Joel E. Kleinman

Abnormal cholecystokinin mRNA levels in entorhinal cortex of schizophrenics

Limbic cortical regions, including anterior cingulate cortex (ACC), prefrontal cortex (PFC) and entorhinal cortex (ERC), have been implicated in the neuropathology of schizophrenia. Glutamate projection neurons connect these limbic cortical regions to each other, as well as to the terminal fields of the striatal/accumbens dopamine neurons. Subsets of these glutamate projection neurons, and of the GABA interneurons in cortex, contain the neuropeptide cholecystokinin (CCK). In an effort to study the limbic cortical glutamate projection neurons and GABA interneurons in schizophrenia, we have measured CCK mRNA with in situ hybridization histochemistry in postmortem samples of dorsolateral (DL)PFC, ACC and ERC of seven schizophrenics, nine non-psychotic suicides and seven normal controls. CCK mRNA is decreased in ERC (especially layers iii vi) and subiculum in schizophrenics relative to controls. Cellular analysis indicates that there is a decrease in density of CCK mRNA in labelled neurons. In so far as ERC CCK mRNA is not reduced in rats treated chronically with haloperidol, this decrease in schizophrenics does not appear to be related to neuroleptic treatment. In contrast, in DLPFC, where schizophrenics do not differ from normals, the suicide victims have elevated CCK mRNA (especially in layers v and vi), and increased cellular density of CCK mRNA, relative to both normals and schizophrenics. These results lend further support for the involvement of ERC and hippocampus in schizophrenia, suggesting that neurons that utilize CCK may be particularly important. Similarly, an increase in CCK mRNA levels in the PFC of suicides adds to a growing body of evidence implicating this structure in this pathological state. In so far as CCK is co-localized with GABA or glutamate in cortical neurons, both of these neuronal populations need to be studied further in schizophrenia and suicide.

Prodynorphin mRNA expression is increased in the patch vs matrix compartment of the caudate nucleus in suicide subjects

Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in psychiatric disorders. Notably, opioid peptide immunoreactivity is altered in the cerebrospinal fluid of chronic schizophrenics and manic-depressive subjects.1–3 Despite these clinical findings, few postmortem investigations4,5 have examined the association of endogenous opioid neuropeptides with schizophrenia and suicide. Anatomically, a tight interaction exists within the neostriatum between the opioid peptide (dynorphin and enkephalin) system and classical neurotransmitters such as dopamine6 which has been implicated in both the psychotic symptoms and the cognitive deficits that characterize schizophrenia (see review).7 The neostriatum is differentially organized into patch and matrix neurochemical mosaic compartments anatomically connected to limbic- and sensorimotor-related brain regions, respectively.6,8 Moreover, the human neostriatum is characterized by a heterogenous expression of the prodynorphin opioid gene: high in the patch, but low in the matrix compartment.9,10 The present results show for the first time a differential alteration of prodynorphin within distinct striatal compartments in postmortem tissue from nonschizophrenic suicide subjects. The prodynorphin patch/matrix mRNA expression was elevated in the caudate nucleus of suicide subjects as compared to normal controls and schizophrenics in which no alterations in opioid peptides or D1 and D2 mRNA expression were apparent. Altogether the findings suggest that discrete dysfunction of the endogenous opioid dynorphin system might contribute to depression and the risk of suicide in nonschizophrenic subjects.

A topographical study of senile plaques and neurofibrillary tangles in the hippocampi of patients with Alzheimer's disease and cognitively impaired patients with schizophrenia

Neuropsychological testing of elderly schizophrenic patients reveals that a significant portion of this population exhibit varying degrees of cognitive impairment. Since Alzheimers disease is the most common cause of dementia in geriatric patients, we investigated whether the cognitive decline observed in schizophrenia is the result of degenerative changes analogous to those characteristic of Alzheimers disease. For this purpose, the number and distribution of senile plaques and neurofibrillary tangles were mapped in the hippocampi of 10 cognitively impaired schizophrenic patients, 10 patients with Alzheimers disease, and 10 patients with dementia not attributed to either schizophrenia or Alzheimers disease. In Alzheimers disease, degenerative changes invariably predominated in the CA1 subfield, subiculum, and proisocortex. By contrast, findings characteristic of Alzheimers disease were virtually never observed in the hippocampi of schizophrenic and other cognitively impaired patients. In some patients with Alzheimers disease, the presence of senile plaques in the molecular layer of the dentate gyrus suggested the existence of an underlying entorhinal cortex lesion. Similar dentate gyrus pathology was never found in any of the other patients. The authors conclude that cognitive impairment in schizophrenia is not the result of degenerative changes analogous to those found in Alzheimers disease.

Astrocytosis in the molecular layer of the dentate gyrus: a study in Alzheimer's disease and schizophrenia.

Recently, several authors have claimed prominent abnormalities in the entorhinal cortex of both patients with Alzheimers disease (AD) and schizophrenia. The entorhinal cortex is the origin of the perforant pathway, a major input to granule cells of the dentate gyrus of the hippocampus. The present study explored the possibility of a lesion in the entorhinal cortex of both AD and schizophrenic patients by quantitating astrocytic markers within the terminal fields of the perforant pathway. An increase in fibrillary astrocytes was found in half (3/6) of the AD patients while none of the schizophrenic (n = 6) or control (n = 7) brains exhibited gliosis. Since the redistribution and hyperplasia of astrocytes within the molecular layer of the partially deafferented dentate gyrus depend on the chronicity of the entorhinal lesion, the abnormalities observed in AD patients are consistent with the progressive course of the illness. Furthermore, the presence of gliosis in the subiculum of three out of six AD patients suggested pathology secondary to projections from the entorhinal region, amygdala, or prepyriform cortex. The absence of similar changes in schizophrenic patients does not disprove previous claims of entorhinal pathology but suggests that the lesion, if it exists, is either static in nature or occurred long before death.

Interaction of opioid peptides and other drugs with multiple kappa receptors in rat and human brain. Evidence for species differences

Previous experiments resolved four kappa binding sites in guinea pig brain termed kappa 1a, kappa 1b, and kappa 2b. The present study was undertaken to examine the occurrence of kappa receptor subtypes in rat and human brain. [3H]U69,593 and [3H]bremazocine were used to label kappa 1 and kappa 2 binding sites, respectively, present in brain membranes depleted of mu and delta binding sites by pretreatment with the irreversible ligands, BIT and FIT. Low levels of [3H]U69,593 binding precluded a detailed quantitative study of kappa 1 binding sites in these species. Quantitative examination of [3H]bremazocine binding resolved two kappa 2 binding sites in both rat and human brain whose ligand selectivity patterns differed from that of the guinea pig. These observations suggest that there may be considerable variation in the ligand recognition site of kappa receptor subtypes among mammalian species.

Quantitative autoradiography of striatal dopamine D1, D2 and re-uptake sites in rats with vacuous chewing movements

Rats treated with haloperidol that developed vacuous chewing movements (VCM), a possible animal model of tardive dyskinesia, were studied with quantitative autoradiography for dopamine type-1 (D1) and type-2 (D2) receptors as well as dopamine re-uptake sites. Haloperidol increased striatal D2 receptors, but did not affect D1 receptors or the dopamine re-uptake site. D2 receptor increases occurred in rats with and without VCMs. In so far as VCM is a model for tardive dyskinesia, haloperidol induced increases in striatal D2 receptors do not appear to be etiologic for these abnormal movements.

The subnuclear distribution of 5-HT3 receptors in the human nucleus of the solitary tract and other structures of the caudal medulla

The distribution of 5-HT3 receptors was examined in the human medulla using [3H]LY278584, a highly selective 5-HT3 receptor antagonist. The highest density of 5-HT3 receptors was found in the substantia gelatinosus subnucleus of nucleus of the solitary tract (NTS) throughout its rostrocaudal extent, followed by the dorsal subnucleus, the area postrema (AP), the commissural subnucleus, the medial subnucleus, and in an arc corresponding to the pars gelatinosus of the spinal trigeminal nucleus (nSp5). The distribution of 5-HT3 receptors in the brain may help explain some of the reported CNS activities of 5-HT3-selective drugs. The anti-emetic and antinociceptive activities of 5-HT3 antagonists may be mediated by receptors in sensory areas of the brainstem.

Increased expression of MARCKS in post-mortem brain of violent suicide completers is related to transcription of a long, noncoding, antisense RNA

Increased expression of MARCKS in post-mortem brain of violent suicide completers is related to transcription of a long, noncoding, antisense RNA

Persistent catalepsy associated with severe dyskinesias in rats treated with chronic injections of haloperidol decanoate

Patients who develop persistent parkinsonism while on chronic neuroleptic therapy may be predisposed towards the development of tardive dyskinesia (TD). We investigated this issue in an animal model of TD by examining the association between catalepsy and the syndrome of neuroleptic-induced vacuous chewing movements (VCMs). VCMs were measured every 3 weeks for 33 weeks while rats received injections of haloperidol decanoate. Catalepsy was measured after the second through the seventh injections of the depot neuroleptic. There were no correlations between the severity of catalepsy scores after the second or third injections of haloperidol and the severity of the overall VCM syndrome. However, the severity of the catalepsy score following the third through seventh injections of haloperidol strongly correlated with the concurrent number of VCMs. Persistent high catalepsy scores across the six catalepsy rating sessions were strongly associated with the development of persistent severe VCMs. These findings suggest that, to the extent that persistent parkinsonian signs in humans are associated with a propensity towards the development of TD, the VCM syndrome in rats is at least a partially faithful animal model of this relationship.

Muscarinic Receptor Density in Skin Fibroblasts and Autopsied Brain Tissue in Affective Disorder

In 1972, Janowsky et al. proposed the cholinergic-aminergic imbalance hypothesis of affective disorders. According to this hypothesis, depression results from an increase in the ratio of central cholinergic to aminergic neurotransmission, whereas mania results from the opposite. The hypothesis was originally formulated largely on the basis of inferences of how therapeutic drugs alter mood. Most of the data that have been generated in subsequent years have been based upon pharmacological effects. The existing evidence is summarized extensively e1~ewhere.Z.~ At this point, it is sufficient to say that cholinomimetic agents (such as physostigmine and arecoline) have been reported to induce depressive-like mood changes in normals and to intensify these feelings in patients with depression. Furthermore, these drugs or ones with similar pharmacological effects can apparently reduce mania. Likewise, attempts have been made to interpret known biological markers of depression in light of cholinergic-aminergic mechanisms. For example, short rapid eye movement (REM) sleep latency is a well-established state marker of moderate to severe depre~sion.~ Based upon both pharmacological and neurophysiological data that indicate that cholinergic neurotransmission induces and aminergic neurotransmission