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Biomedical subjects

R M Post

Publications and source records attributed to R M Post.

At least 91 records · Page 5Linked to original sources
PubMed1997

Comparative antidepressant effects of intravenous and intrathecal thyrotropin-releasing hormone: confounding effects of tolerance and implications for therapeutics.

A significant amount of preclinical and human data indicate that thyrotropin-releasing hormone (TRH) has antidepressant effects. Although early studies showing these effects using intravenous TRH were not consistently replicated, it has been suggested that this could be explained by its poor blood-brain barrier penetration. For this reason we compared the antidepressant effect of intrathecal and intravenous TRH administered in a double-blind design to 2 treatment-refractory patients with bipolar II disorder. Each experienced a robust antidepressant response by both routes; subsequent open trials of intravenous TRH also were effective until apparent tolerance developed. Intrathecal TRH was readministered and both subjects again experienced robust antidepressant responses. These preliminary data suggest a differential mechanism of tolerance to the two routes of administration and raise the possibility that a subgroup of patients may be responsive to the antidepressant effects of TRH independent of its route of administration.

Affect↗
PubMed1997

Amygdala-kindled seizures increase the expression of corticotropin-releasing factor (CRF) and CRF-binding protein in GABAergic interneurons of the dentate hilus.

Kindling, a model of temporal lobe epilepsy, induces a number of neuropeptides including corticotropin-releasing factor (CRF). CRF itself can produce limbic seizures which resemble kindling in some aspects. However, tolerance to the convulsant effects of CRF develops rapidly. Hypothetically, this could be explained should seizures also induce the CRF-binding protein (CRF-BP), which has been postulated to restrict the actions of CRF. Therefore, in the present study, we used in situ hybridization to examine the effects of amygdala-kindled seizures on the mRNA levels of CRF and CRF-BP. Kindled seizures markedly elevated CRF and CRF-BP in the dentate gyrus of rats. CRF and CRF-BP were induced almost exclusively in GABAergic interneurons of the dentate hilus. The CRF and CRF-BP interneurons also expressed neuropeptide Y but not cholecystokinin. CRF appeared to have an excitatory role in the dentate gyrus as it decreased the afterhyperpolarization of dentate granule neurons. These results suggest that CRF may contribute to the development of amygdala kindling. However, the compensatory induction of CRF-BP may serve to limit the excitatory effects of CRF in the dentate gyrus.

Amygdala↗
PubMed1997

Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients.

BACKGROUND: Therapeutic effects of the tripeptide protirelin (thyrotropin-releasing hormone) have been postulated in the affective disorders, but direct assessment in humans has been hindered by poor blood-brain barrier permeability. METHODS: Eight medication-free inpatients with refractory depression received 500 micrograms of protirelin via a lumbar intrathecal injection and an identical sham lumbar puncture procedure, separated by 1 week, in a double-blind crossover design. RESULTS: Five of eight patients responded to intrathecal protirelin, defined as a 50% or greater reduction in an abbreviated Hamilton Rating Scale for Depression score. Suicidality also was reduced significantly (P < .05). Responses were rapid and clinically robust, but short-lived. CONCLUSION: Administration of protirelin by an intrathecal route induced a rapid improvement in mood and suicidality in these refractory depressed patients, supporting the hypothesis that thyrotropin-releasing hormone could be a positive modulator of mood.

Affect↗
PubMed1997

Role of central dopaminergic and 5-hydroxytryptaminergic projections in the behavioral responses elicited by thyrotropin-releasing hormone in rats.

The systemic administration of thyrotropin-releasing hormone (TRH) to rats elicits locomotor activation, wet dog shakes, jaw movements, paw licking and tail rattle. Central dopamine (DA) and 5-hydroxytryptamine (5-HT) systems and peripheral vagal afferents have been implicated in these responses. To define this circuitry further, the effects of lesions of these pathways on the behavioral responses elicited by intraperitoneal (IP) injections of TRH were assessed in rats. Lesions of the DAergic innervation of the nucleus accumbens did not affect the locomotor activation, wet dog shakes, paw licking, jaw movements or tail rattle elicited by TRH. This is consistent with our in vivo microdialysis finding that TRH did not affect the release of DA in the nucleus accumbens at a dose that strongly increased locomotor activity. Depletion of spinal 5-HT significantly decreased the wet dog shakes induced by TRH, while depletion of forebrain 5-HT had no effect on any behavior. Bilateral vagotomy did not affect the locomotor response to TRH or any of the other behaviors measured. Taken together these results suggest that the DAergic mesolimbic, the 5-HTergic projections to the forebrain and vagal afferent systems are not mediators of the behavioral responses to systemic TRH. In contrast, the raphe-spinal 5-HTergic projection system may serve to modulate the wet dog shakes elicited by this peptide.

Animals↗
PubMed1997

Rat nurr1 is prominently expressed in perirhinal cortex, and differentially induced in the hippocampal dentate gyrus by electroconvulsive vs. kindled seizures.

We isolated a rat orphan nuclear hormone receptor from a brain cortex cDNA library. The sequence of the cDNA insert was 2154 bp with an open reading frame of 1794 bp encoding a putative protein of 598 amino acids and predicted molecular mass of 65 kDa. The deduced amino acid sequence showed a strong homology to the mouse nurr1 and human NOT1 orphan nuclear hormone receptors of the NGFI-B/nur77/NAK1 gene subfamily. We refer to this rat clone as r-nurr1. Northern blot analysis showed that r-nurr1 mRNA was highly expressed in the brain and moderately in the lung as a 4.0 kb transcript. A smaller transcript of 2.5 kb was also detected in the testes. The level of r-nurr1 transcript in the heart, skeletal muscle, liver, kidney and spleen was marginal. In situ hybridization showed that r-nurr1 mRNA was constitutively expressed in various regions of the CNS, particularly in the deeper layers (IV to VI) of the perirhinal cortex and area 2 of parietal cortex. We further evaluated the modulation of r-nurr1 expression in CNS by an electroconvulsive seizure (ECS) and by an amgydala-kindled seizure. A single ECS administered via earclip electrodes induced a rapid and transient increase of r-nurr1 mRNA in the granule cells of the dentate gyrus, being significant at 15 min after the seizure, maximal approximately 1 h and back to baseline at 4 h. The amygdala kindled seizure revealed a less robust and restricted nurr-1 induction in the CNS, as only two of the four kindled animals showed a unilateral induction of nurr1 mRNA in the dentate gyrus. These results suggest that r-nurr1 is an immediate-early gene that is differentially induced by ECS vs. kindled seizures. In addition, as r-nurr1 is prominently expressed in the specific brain sites associated with memory acquisition and consolidation, it may play a role in memory processing.

Animals↗
PubMed1997

Lipofectin-facilitated transfer of cholecystokinin gene corrects behavioral abnormalities of rats with audiogenic seizures.

To evaluate the potential for lipofectin-mediated central nervous system gene transfer, the plasmid coding for cholecystokinin was administered intracerebroventricularly to rats, which have congenital audiogenic seizures and high responses to peripheral electric stimulation-induced analgesia. Previous studies had shown that low brain cholecystokinin levels may be the neurochemical variable of rat's audiogenic seizure and high responses to the analgesia because cholecystokinin is an anticonvulsant and anti-opioid neuropeptide. Gene transfer of cholecystokinin corrected the increased susceptibility to audiogenic seizures and the high responses to analgesia for about one week. Similar administration of plasmid expressing beta-galactosidase indicated that the vector mainly transfected ependymal cells lining the ventricle and pia mater cells. The increased cholecystokinin messenger RNA and immunoreactivity in the hippocampus following stereotactic intrahippocampal administration of cholecystokinin plasmid was also demonstrated with in situ hybridization and immunohistochemistry techniques. These results suggest that lipofectin-mediated gene transfer will be useful for studies of brain function, the modification of behavior and gene therapy for central nervous system disorders.

Acoustic Stimulation↗
PubMed1997

Effects of the 5-HT3 antagonist, ondansetron, on the behavioral and physiological effects of pentagastrin in patients with panic disorder and social phobia.

Pentagastrin, a cholecystokinin (CCK) agonist, produces anxiety and panic in patients with panic disorder and social phobia. Preclinical data suggests that pentagastrin-induced anxiogenesis may be mediated via 5-HT3 receptors. In the present study, 14 patients with panic disorder or social phobia underwent pharmacological challenge in three conditions: (1) pretreatment with saline followed by pentagastrin infusion; (2) pretreatment with ondansetron followed by pentagastrin infusion; and (3) pretreatment with saline followed by saline infusion. As expected, pentagastrin administration led to increased anxiety, physical symptoms of panic attacks, pulse, plasma adrenocorticotropic hormone (ACTH), and cortisol. Pentagastrin's behavioral effects were not blocked by ondansetron, and in fact, tended to be exaggerated. Ondansetron pretreatment did not alter the pentagastrin-induced cortisol increase but significantly prolonged the pentagastrin-induced increase in ACTH. These findings suggest that pentagastrin's behavioral effects are not mediated by 5HT3 receptors. Mechanisms by which peripherally administered CCK agonists lead to anxiety remain to be elucidated.

Adult↗
PubMed1997

Emergent properties of neural systems: how focal molecular neurobiological alterations can affect behavior.

Whereas the basic wiring diagram of the mammalian central nervous system (CNS) is genetically preprogramed, its fine tuning throughout different phases of infancy, childhood, and adulthood are highly experience dependent. The potential neurobiological mechanisms and behavioral effects of such experience-dependent neuroplasticity as a function of stage of development are outlined. A basic thesis of this paper is that mechanisms involved in neuronal learning and memory, such as long-term potentiation (LTP) and long-term depression (LTD), are used and reused not only in the sculpting of the CNS in the initial establishment of connections, but also again in the molding of personality and behavior based on experience. It is postulated that for higher order processes such as emotional memory, such neuroplasticity is occurring at increasingly larger numbers of synapses and cell assemblies with increasing mechanistic complexity and self-organization. Just as overexcitation or deprivation can profoundly affect the development of the visual system, it is postulated that similar phenomena exist in the neural substrates of emotional and cognitive development. In addition, a secondary and potentially more widespread series of ramifications are likely to occur in the higher order and integrative systems, such as secondary and tertiary cortical association areas and prefrontal cortex that become the ultimate integrators of emotion and experience, leading to subsequent actions and plans for the future. This process is by definition, plastic, and such remodeling is likely to take place not only at the level of the single synapse, but also at higher levels of network integration of which we currently have only the barest glimpse. Nonetheless, beginning to discuss the neurobiology of such self-organizing plastic systems may begin to change our conceptual approaches to psychopathology and open new avenues of therapeutics for the major psychiatric illnesses that are critically dependent on such higher order learning and memory mechanisms.

Adult↗
PubMed1997

The management of coexisting depression in patients with dementia: potential of calcium channel antagonists.

Depression frequently coexists with dementia, although in many cases the depression is not recognized clinically. Depression represents a major additional burden in dementia, not only for the patients but also for families, caregivers, and, economically, society as a whole. However, depression in patients with dementia does respond to treatment, and appropriate therapy can significantly improve the well-being of these patients. Depression in patients with dementia is currently treated with a variety of standard antidepressive agents (tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), but none is free from significant side effects. Moreover, the use of these drugs is often complicated by a number of age-related factors or effects on the cholinergic neurotransmitter system. Consequently, an antidementia treatment with concomitant antidepressive properties and an acceptable benefit/risk ratio would represent an attractive therapeutic option. The pathogenesis of depression in patients with dementia is not well understood, but may be related to increased intracellular calcium ions in the CNS, the so-called "calcium hypothesis." This hypothesis may explain why some calcium antagonists exert psychotropic effects, including putative antidepressant activity. Animal models and clinical data provide support for the use of calcium channel antagonists for the treatment of depression, with the potential for good tolerability. The latter aspect is especially important for elderly patients with dementia. Although antidepressive effects have been seen with a number of calcium channel antagonists, the dihydropyridine derivative nimodipine shows particular potential for clinical use, perhaps because nimodipine is one of the most lipophilic of these drugs and therefore achieves high concentrations in the CNS, and because of the unique biochemical properties of the dihydropyridine compounds compared with other L type calcium channel blockers. Nimodipine also increases somatostatin levels in CSF, one of the cardinal biochemical deficits in Alzheimer's disease. Data obtained incidentally from the use of nimodipine in the treatment of elderly demented patients clearly demonstrate significant antidepressant activity by the drug in this patient group. Formal clinical evaluation is therefore recommended to establish more clearly the therapeutic benefits offered by nimodipine in patients who suffer from both dementia and depression.

Aged↗
PubMed1997

Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder.

OBJECTIVE: The authors studied the efficacy of valproate plus lithium and of triple therapy with lithium, carbamazepine, and valproate in refractory bipolar illness. METHOD: The subjects were 24 bipolar outpatients who had completed an intended 3-year crossover study comparing lithium, carbamazepine, and their combination. Patients entered a 1-year phase of valproate plus lithium because of inadequate response or major side effects, and patients with inadequate responses were offered an additional year of treatment with all three mood-stabilizing drugs. RESULTS: Six (33%) of the 18 evaluable patients had moderate to marked responses to valproate plus lithium; four of these six had not responded to any previous treatment condition. Three of seven patients responded to triple therapy, although only one response was marked. CONCLUSIONS: Some outpatients with bipolar disorder refractory to lithium and carbamazepine received clinically relevant prophylactic benefit from valproate when used with lithium or in triple therapy.

Adult↗
PubMed1997

Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial.

OBJECTIVE: Preliminary studies have indicated that daily left prefrontal repetitive transcranial magnetic stimulation might have antidepressant activity. The authors sought to confirm this finding by using a double-blind crossover design. METHOD: Twelve depressed adults received in random order 2 weeks of active treatment (repetitive transcranial magnetic stimulation, 20 Hz at 80% motor threshold) and 2 weeks of sham treatment. RESULTS: Changes from the relevant phase baseline in scores on the 21-item Hamilton depression scale showed that repetitive transcranial magnetic stimulation significantly improved mood over sham treatment. During the active-treatment phase, Hamilton depression scale scores decreased 5 points, while during sham treatment the scores increased or worsened by 3 points. No adverse effects were noted. CONCLUSIONS: These placebo-controlled results suggest that daily left prefrontal repetitive transcranial magnetic stimulation has antidepressant activity when administered at these parameters. Further controlled studies are indicated to explore optimal stimulation characteristics and location, potential clinical applications, and possible mechanisms of action.

Adult↗
PubMed1997

Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders.

OBJECTIVE: The author's goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients. METHOD: Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism. RESULTS: Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism. CONCLUSIONS: These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.

Adult↗
PubMed1997

Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study.

OBJECTIVE: Prefrontal mechanisms are implicated in obsessive-compulsive disorder. The authors investigated whether prefrontal repetitive transcranial magnetic stimulation influenced obsessive-compulsive disorder symptoms. METHOD: Twelve patients with obsessive-compulsive disorder were given repetitive transcranial magnetic stimulation (80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes) to a right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control) site on separate days, randomized. The patients' symptoms and mood were rated for 8 hours afterward. RESULTS: Compulsive urges decreased significantly for 8 hours after right lateral prefrontal repetitive transcranial magnetic stimulation, but there were nonsignificant increases in compulsive urges after repetitive transcranial magnetic stimulation of the midoccipital site. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation. Mood improved during and 30 minutes after right lateral prefrontal stimulation. CONCLUSIONS: These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder.

Adult↗
PubMed1997

Blunted left cingulate activation in mood disorder subjects during a response interference task (the Stroop).

Functional neuroimaging studies have found abnormal anterior cingulate activity in depressed subjects, and other studies have shown that the cingulate gyrus becomes active in healthy subjects during interference tasks. The authors hypothesized that subjects with mood disorder might show blunted cingulate activation during the standard Stroop interference task or during a modified version involving sadness-laden words. In contrast to 11 age- and sex-matched healthy control subjects who activated the left cingulate during the standard Stroop, 11 mood-disordered subjects activated the right anterior cingulate gyrus only slightly and instead showed increased activity in the left dorsolateral prefrontal and visual cortex. This study supports theories of blunted limbic and paralimbic activation and abnormal cingulate activity in depression and adds to the growing knowledge of the functional neuroanatomy of depression.

Adult↗
PubMed1997

Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder.

BACKGROUND: We compared the prophylactic efficacy of lithium, carbamazepine, and the combination and identified possible clinical markers of response. METHOD: Fifty-two outpatients who met DSM-III-R criteria for bipolar illness were randomly assigned in a double-blind design for an intended 1 year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and then a third year on the combination. Patients received monthly detailed evaluations, and daily life chart ratings of the degree of functional incapacity associated with mania or depression were completed. RESULTS: For evaluable patients: 13 (31.0%) of 42 failed to complete a full year of lithium therapy owing to lack of efficacy, and 2 dropped out because of side effects; 13 (37.1%) of 35 withdrew from carbamazepine within the first year owing to lack of efficacy, and 10 dropped out because of side effects (9 of the 10 had a rash); 7 (24.1%) of 29 withdrew from the combination therapy owing to lack of efficacy. The percentage of the evaluable patients who had marked or moderate improvement on the Clinical Global Impressions scale was 33.3% on lithium. 31.4% on carbamazepine, and 55.2% on the combination treatment, which was not significantly different. By a variety of measures, lithium was more effective than carbamazepine in the prophylaxis of mania. Patients with a past history of rapid cycling did poorly on monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine), but significantly better on the combination (56.3%, p < .05). CONCLUSION: These prospective, randomized data suggest a high incidence of inadequate response to either mood stabilizer or their combination despite use of adjunctive agents as needed. Additional novel treatment regimens are needed to better decrease affective morbidity in large numbers of bipolar outpatients.

Adult↗