Key Advances Related to Dopamine Receptors

Many of the significant advances in dopamine receptors and the dopamine hypothesis of psychosis or schizophrenia are listed in Table 1.1. Between 1976 and 1979, it became clear that there were two main groups of dopamine receptors, D1 and D2 [23, 35, 36, 37]. The D1-like group of receptors were associated with dopamine-stimulated adenylate cyclase [38, 39], but were not selectively labeled by [3H]haloperidol. The antipsychotic potencies at these D1 receptors did not correlate with clinical antipsychotic potency [26]. The D1-like receptors now consist of the cloned Di and D5 receptors [40,41].

The D2-like receptors did not stimulate adenylate cyclase and are now known to inhibit adenylate cyclase [42, 36, 37, 43, 44, 45]. The D2-like group now includes the cloned D2Short [46, 47], D2Long [48], D2Longer [49], D3 [28], and D4 dopamine receptors [50].

Moreover, each of these receptors has a state of high affinity and a state of low affinity for dopamine, with D2High being the functional state in the anterior pituitary [51, 52], in nigral dopamine terminals (presynaptic receptors [53]), and presumably in the nervous system itself. Although this latter point has not been unequivocably established, Richfield et al. [54] have found that 90% of the D2 receptors in brain slices are in the D2High state. The D2High state can be quickly converted into the D2Low state by guanine nucleotide [55].

The differences in findings on dopamine receptors between laboratories are explained by technically different methods and ligands. For example, the dissociation constant of a ligand at the D2 receptor can vary enormously, depending on the final concentration of the tissue [56]. Moreover, fat-soluble ligands, such as [125I]iodosulpride, [3H]nemonapride, and [3H]spiperone, invariably yield higher dissociation constants than less fat-soluble ligands (such as [3H]raclopride) for competing drugs [21, 57]. This technical effect also occurs with positron emission tomography ligands [58].

Although the density of D2 receptors in postmortem human schizophrenia tissues is elevated [26, 59, 60-62], some of this elevation may have resulted from the antipsychotic administered during the lifetime of the patient. An example of this elevation is shown in Fig. 1.3, where it may be seen that the postmortem tissues from half of the patients who died with schizophrenia revealed elevated densities of

Fig. 1.3 Elevation of dopamine D2 receptors in postmortem caudate-putamen tissues from patients who had died with schizophrenia. Each box indicates the D2 density measured by saturation analysis with [3H]spiperone (Scatchard method for Bmax; centrifugation method) [62]. The D2 densities in the postmortem striata from schizophrenia patients exhibit a bimodal pattern, with half the values being two or three times the normal density. Most of the schizophrenia patients had been treated with antipsychotics during their lifetime. Although the Alzheimer patient tissues also revealed a small elevation of D2 densities, the magnitude and pattern were different than that for schizophrenia (re-drawn and adapted from [82] with permission)

[3H]spiperone-labeled D2-like receptors in the caudate-putamen tissue. The other half of the postmortem schizophrenia tissues were normal in D2 density even though most of the patients were known to have also been treated with antipsychotics during their lifetime.

It is often surprising to encounter people who are resistant to advances in science. For example, I vividly recall one British psychiatrist standing up and shouting at me from the audience: "Post-mortem dopamine receptors? Do you actually expect me to believe that these dead receptors come to life and bind your radioactive material?" I answered that the same type of question was raised a century ago when people seriously questioned whether ferments could be isolated and still have activity, but that we can now buy crystallized enzymes for a few dollars and that these ferments are fully active. And, of course, thanks to many of the contributors to the present book on "The Dopamine Receptors," one can now purchase frozen clones of the five different dopamine receptors.

0 0

Post a comment