The existence of two subtypes of DA receptors, dopamine! (D1) and dopamine2 (D2), was initially established using classic pharmacological techniques in the 1970s (Stoof and Kebabian 1984). Subsequent molecular biological studies have shown that the D1 family contains both the D1 and dopamine5 (D5) receptors, whereas the D2 family contains the D2, dopamine3 (D3), and dopamine4 (D4) receptors (Cooper et al. 2001). D1 receptor family members were originally defined solely on the ability to stimulate adenylyl cyclase (AC), while the D2 family inhibited the enzyme. Interestingly, DA receptors complexed with subunits from other subclasses of DA receptors within a receptor family are able to form distinct hetero-oligomeric receptors (also termed "kissing cousin receptors"). Notably, hetero-oligomeric D1-D2 receptor complexes in the brain require binding to active sites of both receptor subtypes to induce activation of the hetero-oligomeric receptor complex. These receptors have been demonstrated to use traditional D1 receptor intracellular signaling components of Gq/11 and Ca2+/calmodulin-dependent protein kinase II (CaMKII) second-messenger activation as demonstrated in the nucleus accumbens (Rashid et al. 2007). This work suggests possible avenues through which the brain might use different receptor subunit proportions to further fine-tune brain neurophysiology.
The D1 and D5 receptors stimulate adenylyl cyclase activity via the activation of Gs or Golf (a G protein originally thought to be present exclusively in olfactory tissue but now known to be abundantly present in limbic areas) (see Figure 1-4B). Other second-messenger pathways have also been reported to be activated by D1 receptors, effects that may play a role in the reported D1-D2 cross-talk (Clark and White 1987). The frontal cortex contains almost exclusively D1 receptors (Clark and White 1987), suggesting that this receptor may play an important role in higher cognitive function and perhaps in the actions of medications like methylphenidate. The D5 receptor is a neuron-specific receptor that is located primarily in limbic areas of the brain.
Four types of D2 receptors have been identified. The two subtypes of D2 receptors (the short and long forms, D2S and D2L, respectively) are derived from alternative splicing of the D2 gene. Although a seemingly identical pharmacological profile for these receptors exists, there are undoubtedly (yet to be discovered) physiological differences between the two subtypes. D2 receptors mediate their cellular effects via the Gi/Go proteins and thereby several effectors (see Figure 1-4B). In addition to the well-characterized inhibition of adenylyl cyclase, D2 receptors in different brain areas also regulate PLC, bring changes in K+ and Ca2+ currents, and possibly regulate phospholipase A2. D2 receptors are located on cell bodies and nerve terminals of DA neurons and function as autoreceptors. Thus, activation of somatodendritic D2 receptors reduces DA neuron firing activity, likely via opening of K+ channels, whereas activation of nerve-terminal D2 autoreceptors reduces the amount of DA released per nerve impulse, in large part by closing voltage-gated Ca2+ channels. As discussed extensively in Chapters 27 and 46, D2 receptors have long been implicated in the pathophysiology and treatment of schizophrenia. Recently, transgenic mice overexpressing D2 receptors in the striatum have been found to display many phenotypic hallmarks of schizophrenia (Kellendonk et al. 2006).
D3 receptors possess a different anatomical distribution than do D2 receptors and, because of their preferential limbic expression, have been postulated to represent an important target for antipsychotic drugs. Numerous studies have investigated the position association of a polymorphism in the coding sequence of the D3 receptor with schizophrenia, with equivocal results. It has been suggested that brain-derived neurotrophic factor (BDNF) may regulate behavioral sensitization via its effects on D3 receptor expression (Guillin et al. 2001).
The D4 receptor has received much interest in psychopharmacological research in recent years because of the fact that clozapine has a high affinity for this receptor. Studies are currently underway that are investigating more selective D4 antagonists as adjunctive agents in the treatment of schizophrenia. Furthermore, considerable attention has focused on the possibility that genetic D4 variants may be associated with thrill-seeking behavior (Zuckerman 1985), attention-deficit/hyperactivity disorder (Roman et al. 2001), and responsiveness to clozapine (Van Tol et al. 1992).
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