Auditory evoked potentials as indicator of serotonergic neuronal activity — An animal study using microinjection techniques into the dorsal raphe nucleus

PI Affective disorders andantideprzssants

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Auditory evoked potentials as indicator of serotonergic neuronal acitivity - An animal study using microinjection techniques into the dorsal raphe nucleus

G. Juckel’, U. Hegerl’, M. MO&, V. Cs6pe2, G. Kmmos2. IDepartment of Psychiatry, Ludwig-Maximilians-University, Munich, Germany; 2Department of Psychophysiology, Institute for Psychology, Hungarian Academy of Sciences Budapest, Hungary A valid indicator of central serotonergic neurotransmission would be useful for various diagnostic and psychophsrmacological purposes in psychiatry. Known peripheral serotonergic measures reflect, however, only partially serotonergic function in the brain. Previous lindings suggest that the intensity dependence of auditory evoked potentials (AEP) is closely related to central serotonergic activity. The present study examined the effects of microinjection of a 5-HTtA agonist (I-OH-DPAT) and a ~-HT~A antagonist (spiperone) into the dorsal raphe nucleus (DRN) on AEP recorded epidurally from the primary and secondary auditory cortex in behaving cats. We found a stronger intensity dependence only of AEP from the primary auditory cortex after 8-OH-DPAT, which inhibits the tiring rate of serotonergic DRN neurons, and a weaker intensity dependence after spiperone, which increases serotonergic cell fhing, compared to baseline measurements. These results demonstrate that the intensity dependence of AEP is inversely related to serotonergic neuronal activity and that it may be a promising tool for assessing central serotonergic function in humans (e.g., identifying patients with low serotonergic neurotransmission). References [l] Hegerl U, Juckel G (1993): Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry 33: 173-187 [2] Juckel G, Cs&pe y Mob& M, Hegerl U, Karmos G (1996) Intensity dependence of auditory evoked potentials in behaving cats. Electroencephal clin Neurophysiol 100: 527-537 [3] Juckel G, Mom&r M, Hegerl U, Csepe V, Kannos G (1997): Auditory evoked potentials as indicator of brain serotonergic activity - first evidence in behaving cats. Biol Psychiatry 41: 1181-l 195

could be sustained by the finding of increased numbers of CRHexpressing neurons in the hypothalamic paraventri~ular nucleus of depressed patients. Also a large body of animal studies support the view that unrestrained secretion of CRH in the central nervous system produces several signs and symptoms of depression and anxiety disorders through continous activation of CRHr receptors. Intracerebroventricular or site specific injection of CRH to rats or mioe results in arousal and anxiety like behavior with seizure activity becoming evident at higher doses. The clinical data and. the behavioral data derived from manipulations of the CRH system in animals are consistent with exaggerated CRH secretion as the driving force behind the neuroendocrine and the psychopathological symptoms of depression and anxiety disorders via continous activation of CRHt receptors. These tindings have prompted the development of compounds that selectively antagonize CRHl receptors. In an open label trial of patients with major depression, we have examined the antidepressant potential of R121919, a water soluble pyrazolopyrimidine that binds with high afhnity to human CRHt receptors. This compound was administered to 22 inpatients with a major depressive episode primarily to investigate whether its endocrine mode of action compromises the stress hormone system or whether other safety and tolerability issues may exist. The patients were enrolled in two dose-escalation panels, one where the dose range increased from 5-40 mg and the other ranging from 40-80 mg for a period of 30 days. We found that R12 1919 was safe and well tolerated by all patients within this observation period. Moreover, the data suggested that treatment at these doses did not impair the corticotropin and cortisol secretory activity at baseline or following CRH stimulation supporting the belief that these compounds will reduce central behavior-related effects of CRH without altering the basal and stress-elicited activity of the HPA axis. We ,also observed significant reductions in depressive and anxiety scores using both, patient and clinician ratings. These findings coupled with the observed worsening of affective symptomatology after drug discontinuation suggested that this drug may have considerable therapeutic potential in treatment and prevention of diseases where central regulation of CRH is impaired, leading to CRH hypersecretion in various brain areas. These areas often, but not always include the hypothalamus as reflected peripherally by increased release of ACTH and cortisol.

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CRH, HPA system hyperactivity and depression

A.W. Zobel, T. Nickel, H. Ktinzel, N. Ackl, A. Sonntag, M. Ising, F. Holsboer. Max Planck Institute of Psychiatry, Munich, Germany Clinical and preclinical data suggest that alterations of the hypothalamic-pituitary-adrenocortical (HPA) system are causally related to affective and anxiety disorders. First evidence emerged from clinical studies that found decreased corticotropin-releasing hormone (CRH) binding in the prefrontal cortices of depressed suicide victims and elevated CRH levels in the cerebrospinal fluid of patients with major depression. The suggestion of increased release of CRH in the limbic brains of patients with depression was also indirectly supported by studies that found ACTH release to be blunted in these patients after injection of CRH. Recently the hypothesis of continous hypersecretion of CRH in depression

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Cortisol response to the DexlCRH test predicts medium-termsutcome in patients ;H/th remitted depression

A.W. Zobel, R.M. Frieboes, M. Ising, E Holsboer. Max Planck Znstituteof Psychiatry, Munich, Germany Treatment of depression is complicated by the fact that valid indicators of the course of the disease and adequacy of treatment are not yet available. Psychiatrists can only refer to the current individual psychopathology, which can often be misleading. However there is convincing evidence from a large body of clinical and basic research that alterations of the hypothalamic-pituitaryadrenocortical (HPA) system are causally related to depression and anxiety. Therefore neuroendocrine challenge tests promise to be useful for phenotyping depressed patients at the neuroendocrine level and also seem to have a potential for the purpose of short-term and medium-term prognosis. In order to test this hypothesis the combined dexamethasone/corticotropin-releasing