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4BÀ/À mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4BÀ/À mice. Compared to PDE4B + / + littermates, PDE4BÀ/À mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light-dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4BÀ/À mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4BÀ/À mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4BÀ/À mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.

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“…Analogies between compounds that affect the GABA-receptor-channel complex and also affect adenosine receptors have been made previously [27]. Etazolate also is a potent phosphodiesterase inhibitor [38]. It should be noted that barbiturates represent another class of compounds that enhance diazepam binding to the GABA-receptor-channel complex [39] and have similar potencies at such complexes and as antagonists at adenosine receptors [28,29], suggesting again structural analogies between certain regulatory sites on the GABA-receptor-channel complex and antagonist sites on adenosine receptors.…”

Section: Pyrazolopyridinesmentioning

confidence: 99%

Non-xanthine heterocycles: Activity as antagonists of A1 and A2-adenosine receptors

Daly

Hong

Padgett

et al. 1988

Biochemical Pharmacology

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A variety of non-xanthine heterocycles were found to be antagonists of binding of [ 3 H]phenylisopropyladenosine to rat brain A 1 -adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxarnidoadenosine with A 2 -adenosine receptors in human platelet and rat pheochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A 1 -and A 2 -adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N 6 -substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A 1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A 1 and A 2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A 1 -and A 2 -adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and β-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak noncompetitive adenosine antagonist.Xanthines, such as theophylline, caffeine and various 8-aryl-1,3-dialkylxanthines, have been widely used as antagonists of A 1 and A 2 -adenosine receptors [1]. The 8-aryl-1,3-dialkylxanthines are very potent at both subclasses of adenosine receptors [2][3][4][5][6][7][8][9][10][11]. Certain 8-aryl-1,3-dipropylxanthines exhibit selectivity for A 1 receptors [4,8,9] and certain caffeine analogs exhibit some selectivity for A 2 receptors [12,13]. Other classes of heterocyclic compounds exhibit antagonist activity at adenosine receptors. These include: 9-methyladenines [10,14], various pyrazolopyridines (etazolate, cartazolate, tracazolate) [15][16][17][18], various pyrazolopyrimidines [19,20], imidazopyrazines [21], a phenyl-substituted pyrazoloquinoline (CGS 8216) [22,23], a furyl-sub-stituted triazoloquinazoline (CGS 15943a) [24], a triazolopyridazine (CL218872) [15], various mesoionic analogs of xanthines [25], pteridin-2,4-diones (lumazine) and benzopteridin-2,4-diones [10,26], β-carbolines [15,27], barbiturates [28,29] and dibenzazepines (carbamazepine) [30][31][32][33]. A phenylaminoimidazoline, clonidine, has been reported to antagonize adenosine responses in physiological experiments [34].The non-xanthine adenosine antagonists have been largely neglected in behavioral and physiological studies, and little is known of structure-activity relationships within such METHODS MaterialsThe sources from which we obtained our mat...

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Cyclic Adenosine Monophosphate Phosphodiesterase in Brain: Effect on Anxiety

Cited by 201 publications

References 18 publications

The cyclic AMP phenotype of fragile X and autism

The cyclic AMP phenotype of fragile X and autism

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Non-xanthine heterocycles: Activity as antagonists of A1 and A2-adenosine receptors

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