D1 family receptors (D1R) in prefrontal cortex (PFC) are critical for normal cognition and are implicated in pathological states such as schizophrenia. The two D1R subtypes, D 1 and D 5 , cannot be pharmacologically distinguished but have important functional differences. To understand their contributions to cortical function, we quantified their localization in the neuropil of primate PFC. We identified different patterns of distribution for the two receptors that showed variation across cortical laminae. Although D 1 was enriched in spines and D 5 in dendrites, there was considerable overlap in their distribution within neuronal compartments. To determine whether the D 1 and D 5 receptors are localized to separate populations of synapses, we employed double-labeling methods. We found the two receptors colocalized and quantified the overlap of their distribution in spines and axon terminals of prefrontal cortical area 9 in the Macaca mulatta monkey. The two receptors are found in partially overlapping populations, such that the D 5 receptor is found in a subpopulation of those spines and terminals that contain D 1 . These results indicate that dopamine activation of the two D1R subtypes does not modulate disparate populations of synapses onto dendritic spines in prefrontal cortical area 9; rather, dopamine can activate D 1 and D 5 receptors on the same spines, plus an additional group of spines that contains only D 1 . The implications of these results for the dosedependent relationship between D1R activation and PFC function are discussed.
Indexing termselectron microscopy; circuitry; working memory; primate; ultrastructure; pyramidal cells; prefrontal cortex Dopamine neurotransmission in prefrontal cortex (PFC) is crucial for normal cognition in humans and animals (Brozoski et al., 1979;Luciana et al., 1998;Castner et al., 2000;Harmer et al., 2001). In particular, activation of the D1 family of dopamine receptors (D1R) in PFC is critical for working memory (WM) performance (Sawaguchi and Goldman-Rakic, 1991;Williams and Goldman-Rakic, 1995;Muller et al., 1998). Schizophrenia is associated with altered dopamine neurotransmission in the PFC (Weinberger et al., 1988;Akil et al., 1999
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript Abi-Dargham et al., 2002), and schizophrenic patients show pronounced impairments in WM performance (Park and Holzman, 1992;Goldman-Rakic, 1994;Callicott et al., 2003), which is strongly correlated with increased D1R availability in the PFC (Abi-Dargham et al., 2002). Furthermore, treatments that reduce D1R expression in the PFC impair WM performance in normal monkeys, and this is reversed by D1R agonist treatment (Castner et al., 2000). Given the importance of D1R activity for proper PFC functioning, it is critical to understand fully their roles within PFC cortical circuitry.There are two subtypes of D1R, the D 1 and the D 5 receptors (Grandy et al., 1991;Sunahara et al., 1991;Tiberi et al., 1991). D 1 and D 5 share 80% homology in their transmembra...