Adrenergic, cholinergic, GABAergic, and glutaminergic receptor function in the CNS.

Adrenergic Receptors There are many adrenergic receptors in the human body. The appropriately named fight-or-flight response is a system of messages and codes that assists the body in dealing with crises requiring heightened levels of somatic activity (Martini, 1998). The sympathetic division of the autonomic nervous system (ANS) enables the body to handle this type of stress. Activation of the sympathetic nervous system stimulates membrane proteins known as adrenergic receptors. These receptors are sensitive to the catecholamines norepinephrine and epinephrine. Adrenergic receptors can be grouped into two main systems of the body: the central nervous system (CNS) and the peripheral nervous system. While the primary emphasis of this article is central functions, peripheral adrenergic receptor function is of interest due to adverse responses to psychotropic agents, which are mediated by these receptors. Central Adrenergic Receptors Norepinephrine (NE) is produced in the CNS. There are two central norepinephrine or noradrenergic systems. The first and best recognized NE system is found in a group of pontine pigmented neurons called the locus ceruleus. It contains about half the total number of norepinephrine-synthesizing neurons in the brain. The second NE system begins in the lateral tegmentum of the medulla. NE fibers from both the pons and the medulla travel pathways to synapse with adrenergic receptors in the spinal cord; brain stem, cerebellum, diencephalon, basal forebrain (i.e., the septum, amygdala, olfactory bulbs, and hippocampus), limbic area, and the cortex. Because NE plays an important role in the psychiatric realm of health, damage to this area of the brain can have serious repercussions, especially in disorders that have a mood component. In addition, because of the extensive connection that the locus ceruleus makes with the hippocampus and cortex, the adrenergic nervous system has been implicated in mechanisms that underlie cortical activation, learning, memory, and attention (Cameron, 1994). Depressive illness was first recognized as a biochemical phenomenon in 1965, when Schildkraut published an article describing what he called the catecholamine hypothesis of depression. Over the years, Schildkraut's hypothesis was broadened to the monoamine hypothesis (which included serotonin) and then to the monoamine receptor hypothesis of depression (Stahl, 1998). Stahl suggests it is not the increase in intrasynaptic monoamine availability that accounts for the effectiveness of antidepressants, but rather the changes (i.e., downregulation) in adrenergic receptors. In 1948 Alquist classified adrenergic responses and receptors into two overarching categories, alpha and beta (Insel, 1987), subsequently refined further to include alpha-l, alpha-2, beta-l, and beta-2. Alpha-1 and beta-1 receptors are located throughout the cerebrum and in the diencephalon. Depletion of NE, whether drug induced (e.g., reserpine) or idiopathic, has been associated consistently with an increase in both alpha-1 and beta-1 receptor sites. Long-term use of antidepressants downregulate alpha-1 and beta-1 receptors (a decrease in numbers and sensitivity). This change occurs after 2 to 4 weeks of therapy, or roughly about the same amount of time required for a clinical response to occur. Alpha-2 receptors are located in the cortex, limbic system, and locus ceruleus. Alpha-2 receptors serve as autoreceptors and, when stimulated, decrease the release of NE. While peripheral alpha-2 receptors are located presynaptically, centrally they are located postsynaptically. The mechanism by which they influence presynaptic neurons to release or not release NE from their postsynaptic position is not clear. Peripheral Adrenergic Receptors There are three primary neurotransmitters in the peripheral nervous system: NE, epinephrine, and acetylcholine (dopamine receptors play a less important role peripherally). …