Abnormal fluid homeostasis in apelin receptor knockout mice.

The apelinergic system, comprised of apelin and its G protein-coupled receptor (APJ; APLNR as given in MGI Database), is expressed within key regions of the central nervous system associated with arginine vasopressin (AVP) synthesis and release as well as in structures involved in the control of drinking behaviour, including the magnocellular neurones of the hypothalamus, circumventricular organs, and the pituitary gland. This localisation is indicative of a possible functional role in fluid homeostasis. We investigated a role for APJ in the regulation of fluid balance using mice deficient for the receptor. Male APJ wild-type and knockout (APJ(-/-)) mice were housed in metabolic cages to allow determination of water intake and urine volume and osmolality. When provided with free access to water, APJ(-/-) mice drank significantly less than wild-types, while their urine volume and osmolality did not differ. Water deprivation for 24 h significantly reduced urine volume and increased osmolality in wild-type but not in APJ(-/-) mice. Baseline plasma AVP concentration increased comparably in both wild-type and APJ(-/-) mice following dehydration; however, APJ(-/-) mice were unable to concentrate their urine to the same extent as wild-type mice in response to the V2 agonist desmopressin. Analysis of c-fos (Fos as given in MGI Database) mRNA expression in response to dehydration showed attenuation of expression within the subfornical organ, accentuated expression in the paraventricular nucleus, but no differences in expression in the supraoptic nucleus nor median pre-optic nucleus in APJ(-/-) mice compared with wild-type. These findings demonstrate a physiological role for APJ in mechanisms of water intake and fluid retention and suggest an anti-diuretic effect of apelin in vivo.

The effects of apelin on hypothalamic-pituitary-adrenal axis neuroendocrine function are mediated through corticotrophin-releasing factor- and vasopressin-dependent mechanisms.

The apelinergic system has a widespread expression in the central nervous system (CNS) including the paraventricular nucleus, supraoptic nucleus and median eminence, and isolated cells of the anterior lobe of the pituitary. This pattern of expression in hypothalamic nuclei known to contain corticotrophin-releasing factor (CRF) and vasopressin (AVP) and to co-ordinate endocrine responses to stress has generated interest in a role for apelin in the modulation of stress, perhaps via the regulation of hormone release from the pituitary. In this study, to determine whether apelin has a central role in the regulation of CRF and AVP neurones, we investigated the effect of i.c.v. administration of pGlu-apelin-13 on neuroendocrine function in male mice pre-treated with the CRF receptor antagonist, alpha-helical CRF(9-41), and in mice-lacking functional AVP V1b receptors (V1bR KO). Administration of pGlu-apelin-13 (1 mg/kg i.c.v.) resulted in significant increases in plasma ACTH and corticosterone (CORT), which were significantly reduced by pre-treatment with alpha-helical CRF(9-41), indicating the involvement of a CRF-dependent mechanism. Additionally, pGlu-apelin-13-mediated increases in both plasma ACTH and CORT were significantly attenuated in V1bR KO animals when compared with wild-type controls, indicating a role for the vasopressinergic system in the regulation of the effects of apelin on neuroendocrine function. Together, these data confirm that the in vivo effects of apelin on hypothalamic-pituitary-adrenal neuroendocrine function appear to be mediated through both CRF- and AVP-dependent mechanisms.

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B.

RATIONALE: The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy. OBJECTIVES: We report the in vivo characterization of the novel 5-HT(1A/1B) autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B. MATERIALS AND METHODS: Ex vivo binding was used to ascertain 5-HT(1A) receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT(1A) and 5-HT(1B) receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B. RESULTS: SB-649915-B (1-10 mg/kg p.o.) produced a dose-related inhibition of 5-HT(1A) receptor radioligand binding and inhibited ex vivo [(3)H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1-10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT(1A) and 5-HT(1B) receptors, respectively. SB-649915-B (0.1-3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs. CONCLUSIONS: Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors.

Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties.

Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D(2) receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD(2) receptor function and affinity, and of in vivo models of dopamine rat D(2) receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD(2) receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D(2) receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.