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

Abstract

Serotonin (5-HT) uptake sites were mapped by autoradiographic means with PH]cyano-imipramine , the 5-HTIA receptor with [3HJ8-hydroxy-2-[di-n-propyl-amino]tetralin ([3HJ8-0H-DPAT), and the 5-HTz receptor with both pH]ketanserin and {l251]1ysergic acid diethylamide ([lZ5IJLSD) in eight nonneurologic controls and 10 cases with a diagnosis of schizophrenia. In the striatum, there was a marked heterogeneous patterning of 5-HT uptake sites that corresponded to the striosomallmatrix campartmentalization of the striatum. This organization was not matched with an equally heterogeneous pattern � either 5-HTz or 5-HTIA receptors. For the isocortex, a general organizational scheme was observed with the 5-HTIA receptor expression high in the external laminae and deep laminae, but 5-HT2 receptor expression was higher in the internal laminae. There was a laminar distribution of 5-HT uptake sites that approximated the cambined distributions of the 5-HTIA receptor and the 5-HT2 receptor. In the parahippocampal gyrus and hippocampus, the distribution of 5-HT uptake sites was camplementary to the distribution of 5-HTIA and 5-HT2 receptors. In schizophrenic cases, there was a large increase in the number and altered striosomallmatrix organization of 5-HT uptake sites in the striatum. There was also an increase in the numbers of 5-HT2 receptors in the nucleus accumbens and ventral putamen of the schizophrenics. The number of 5-HTIA receptors was not modified. There was a marked reduction in 5-HT uptake sites in the external and middle laminae of the anterior cingulate, frontal cortex, and posterior cingulate, and no changes were observed in the motor cortex, temporal cortex, or hippocampus. Increased numbers of 5-HTIA receptors were found in the posterior cingulate, motor cortex, and hippocampus. Serotoninz receptors were substantially elevated in the posterior cingulate, temporal cortex, and hippocampus, but not in the frontal, anterior cingulate, or motor cortices. Examination of the temporal lobe and hippocampus of a group of nonschizophrenic suicides (n "" 8) indicated the alterations in 5-HT system in the limbic regions of the striatum, the limbic cortex, and hippocampus of the schizophrenic cases may be disease specific.

5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride

“…Nevertheless, the present findings suggest that stimulation of 5-HT, presumably 5-HT 2 and 5-HT 1 receptors, can lead to an increase in striatal dopamine efflux which may contribute to the psychotomimetic effects of psilocybin. Of particular interest to the present study are indications that abnormalities in the number of 5-HT 1A and 5-HT 2A receptors have been found in the frontal cortex, nucleus accumbens, striatum, and hippocampi of schizophrenic patients (Mita et al 1986;Arora and Meltzer 1991;Joyce et al 1993;Laruelle et al 1993;Gurevich and Joyce 1997). Thus, the present data also support further evaluation of the 5-HT system in the pathophysiology of schizophrenia (Meltzer 1991).…”

Serotonin and Schizophrenia

“…Two postmortem studies applying [ 3 H]cyano-imipramine and [ 3 H]paroxetine have initially shown that the density of SERT is decreased in the frontal cortex (Joyce et al, 1993;Laruelle et al, 1993a (Dean et al, 1995;Naylor et al, 1996;Gurevich and Joyce, 1997;Dean et al, 1999b). In fact, three of these studies did not report altered SERT densities but did find a decrease in the affinity of [ 3 H]paroxetine for SERT in hippocampal membranes, whereas the affinity of [ 3 H]paroxetine for SERT binding in the frontal cortex was unaltered (Dean et al, 1995Naylor et al, 1996).…”

Ionotropic Glutamate Receptor Modulation of 5-HT6 and 5-HT7 mRNA Expression in Rat Brain

“…Of note, atypical antipsychotics have high 5-HT 2 receptor antagonist properties, which is postulated to be a mechanism that confers the unique therapeutic profile of atypical antipsychotics (Meltzer 1992). Abnormalities of 5-HT 2 receptor expression have been demonstrated in schizophrenic brain, as well (Burnet et al 1996;Joyce et al 1993;Laruelle et al 1993). Taken together, these findings suggest that schizophrenia is associated with altered 5-HT 2 -like receptor activity in limbic structures.…”

“…Although there are multiple serotonin receptors, psychotic symptoms are most likely associated with 5-HT 2 -like receptors (Meltzer 1992). 5-HT 2 receptors are localized in multiple limbic structures associated with schizophrenia, particularly in the hippocampus and nucleus accumbens (Joyce et al 1993). Agonists of 5-HT 2 receptors, such as lysergic acid, are psychotomimetic, and antipsychotics often have 5-HT 2 receptor antagonist properties.…”