Organization of dopamine D1 and D2 receptors in human striatum: Receptor autoradiographic studies in Huntington's disease and schizophrenia

Abstract

The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2/D1 receptors is altered in favor of the D2 population, particularly in the NAS.

Serotonin Uptake Sites and Serotonin Receptors Are Altered in the Limbic System of Schizophrenics

“…This is consistent with previous studies that show two to threefold higher densities in the isocortex than in the basal ganglia and hippocampus (Pazos et al 1987b;Schotte et al 1983). We did not fInd a heterogeneous pattern of 5-HTIA or 5-HT2 receptors in the striatum, unlike that for DA receptors (Joyce et al 1986(Joyce et al , 1988(Joyce et al , 1991, muscarinic receptors (Lowenstein et al 1990), and 13-adrenergic receptors (Joyce et al 1992) .…”

“…Receptor autoradiography can be a particularly use ful tool for exploring the altered expression of trans mitter systems in brains of patients with neuropsy chiatric disorders (Joyce et al 1988(Joyce et al , 1992. Studies that directly explore the relationship between the distribu tion of 5-HT uptake sites and 5-HT receptors in human brain by using autoradiographic means have not been published.…”

Loss of Dopamine D2 Receptors in Alzheimer's Disease with Parkinsonism But Not Parkinson's or Alzheimer's Disease

“…Numerous amyloid deposits have been identified in the striatum in AD, particularly in those with parkinsonian features, and this may contribute to altered processing of proteins in these cells (e.g., receptors) (Braak and Braak 1990). Consequently, the ability of striatal neurons to synthesize D 2 receptor protein and transport these proteins to the appropriate synapses may be significantly affected (see Joyce et al 1988). However, it is unclear why D 2 -like receptors would be reduced in number when other DA (e.g., D 1 ) receptors expressed in the striatum were not.…”

“…For autoradiographic experiments, the brains were sectioned at 20 m in a Lipshaw 1800-N cryotome at Ϫ 15 Њ C, thaw-mounted onto gelatin subbed slides, dried at 0 Њ C under reduced pressure, and then stored at Ϫ 70 Њ C until further use. (Joyce et al 1988). Slide-mounted sections were brought to 0 Њ C 30 min prior to incubation.…”

In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia

“…For instance, schizophrenic patients may have greater dopaminergic innervation in the striatum. Regulation of transmitter release, and uptake, could be normal, while greater terminal density could lead to more release of dopamine after re-uptake blockade and vesicular release by amphetamine.Although post-mortem studies have found normal density of presynaptic dopamine markers, such as the dopamine transporter (Hirai et al 1988;Joyce et al 1988;Pearce et al 1990) and expressed mRNA for tyrosine hydroxylase (Ichinose et al 1994), excessive innervation could be obscured by normal aging and more rapid degeneration of terminals in schizophrenia. Dopamine receptors Volkow et al 1996b), transporters (Volkow et al 1996a), and vesicles (Frey et al 1998 all decline with aging, with rates estimated at 2-8% per decade.…”