Alpha-2 Adrenoceptors in the Paraventricular Thalamic Nucleus: Effects of Agonist Stimulation and Chronic Psychosocial Stress

Abstract

The catecholamines are important modulators of nerve cell activity. They exert their actions via G-protein coupled receptors among which are the alpha-2 adrenoceptors. The alpha-2 adrenoceptor family consists of three members, the alpha-2 adrenoceptor subtypes A, B and C that show differential expression in different areas of the mammalian brain. While subtypes A and C have been well studied before, little is known about subtype B that is strongly expressed in the thalamus. In the present thesis, the function of the alpha-2B adrenoceptor in the paraventricular thalamic nucleus (PVT) was studied using electrophysiological techniques (part I). The effects of chronic stress on expression of the thalamic alpha-2B adrenoceptor and on alpha-2 adrenoceptor ligand binding were investigated using in situ hybridization and in vitro receptor autoradiography, respectively (part II). Part I: In order to elucidate the cellular actions of the alpha-2B adrenoceptor and the morphology of PVT cells that are modulated by this receptor, electrophysiological whole-cell recordings and cell tracing methods were applied to slices of the rat brain. Based on pharmacological and physiological characterization, three distinct classes of PVT neurons were identified. The first class of neurons exhibits membrane hyperpolarization and a reduction in input resistance mediated by postsynaptic alpha-2 adrenoceptors upon stimulation with the agonist alpha-methyl-norepinephrine. In a second class of neurons, alpha-methyl-norepinephrine induces a slow membrane depolarization and an increase in input resistance mediated by postsynaptic alpha-1 adrenoceptors. These two effects (hyperpolarization versus depolarization) occur in distinct PVT neurons which differ in their resting properties and morphology. The actions of alpha-1/alpha-2 adrenoceptors are - at least partially - mediated through a modulation of putative potassium currents. Also, the firing patterns of PVT cells are temporarily changed by the influence of a lpha-methyl-norepinephrine. Finally, the third class of PVT neurons is insensitive to alpha-methyl-norepinephrine, has a lower input resistance and a larger dendritic tree compared to the two classes mentioned above. Part II: Alpha-2 adrenoceptor expression is known to be regulated by endogenous norepinephrine and previous studies have shown that a stress-induced increase in noradrenergic activity leads to changes in expression of the alpha-2A autoreceptor. The present work describes the effects of chronic psychosocial stress on the alpha-2B adrenoceptor in the thalamus using an established animal model, chronic social stress in tree shrews. In humans, chronic stress is known to play a role in psychiatric diseases such as depression and alpha-2 adrenoceptors have been reported to be changed in depressive subjects. In situ hybridization with a specific alpha-2B adrenoceptor probe was performed to quantify mRNA for the receptor, and in vitro receptor autoradiography with the non-selective alpha-2 adrenoceptor ligand [3H]RX821002 was used to determine receptor binding. The results show that the alpha-2B adrenoceptor is upregulated after a period of daily social stress lasting 44 days and that this effect is also found after a 10 days post stress recovery period. These results show that the thalamus, a brain region known for its gating functions with respect to information transfer to cortical brain regions, is affected by stress and that the effect persists post stress.