Dopamine has multiple central and peripheral physiological effects. In the brain, dopamine controls a multitude of functions including locomotor activity, cognition, emotion, positive reinforcement, food intake and endocrine regulation. In the periphery, dopamine modulates cardiovascular activity (both cardiac and vascular function), catecholamine release, hormone secretion, renal function and gastrointestinal motility . Dopamine mediates its action via the 5 known dopamine receptors (D1-D5). These five receptors can be subdivided into two general groups, the D1 receptor/D5 receptor group (D1-like) and the D2 receptor/D3 receptor/D4 receptor group (D2-like), based on their molecular structures, pharmacological activities, and physiological functions [1–5]. The D1-like receptors predominantly signal by coupling to Gαs which leads to the activation of adenylyl cyclase and the formation of cAMP [1, 3, 6, 7]. The D2-like receptors signal mainly by coupling to Gαi, thereby inhibiting the activity of adenylyl cyclase [1, 3, 8, 9]. In addition, alternative G protein coupling has been described for both the D1-like receptor and the D2-like receptor groups under specific conditions [10–13]. The dopamine receptors have been cloned from many species, including humans, with splice variants of many of the dopamine receptors identified [1, 3]. Gene expression analysis of the dopamine receptors has demonstrated that the D1-like receptor group is expressed centrally in many areas of the brain and peripherally in blood vessels, the adrenal gland, skeletal muscle and the kidneys [1, 4, 14–17]. The D2-like receptor group is also expressed centrally in many areas of the brain and peripherally in the pituitary, blood vessels, the heart, the adrenal gland, and the kidneys [1, 4, 15, 17]. Pharmacologically, agonists and antagonists that functionally differentiate dopamine receptors have been described and have been useful in matching biological activity with individual dopamine receptors [1, 17, 18].
Skeletal muscle is a plastic tissue which readily changes mass in response to alterations in physiological demand for work and metabolic need. Loss of skeletal muscle mass (atrophy) can be initiated by a variety of stimuli including disuse, nerve damage, glucocorticoid use, sepsis, cachexia, chronic pulmonary obstructive disease, congestive heart failure and muscular dystrophy [19–28]. Several agents have been shown to modulate skeletal muscle mass including anabolic steroids, growth hormone, insulin-like growth factor I, corticotrophin releasing factor 2 receptor agonists, phosphodiesterase 4 inhibitors, vasoactive intestinal peptide 2 receptor agonists and beta 2 adrenergic receptor agonists [29–36]. We have previously demonstrated that modulation of skeletal muscle cAMP levels by activation of receptors that are positively coupled to adenylate cyclase and by inhibition of phosphodiesterases that degrade cAMP increase skeletal muscle mass under both physiological and pathological conditions [31–34]. We were therefore interested in determining if activation of the dopamine 1 and dopamine 5 receptors would increase skeletal muscle cAMP thereby resulting in increased muscle mass and force. To do this, we utilized a selective dopamine 1/dopamine 5 receptor agonist (SKF 81297) to treat wild-type, dopamine 1 receptor knockout and dopamine 5 receptor knockout mice and measured skeletal muscle cAMP levels, skeletal muscle mass and skeletal muscle force production.