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Biomedical subjects

C D Conrad

Publications and source records attributed to C D Conrad.

12 recordsLinked to original sources
PubMed1997

The effects of type I and type II corticosteroid receptor agonists on exploratory behavior and spatial memory in the Y-maze.

We investigated the effects of two adrenal steroid agonists on adrenalectomized (ADX) rats' performance on the Y-maze. The Y-maze was chosen because memory can be assessed quickly and because it is sensitive to various parameters of exploratory behavior and spatial memory performance. Four days after surgery, ADX rats were injected with aldosterone (ALDO, a selective Type I receptor agonist), RU362 (a selective Type II receptor agonist) or sesame vehicle at three different time points (120 min prior to Trial 1, immediately after Trial 1 or 120 min after Trial 1). SHAM-operated rats injected with vehicle were also tested. The results indicate that vehicle-treated ADX rats were impaired on spatial recognition memory compared to SHAM rats. Treatment with ALDO restored spatial recognition memory performance of ADX rats to a level comparable to SHAM-treated rats by acting on acquisition and consolidation, whereas treatment with RU362 did not change the poor spatial recognition memory performance of ADX rats. Discrimination memory was improved only when either agonist was injected prior to the first trial, strongly suggesting a non-selective effect of corticosteroids on discrimination memory such as increasing arousal. A detailed analysis of exploratory behavior showed that both the ALDO- and RU362-treated rats explored the Y-maze more than the ADX and SHAM groups at all periods of the experiment. These results show that the non-specific increase in exploratory behavior induced by replacing corticosteroids targeted at Type I and Type II receptors was used differentially with the ALDO-treated rats learning and consolidating spatial information better than the RU362-treated rats. These data are discussed along with other evidence to suggest that Type II receptors may require the simultaneous occupancy of Type I receptors to affect learning and memory processes.

Adrenalectomy↗
PubMed1997

Prevention of stress-induced morphological and cognitive consequences.

Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.

Animals↗
PubMed1997

Long-term adrenalectomy can decrease or increase hippocampal dentate gyrus volumes.

Male and female Long-Evans adult rats were adrenalectomized and sacrificed 6 weeks later to determine whether dentate gyrus damage would differ in females and males. A subset of adrenalectomized rats of both sexes had significantly reduced dentate gyrus volumes compared to the same sex SHAM operated rats. The remainder of the male and female adrenalectomized rats which did not have clear dentate gyrus damage had significantly larger dentate gyrus volumes compared to the same sex SHAM rats. The dentate gyrus volumes of all adrenalectomized rats were significantly correlated with two indices of residual hormonal levels (Na+/K+ ratios and body weight gain 6 weeks after surgery), indicating that endogenous corticosterone levels may be a determining factor in the response of the dentate gyrus to adrenalectomy. These dentate gyrus volumetric changes could not be attributed to tissue shrinkage as there were no changes in CA3 volumes in any of the groups. These results suggest that long-term adrenalectomy can result in either increased or decreased dentate gyrus volumes and that the adrenal steroid levels of each individual adrenalectomized rat may be the factor determining the direction of the dentate gyrus volumetric response.

Adrenal Glands↗
PubMed1996

Calcitonin gene-related peptide level in the rat dentate gyrus increases after damage.

Calcitonin gene related peptide-like immunoreactivity (CGRP-LI) was examined in rat dentate gyrus (DG) following damage to granule cells by adrenalectomy or intrahippocampal colchicine injections. In normal DG, CGRP-LI was present in a diffuse hand within the inner third of the molecular layer (ITML) and in hilar cells. Following the experimental procedures, levels of CGRP-LI increased bilaterally in the ITML and in hilar interneurons resembling mossy cells. Ultrastructural analysis of the ITML revealed that CGRP-LI is associated with large, dense-core vesicles within axon terminals which form asymmetrical synapses with dendritic spines, and within dendritic spines. The increase in CGRP-LI level following granule cell damage suggests a protective role for CGRP in the response to hippocampal injury.

Adrenalectomy↗
PubMed1996

Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment.

Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.

Animals↗
PubMed1995

Dentate gyrus destruction and spatial learning impairment after corticosteroid removal in young and middle-aged rats.

We investigated the functional and behavioral implications of chronic corticosteroid removal in young and middle-aged rats. Prepubertal and 13-month-old rats were adrenalectomized (ADX) or sham operated (SHAM). The young ADX rats were divided further into three groups: ADX with no hormone replacement, ADX given corticosterone chronically, (chCORT), and ADX given corticosterone acutely at the time of Morris water maze testing (acCORT). All rats were run on the Morris water maze 12 weeks after surgery. They were then sacrificed and the brains were removed for histological analysis. The results showed that prolonged corticosteroid absence caused major damage to the dentate gyrus and learning impairment on the Morris water maze. The chCORT rats had little dentate gyrus cell loss and were as efficient as the controls in Morris water maze performance, whereas the acCORT rats had dentate gyrus cell loss and were impaired in the spatial acquisition task. Furthermore, exogenously administered corticosterone had an interactive effect on ADX rats. Water maze performance was improved in dentate gyrus damaged rats (acCORT) compared to ADX rats not given corticosterone, whereas ADX rats with very little dentate gyrus damage (chCORT) did not exhibit better water maze performance relative to controls. Middle-aged ADX rats lost cells only in the dorsal blade of the dentate gyrus but they did not show a learning impairment in the Morris water maze relative to the middle-aged controls. These results indicate that corticosteroids are trophic for the dentate gyrus, that mature granule cells are less affected by adrenalectomy, that corticosteroid absence is responsible for some water maze impairment in ADX rats, but that in addition to corticosteroid absence, a substantial amount of dentate gyrus damage is necessary to impair spatial learning.

Adrenal Cortex Hormones↗
PubMed1993

Selective loss of hippocampal granule cells following adrenalectomy: implications for spatial memory.

We examined the effects of long-term adrenalectomy (ADX) on hippocampal anatomy and behavioral learning in two spatial memory tasks. We assessed damage throughout the hippocampus by stereological analysis of the dentate gyrus and Ammon's horn. Rats were ADX or sham operated, and then tested in the Morris water maze 12 weeks after surgery, followed by testing on an eight-arm, alternating-baited radial maze at 22 weeks postsurgery. Animals were killed 7 1/2 months after surgery. ADX rats had selective volume reduction in the dentate gyrus with no changes in pyramidal regions CA1, CA2, CA3, or CA4. Dentate gyrus damage in some cases occurred throughout the entire rostrocaudal extent of the hippocampus. Analysis of corticosterone serum levels, serum Na+/K+ ratios, and body weight gain suggested that individual differences in dentate gyrus damage appear to be due to incomplete adrenalectomies or remaining ectopic tissue. ADX rats were able to learn in both the Morris water maze and eight-arm radial maze, even when the dentate gyrus was severely damaged (80% volume reduction). However, in the Morris water maze, the ADX rats' learning rate was significantly slower compared to controls. There was no difference between ADX and controls during reversal in either task. These data indicate that damage to the dentate gyrus following long-term ADX is severe enough to cause learning impairment in selected learning tasks. Such damage is restricted to the dentate gyrus and can occur throughout the rostrocaudal regions of the hippocampus.

Adrenalectomy↗
PubMed1986

Symptom exacerbation in psychotically depressed adolescents due to high desipramine plasma concentrations.

The pharmacological treatment of two female adolescent patients meeting DSM-III criteria for psychotic depression is described. A combined antipsychotic and tricyclic antidepressant regimen led to clinical remission. However, a recrudescence in both psychotic and depressive symptoms developed as plasma desipramine levels rose 4 times higher than anticipated from the oral doses prescribed. Clinical improvement occurred in both cases when plasma desipramine levels were reestablished below 200 ng/ml. Thus, we recommend prospective monitoring of desipramine plasma levels, especially when an antipsychotic agent that inhibits the metabolism of the tricyclic antidepressant is also used. We further suggest that deterioration with the reemergence of the presenting clinical syndrome, without signs of delirium, represents a distinct manifestation of antidepressant toxicity. Finally, these cases support the existence of a therapeutic upper limit for desipramine plasma concentrations, above which clinical deterioration occurs.

Adolescent↗
PubMed1975

Direct visual input to the limbic system: crossed retinal projections to the nucleus anterodorsalis thalami in the tree shrew.

Evidence for a direct projection from the retina to the nucleus anterodorsalis thalami in the insectivore, Tupaia glis, is presented. 100 muCi tritiated amino acid or amino acid/monosaccharide cocktail were administered as two separate intravitreal injections of 50 muCi each. Fibers were traced using thawmount autoradiography in which tissue is frozen in liquid propane, cryostat-cut, and mounted on photographic emulsion precoated slides (Conrad and Stumpf, 1974). From the dorsolateral geniculate body, contralateral retinal fibers continue as a dorsomedial extension of the optic tract. When traced rostrally from this point, the fibers form a thin fascicle coursing medially under the third ventricle. In the anterior thalamus the bundle arborizes within the n. anterodorsalis, infiltrating its caudal pole completely but only encapsulating the nucleus anteriorly. This new retino-anterodorsal thalamic projection, together with the known anterior thalamic-retrosplenial projection, represents a third visual pathway in Tupaia glis distinct from the retino-geniculo-striatal and retino-tecto-pulvinar-peristriatal systems. It is significant that each of these thalamic relay nuclei projects to an architectonically different cortical region, with the nucleus anterodorsalis sending afferents to the phylogenetically most primitive of the visual cortices, the retrosplenial proisocortex or prostriata (Vitzthum and Sanides, 1967). It is proposed that the retino-anterior thalamic-retrosplenial circuit forms an anatomical substrate by which light cues may affect emotional behavior and corresponding neurovisceral responses.

Amino Acids↗