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Biomedical subjects

R M Post

Publications and source records attributed to R M Post.

At least 163 records · Page 9Linked to original sources
PubMed1993

Contingent tolerance to carbamazepine is not affected by calcium-channel or NMDA receptor blockers.

We previously demonstrated that tolerance to carbamazepine's anticonvulsant effects occurs only with contingent presentation of the drug relative to the seizure (i.e., drug administration before but not after the seizure). Moreover, this tolerance can be reversed by altering the contingencies of drug administration (e.g., giving the drug after the seizure has occurred) without discontinuation of drug treatment. These findings imply an associative component to tolerance development in this model. Thus, we evaluated the effects on contingent tolerance development of two agents that have been shown to affect rate of tolerance development and acquisition or retention in other learning paradigms. Rats were electrically kindled in the amygdala until they reliably experienced seizures with each stimulation. In three separate studies, MK-801 (0.3 and 0.15 mg/kg), an NMDA receptor antagonist, and nimodipine (20 mg/kg), an L-type calcium channel blocker, were coadministered with carbamazepine prior to each kindling stimulation to evaluate the rate of tolerance development compared to controls. No effect of either drug was seen on the rate of contingent tolerance development to carbamazepine, suggesting that neither NMDA receptors nor L-type calcium channels are critically involved in this type of tolerance. The contingent tolerance paradigm may, however, prove useful in elucidating novel biochemical mechanisms of associative learning that might ultimately be explored in clinical situations where tolerance is a problem.

Animals↗
PubMed1993

Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation.

We report the initial results of the first controlled double-blind trial of nimodipine, a calcium channel antagonist, in the acute and prophylactic treatment of patients with treatment-refractory affective dysregulation. Active drug nimodipine (A) was substituted for placebo (B) in 12 patients. Patients were studied in a B-A-B design, with 3 of the 12 patients rechallenged with active drug in a B-A-B-A design (patients 9, 10, and 11). Five of the nine patients who completed the drug trial responded. One of three patients suffering from ultra-ultra-rapid (ultradian) cycling bipolar II disorder (patient 6) showed an essentially complete response; the other two ultradian patients (patients 4 and 9) showed evidence of a partial response on manic and depressive oscillations, one of which was confirmed in a B-A-B-A design. Only one of five less rapidly, but continuously cycling patients showed an excellent response (patient 10), and this was confirmed in a B-A-B-A design. The one patient who had recurrent brief depression (patient 11) showed a complete resolution of severe depressive recurrences, with response re-confirmed in an extended prophylactic trial with a B-A-B-A design. In the eight patients who completed self-ratings, nimodipine was associated with a significant reduction in the magnitude of mood fluctuations compared with the baseline placebo condition. Further clinical study of nimodipine, a calcium channel blocker with a unique profile of behavioral and anticonvulsant properties, appears warranted in patients with treatment-refractory affective illness characterized by recurrent brief depression and ultradian cycling.

Adult↗
PubMed1993

Cross-tolerance between carbamazepine and valproate on amygdala-kindled seizures.

Carbamazepine and valproate are two clinically used anticonvulsants which are also effective in the treatment of manic-depressive illness. Although the biochemical profiles of these drugs are markedly different, some mechanisms in common may be implied by their partially overlapping spectrum of therapeutic efficacy in seizure and affective disorders. Further evaluation of common biological targets of these agents was attempted by determining whether cross-tolerance would occur to the anticonvulsant effects of carbamazepine and valproate on amygdala-kindled seizures. It had previously been shown that tolerance to carbamazepine's anticonvulsant effects on amygdala-kindled seizures occurs only with contingent drug administration, i.e., it occurs only when the drug is injected before the kindling stimulation, and not when the drug is given after the seizure. In the current studies, rats that were made tolerant to carbamazepine showed cross-tolerance to valproate. Kindled rats given carbamazepine after each seizure stimulation (i.e., non-tolerant controls) did not show tolerance to valproate's anticonvulsant effects, indicating that the cross-tolerance between carbamazepine and valproate was also contingent. The clinical implications and potential common biochemical target mechanisms of the cross-tolerance between carbamazepine and valproate deserve further investigation.

Amygdala↗
PubMed1993

Differential effects of kindled and electrically induced seizures on a glutamate receptor (GluR1) gene expression.

To address the question of whether the mode of seizure induction contributes to the effects of seizures on glutamate receptor gene expression, we examined rat dorsal hippocampal slides by in situ hybridization after kindling by electrical stimulation of the amygdala, or after electrically induced tonic-clonic seizures. Levels of a glutamate receptor subtype (GluR1) mRNA were analyzed at three periods post kindled seizures and found to be decreased only in brains that were obtained 24 h after the last kindled seizure. This downregulation of GluR1 mRNA was transient and was observed only in animals that had behavioral manifestations after being electrically stimulated. It is probable that maintenance of the kindled state cannot be explained by a long-lasting change in GluR1 gene expression. Repeated electroshock-induced seizures increased GluR1 mRNA levels in the hippocampus. Our results show that mode of induction is an important determinant of the effects of seizures on the levels of expression of a glutamate receptor gene.

Analysis of Variance↗
PubMed1993

Antidepressant response to sleep deprivation as a function of time into depressive episode in rapidly cycling bipolar patients.

Three patients with treatment-resistant rapidly cycling bipolar disorder were studied with multiple sleep deprivations (SD) during several depressive episodes to assess the effect of phase or duration of a depressive episode on SD response. There was little response to SD early in a depressive episode, but responses were often robust late in an episode, sometimes triggering its termination. In 2 subjects, the duration of antidepressant response to SD increased linearly as time into episode increased. Neither the number of SD given in an episode nor the medication status of the patients appeared to account for the observed increases in antidepressant response. These results suggest that the neurobiological substrates underlying depression may change over the course of an episode, resulting in an increased responsivity to sleep deprivation later compared with earlier in the course of an episode in rapidly cycling patients. The generalizability of these findings to unipolar patients remains to be explored.

Adult↗
PubMed1993

New developments in the use of anticonvulsants as mood stabilizers.

There is increasing recognition that lithium is inadequate in the treatment of up to 50% of bipolar patients. In addition to subgroups that are nonresponsive from the outset, loss of efficacy (tolerance) and discontinuation-induced refractoriness have recently been observed. The anticonvulsants carbamazepine and valproate are effective alternative or adjunctive treatments, but tolerance can also occur during their long-term prophylactic use. New treatment algorithms for this loss of efficacy, including combination therapies, require further systematic study. Preliminary data suggesting that some patients with extremely rapid and chaotic mood fluctuations may respond to the L-type calcium channel blocker nimodipine are presented, and the theoretical implications discussed.

Affect↗
PubMed1993

Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion.

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushing's disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushing's disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 +/- 2.9 vs. 37.4 +/- 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 +/- 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushing's disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-Releasing Hormone↗
PubMed1993

Brain regions involved in recognizing facial emotion or identity: an oxygen-15 PET study.

The functional neuroanatomy of emotion recognition is inadequately understood despite well-documented clinical situations where emotion recognition is impaired (aprosodia). Oxygen-15 water positron-emission tomography (PET) was used to study 9 healthy women volunteers during three match-to-sample conditions, each repeated twice: a study task matching facial emotions and control tasks matching spatial positions or facial identity. Results suggest that the higher order functional neural network for recognizing emotion in visual input likely involves the right anterior cingulate and the bilateral inferior frontal gyri.

Adult↗
PubMed1993

SPECT and PET imaging in mood disorders.

Single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies are yielding a picture of clinical depression as a disorder associated with dysfunction in specific brain regions. These data support the view of depression as a disease of the brain in general and of the frontal and temporal lobes in particular. Frontal lobe hypometabolism is emerging as a common final pathway for most types of primary and secondary depression, regardless of the original cause. The severity of depression is often related to the degree of frontal hypometabolism, and preliminary studies indicate that the hypometabolism normalizes after treatment in concert with the patient's improved mood. Primary depression also is associated with abnormal activation of key brain areas, including discrete aspects of the frontal and temporal lobes, the amygdala, and the cingulate gyrus. Several areas of research are currently under way using SPECT or PET to explore further the neuroanatomy of depression.

Brain↗
PubMed1992

Ziskind-Somerfeld Research Award 1992. Endogenous biochemical abnormalities in affective illness: therapeutic versus pathogenic.

Examination of the neurobiology of psychiatric illness in general, and of affective disorders in particular, reveals a variety of associated biochemical abnormalities. These have generally been assumed to be part of the pathological process or secondary to it, and thus deserving of therapeutic efforts aimed at reversal. However, recent clinical and preclinical data suggest that some alterations occurring in the affective disorders may be compensatory and adaptive; that is, part of an endogenous therapeutic mechanism rather than part of the evolving disease process. For example, the symptom of sleep loss in depression seems to fall under this rubric inasmuch as sleep deprivation induces mood improvement in depressed patients. Preclinical data are presented that another primary pathological process--the occurrence of kindled seizures--can evoke endogenous compensatory processes that are either anticonvulsant in their own right, or enable the anticonvulsant effects of a drug such as carbamazepine. It may be that some biochemical abnormalities occurring in affective illness are similarly adaptive. As one example, increased thyrotropin-releasing hormone (TRH) has been reported in the cerebrospinal fluid (CSF) of depressed patients. This elevation of TRH and the resulting neuroendocrine profile may be part of an endogenous counter-regulatory process aimed at mood improvement. Again, preclinical seizure models are supportive in that TRH not only is induced following repeated seizures, but also exerts anticonvulsant effects on these same seizures. In an analogous fashion, TRH elevations in depressed patients may also exert ameliorating effects on depressive symptomatology. This formulation presents directly testable hypotheses that could importantly impact on our understanding of the pathophysiology of affective disorders, and suggests novel therapeutic strategies through the enhancement of endogenous compensatory mechanisms.

Amygdala↗
PubMed1992

Expression of c-fos mRNA in acute and kindled cocaine seizures in rats.

In situ hybridization for c-fos mRNA was performed on brain sections (a) from rats after an acute cocaine-induced seizure or from saline-injected controls and (b) from rats after their first cocaine-kindled seizure, as well as from rats that had not yet developed cocaine-kindled seizures (but were exposed to the same amount of cocaine as those that did exhibit convulsions) and from saline-injected controls. Increased expression of c-fos mRNA was observed in animals demonstrating cocaine-induced seizures acutely or following pharmacological kindling. Rats that experienced acute seizures after cocaine (65 mg/kg) showed pronounced increase in expression of c-fos mRNA in the dentate gyrus of the hippocampus and olfactory bulb. Increases were also observed in several other limbic cortical regions, as well as the striatum and ventromedial hypothalamic nucleus (VMH). In rats that were injected daily with an initially subconvulsive dose of cocaine-HCl (40 mg/kg), the cocaine-kindled seizures induced elevations in c-fos mRNA in the same brain regions as with an acute cocaine-induced seizure with the single exception of the VMH. These findings not only suggest the involvement of limbic, cortical and striatal structures in the cocaine-induced seizure, but also raise the possibility that alterations in the proto-oncogene c-fos and its subsequent impact on gene expression could play a role in the changes in neural excitability associated with cocaine-induced kindling.

Animals↗
PubMed1992

Impaired recognition of affect in facial expression in depressed patients.

Measures of recognition of seven affects in facial and verbal expressions to 17 depressed patients and 31 controls were administered. Depressed patients were significantly impaired in the recognition of affect in the facial, but not verbal, expressions. Among the seven affects examined, depressed patients made significantly or near significantly fewer correct matches for sad, happy, and interested face items. The performance of the depressed patients was similar to that observed by Kolb and Taylor in patients with right, but not left, hemisphere cortical excisions. The neurobiology of facial recognition is reviewed, and the relevance of the observed perceptual deficit in depressed patients to the pathophysiology and symptomatology of depression is discussed.

Adult↗
PubMed1992

Cerebral metabolism and depression in patients with complex partial seizures.

Twenty-three patients with complex partial seizures were evaluated with 18F-2-deoxyglucose positron emission tomography and with the Beck Depression Inventory. Five of 10 patients with left and zero of eight with right temporal electroencephalographic foci had depressive symptoms; one of five patients with poorly localized electroencephalographic foci also scored in the depressed range. Temporal, frontal, caudate, and thalamic normalized glucose metabolic rates among five patients with depressive symptoms and well-localized left temporal epileptogenic regions were compared with five patients without depressive symptoms but with similar electroencephalographic characteristics. Multifactorial analysis of variance yielded a significant nonlateralized mood by region interaction. Of nine individual regions compared, only inferior frontal cortex showed a significant difference in normalized regional metabolic rate between depressed and nondepressed patients. Metabolism in this region also distinguished patients with depressive symptoms from normal control subjects. Depressive symptoms in patients with complex partial seizures are associated with a bilateral reduction in inferior frontal glucose metabolism, compared with patients without depressive symptoms and normal control subjects. The frontal lobe hypometabolism observed in patients with depressions associated with epilepsy, Parkinson's disease, and primary affective disorder suggests that similar frontal lobe metabolic disturbances could underlie these conditions.

Adolescent↗
PubMed1992

Induction of constitutive heat shock protein 73 mRNA in the dentate gyrus by seizures.

We examined the effects of generalized seizures on heat shock protein (hsp) mRNA induction in the rat brain using in situ hybridization. Seizures induced by electroconvulsive shock, electrical or cocaine kindling caused a selective induction of the constitutive hsp 73 gene in the dentate gyrus. In these seizure paradigms, not thought to induce widespread tissue damage, neither the heat-inducible hsp 72 gene nor a member of the hsp 90 family (hsp 84) were induced. Hsp 73 may play a role in the adaptation and/or in the maintenance of dentate granule cell integrity following seizures.

Amygdala↗
PubMed1992

Alterations in mRNA of enkephalin, dynorphin and thyrotropin releasing hormone during amygdala kindling: an in situ hybridization study.

The present study examined changes in mRNA expression of various neuropeptides at several stages of amygdala kindled seizures. 35S-labelled oligonucleotide probes for mRNA of enkephalin (ENK), dynorphin (DYN) and thyrotropin releasing hormone (TRH) were hybridized to brain sections of rats sacrificed 24 h after a stage 1 or stage 5 seizure, or 2 weeks after a stage 5 seizure. Changes in expression developed as kindling progressed, with long-lasting changes in ENK and transient changes in DYN and TRH. ENK mRNA levels increased in pyriform and entorhinal cortices at stage 1 and 5 and remained elevated in the pyriform two weeks after a stage 5 seizure. In contrast, DYN mRNA was decreased bilaterally in the dentate gyrus 24 h after a stage 5 seizure, but returned to control levels two weeks after a stage 5 seizure. TRH mRNA was dramatically increased 24 h after a stage 1 or stage 5 seizure. After a stage 1 seizure two patterns developed. One showed increases in the pyriform, entorhinal and perirhinal cortices ipsilateral to the stimulation. The other pattern displayed bilateral increases in the dentate gyrus with or without the unilateral increases the limbic cortices. Twenty-four hours after a stage 5 seizure, large bilateral increases were found in these areas, but these returned to baseline levels by two weeks after a stage 5 seizure. The data demonstrate a constellation of alterations in several peptide systems with distinct spatiotemporal patterns, particularly in regions known to be important in kindling and epilepsy, such as the dentate gyrus and pyriform and entorhinal cortices. The relationship of these neuropeptide mRNA changes to those previously found in c-fos mRNA expression during the development of kindling is discussed.

Amygdala↗