Prodynorphin and κ opioid receptor mRNA expression in the cingulate and prefrontal cortices of subjects diagnosed with schizophrenia or affective disorders
Introduction
Dynorphin opioid neuropeptides and their main receptors, the κ opioid receptors, exhibit a widespread distribution throughout the mammalian brain 10, 15, 18, 26, 27, 30, 32, 35, 46, 54, 60. This opioid neuropeptide system has been implicated in the control of motor, endocrine, and cognitive functions and is intricately linked with dopamine (DA) and serotonin (5-HT) neurotransmitters, which are believed to play a strong role in schizophrenia and depression disorders. Catecholaminergic neurons send terminal projections to dynorphin-containing neuronal populations [56] and influence the activity of the opioid cells. DA agonists increase dynorphin gene expression 17, 19, 24, 41 and protein 41, 45, 47, 59 levels and dynorphin and other κ agonists in their turn decrease DA release 13, 49. It has also been demonstrated that destruction of the raphe nucleus [34], which provides the main serotoninergic innervation of the central nervous system, or pharmacological serotoninergic manipulations [16] alter gene expression in dynorphinergic neurons. Moreover, activation of the κ opioid receptors depresses evoked excitatory postsynaptic potentials of serotonergic cells in the dorsal raphe nucleus [39] and reduces the release of 5-HT [11]. In the human brain, the κ opioid receptor mRNA is expressed in dopaminergic neurons of the substantia nigra as well as in neurons of the raphe nuclei [37].
Several lines of evidence suggest that, in addition to DA and 5-HT, the endogenous dynorphin peptides and the κ opioid receptors may also play a role in the pathophysiology of mental illnesses. Initial studies carried out in the mid-1980s with healthy human volunteers reported psychomimetic and dysphoric effects upon activation of κ opioid receptors 29, 38. Moreover, drugs acting at κ opioid receptors have been shown to have strong antidepressant 7, 14 and antipsychotic [43] effects.
The prefrontal cortex is an important brain area for high-level cognitive and emotional processes. In schizophrenics, a growing body of evidence has been accumulated showing neuropathological, neuropsychological, and cerebral blood flow dysfunction related to the dorsolateral prefrontal cortex 1, 2, 3, 28, 33, 48, 52. Abnormalities have also been reported in the cingulate and prefrontal cortices in subjects with major depression and bipolar disorder 5, 6, 8, 9, 36, 42, 57. Despite the implications of an involvement of the dynorphin/κ opioid receptor cortical system in psychiatric disorder, no studies have directly examined the mRNA expression of either prodynorphin or the κ opioid receptor in individuals with psychiatric illnesses. In the current study, in situ hybridization histochemistry was used to determine the expression levels of the κ opioid receptor and the prodynorphin mRNAs in the anterior cingulate and dorsolateral prefrontal cortices of three groups of patients diagnosed with specific psychiatric disorders and in normal control subjects.
Section snippets
Materials and methods
Dorsolateral prefrontal (Brodmann area 46 and 9) and anterior cingulate (Brodmann area 23) cortical tissues were obtained from the Stanley Foundation Neuropathology Consortium that collected the brains under approved ethical guidelines. Four groups were studied: schizophrenia (n = 14), bipolar disorder (n = 15), major depression without psychotic feature (n = 15), and normal controls (n = 15). The schizophrenic subjects (9 males and 5 females; 12 White and 2 Asian) ranged in age from 25 to 62
Results
The use of the prodynorphin and κ opioid receptor riboprobes resulted in different hybridization patterns with signals expressed only in the cortex and not in the adjacent white matter. In the prefrontal cortex, hybridizations carried out with the prodynorphin riboprobe resulted in a characteristic labeling concentrated to layer IV (Fig. 1C), whereas the κ opioid receptor probe labeled primarily the deeper layer V and VI (Fig. 1D). In the cingulate cortex both probes (though relatively weaker
Discussion
This is the first report regarding prodynorphin and κ opioid receptor mRNA expression levels in the prefrontal and cingulate cortices of subjects with specific psychiatric diagnoses. We confirm the characteristic cortical lamination expression patterns of both mRNAs that has been described previously 21, 37. However, no significant effects of diagnosis on the prodynorphin or κ opioid receptor mRNA levels were detected in either cortical region and none of the psychiatric groups showed evidence
Acknowledgements
This work was funded by the Karolinska Institute, Swedish Medical Research Council (11252), and the Stanley Foundation. Postmortem brains were donated by the Stanley Foundation Brain Consortium courtesy of Drs. Llewellyn B. Bigelow, Juraj Cervenak, Mary M. Herman, Thomas M. Hyde, Joel E. Kleinman, José D. Paltán, Robert M. Post, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken. We thank Mrs. Barbro Berthelsson and Miss Pia Eriksson for their valuable technical assistance and Elisabeth
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