D4 receptor protein

Till date, there exist, no reliable and widely used radioligands or systems for the study of the D4 dopamine receptors. However, a number of attempts have been made using various pharmacological blockers to selectively label the D4 dopamine receptors. Seeman et al. (1993) used an indirect method, by comparing the densities of the two radioligands [3H]nemonapride (with a high affinity for D2 dopamine and D4 dopamine receptors) and [3H]raclopride (with a high affinity for D2 dopamine, but low for the D4 dopamine receptors). A similar approach has been used by others (Murray et al., 1995). 

However, these results have been questioned, and are not considered reliable (Seeman and Van Tol, 1995). More specific radioligands have been developed recently. Using the new D4 dopamine receptor radioligand [3H]NGD-94-l, D4 dopamine receptors were identified in the hippocampus, hypothalamus, dorsal medial thalamus, entorhinal cortex, insular cortex, prefrontal cortex and lateral septal nucleus (Primus et al., 1997 Lahti et al., 1998). In contrast to the distribution of DrD3 dopamine receptors, no binding was seen in the basal ganglia. These results correspond to the distribution of D4 dopamine receptor mRNA. 

Immunohistochemical analyses have provided evidence of D4 receptors in mediumsized spiny neurons in the human striatum (Khan et al., 1998). Using immunohistochem-istry, D4 dopamine receptors were also localized within the GABA-containing cells of the striatum as well as GABAergic cells in the cerebral cortex, hippocampus, globus pallidus, substantia nigra and thalamic reticular nucleus of the nonhuman primate (Mrzljak et al., 1996). Thus, dopaminergic transmission via the D4 dopamine receptor appears to be predominantly inhibitory, so that blockade of D4 dopamine receptors may result in disinhibition of excitatory transmission in intrinsic cortical, thalamocortical and extrapyramidal pathways. 

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