Abstract:The a 2A -adrenoceptor has been identified as an important regulator of blood glucose homeostasis. a 2A -Adrenoceptors on pancreatic b-cells inhibit insulin secretion, and a 2A -adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human a 2A -adrenoceptor gene polymorphisms that influence a 2A -adrenoceptor expression and function have been described. Increased a 2A -adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of a 2 -adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished a 1 -and b-adrenoceptor activation. a 2 -Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active a 2A -adrenoceptors on pancreatic b-cells, but may also enhance sympathoadrenal output. In addition, a 2 -adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The a 2 -adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated a 2 -adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent a 2 -adrenoceptor antagonists. In the treatment of type 2 diabetes, a 2 -adrenoceptor agonists could possibly protect against sulphonylureainduced hypoglycaemia, and a 2 -adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on a 2A -adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.Glucose production and cellular glucose utilization are tightly regulated by glucose itself and other nutrients, by hormones such as insulin, glucagon, adrenaline, glucocorticoids and incretins and by neuronal input. The sympathoadrenal system provides a means to rapidly increase blood glucose levels. Noradrenaline released from postganglionic sympathetic nerve endings and adrenaline and noradrenaline secreted from the chromaffin cells of the adrenal medulla elevate blood glucose levels by inhibiting insulin secretion and by increasing glucagon secretion from the endocrine pancreas, and by increasing gluconeogenesis and glycogenolysis in the liver (table 1). The effects of noradrenaline and adrenaline are mediated via a 1 -adrenoceptors (a 1A , a 1B and a 1D ), a 2 -adrenoceptors (a 2A , a 2B and a 2C ) and b-adrenoceptors (b 1 , b 2 and b 3 ), all of which are members of the G-proteincoupled receptor (GPCR) superfamily. a 2 -Adrenoceptors modulate sympathoadrenal output and insulin secretion at both presy...

Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.