Biomedical subjects

David J Echevarria

Publications and source records attributed to David J Echevarria.

8 recordsLinked to original sources

PubMed2005

Role of brain norepinephrine in the behavioral response to stress.

The brain noradrenergic system is activated by acute stress. The post-synaptic effects of norepinephrine (NE), exerted at a cellular or neural circuit level, have been described as modulatory in nature, as NE facilitates responses evoked in target cells by both excitatory and inhibitory afferent input. Over the past few years, we have undertaken a series of studies to understand how these cellular modulatory effects of NE, elicited by acute stress, might translate into modulation of the behavioral-affective components of the whole-animal response to stress. Using microdialysis, we have demonstrated that acute immobilization stress activates NE release in a number of stress-related limbic forebrain target regions, such as the central and medial amygdala, lateral bed nucleus of the stria terminalis, medial prefrontal cortex, and lateral septum. Using microinjections of adrenergic antagonist drugs directly into these regions, we have shown that this stress-induced release of NE facilitates a number of anxiety-like behavioral responses that are mediated in these regions, including stress-induced reduction of open-arm exploration on the elevated plus-maze, stress-induced reduction of social interaction behavior, and activation of defensive burying behavior by contact with an electrified probe. Dysregulation of the brain noradrenergic system may be a factor in determining vulnerability to stress-related pathology, or in the interaction of genetic vulnerability and environmental sensitization. Compared to outbred Sprague-Dawley rats, we have shown that the modulatory effect of NE is deficient in Wistar-Kyoto rats, which also exhibit attenuated behavioral reactivity to acute stress, as well as increased vulnerability to stress-induced gastric ulcers and exaggerated activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. Further, repeated exposure to mild intermittent cold stress resulted in a much greater sensitization of both the brain noradrenergic system and the HPA axis in Wistar-Kyoto rats compared to Sprague-Dawley rats. The recruitment of a robust noradrenergic facilitatory influence following repeated cold exposure in this previously deficient strain resulted in an aberrant HPA response, which may be illustrative of the kinds of neurobiological changes that may contribute to the development of stress-related neuropsychiatric disorders such as depression, post-traumatic stress disorder, or other anxiety disorders in predisposed or susceptible individuals. On the other side of the same issue, regulatory alterations in noradrenergic neurotransmission, or in the stress-modulatory functions of NE, may be important in the behavioral effects of chronic antidepressant drug treatment. We present recent preliminary results addressing the effects of chronic treatment with the selective NE reuptake inhibitor, desipramine, on acute behavioral reactivity to stress. A better understanding of the role of NE in adaptive responses to acute stress, the pathological consequences of prolonged, repeated or severe stress, and the mechanisms of action of drugs used to treat stress-related diseases, may contribute to the future development of more effective strategies for the treatment or even prevention of such disorders.

Animals↗

PubMed2005

Administration of the galanin antagonist M40 into lateral septum attenuates shock probe defensive burying behavior in rats.

Galanin (GAL) has been implicated in modulating anxiety, although a precise role remains unclear. Previous studies revealed anxiolytic effects, anxiogenic effects, or no effect, depending on the test, brain region, route of drug administration and context. We have shown previously that microinjection of the GAL antagonist M40 into central amygdala blocked an anxiolytic response to acute stress on the elevated plus maze when rats were pretreated with yohimbine, suggesting an anxiolytic effect of GAL. By contrast, we also showed that microinjection of M40 into the lateral bed nucleus of the stria terminalis attenuated anxiety-like behavioral responses to stress on the plus maze and social interaction tests, implying an anxiogenic effect for GAL. The behavioral response to stress on both these tests is a reduction of an ongoing behavior (open-arm exploration or social interaction, respectively). To better understand the anxiety-modulating role of GAL, it is also important to ascertain its effect on a response that represents an activation rather than suppression of behavior. Thus, in this study, we investigated an active behavioral response to acute stress in rats, the shock-probe defensive burying response. Bilateral microinjections of M40 into lateral septum (LS), a region important to this response and innervated by GAL, dose-dependently decreased burying without affecting immobility. No change was seen in hindpaw withdrawal latency on a thermosensitivity assay, suggesting that the reduction in burying behavior was not attributable to changes in cutaneous pain sensitivity. These results indicate that in LS, GAL facilitates the active anxiety-like behavioral response on the defensive burying test, similar to its facilitatory effect on anxiety-like stress-induced suppression of behavior in the lateral bed nucleus. These results highlight the fact that, rather than a unified system-like role in modulating anxiety, the effects of GAL can be either facilitating or attenuating, and are region-specific, context-specific and response-specific.

Animals↗

PubMed2005

Galanin and perseveration.

Galanin is a 29/30 amino acid neuropeptide that has been shown to impair learning and memory task performance and also have roles in somatosensation, stress responses, sexual behavior, and feeding regulation. However, little is known about galanin involvement in higher cognitive processes, especially executive processes. Perseveration is a classic sign of frontal cortex damage and failure of executive control. Galanin has been shown to disrupt the performance of maze delayed alternation tasks and the operant, spatial delayed nonmatch-to-position (DNMTP) working memory task, tests especially sensitive to perseverative responding. To better understand this potential involvement of galanin in executive control, the present study tested the hypothesis that galanin induces perseveration. The first experiment examined the effects of galanin (10, 20 microg i.c.v.) on the performance of a simple operant response alternation task in which stimuli were assigned to one of two spatially distinct locations to produce extended sequences of presentations to one location, separated by a 10-s intertrial interval. The second experiment looked at the effects of galanin (5, 20 microg i.c.v.) on the performance of non-delayed match-to-position and nonmatch-to-position conditional discrimination operant tasks in which a minimal 1.0 s time interval separated responses. Finally, the effects of galanin (10, 20 microg i.c.v.) on delayed match-to-position (DMTP) performance were examined to determine whether response alternation (i.e., nonmatching) was critical to observing a galanin-induced impairment in this task. Galanin reduced the rate of trial completion in all the tasks, but did not alter simple or conditional discrimination accuracy. Galanin (10 microg) impaired DMTP performance in a delay-independent manner. Together, these data suggest that galanin does not produce perseveration, but are consistent with a galanin-induced decrease in reinforcer strength.

Animals↗

PubMed2005

Memory facilitation by methylene blue: dose-dependent effect on behavior and brain oxygen consumption.

Methylene blue administered post-training improves memory retention in avoidance and appetitive tasks, and restores spatial memory impaired by an inhibitor of cytochrome oxidase. Methylene blue may improve memory retention by increasing brain oxygen utilization. We investigated which doses improve memory without nonspecific behavioral effects, and whether methylene blue enhances brain oxygen consumption. Different doses were evaluated 24 h after administration in wheel running, feeding, open field habituation and object recognition tests. The 1-10 mg/kg methylene blue-treated rats were not different from saline-treated rats in locomotion or feeding behavior. The 50-100 mg/kg doses decreased running wheel behavior. The 4 mg/kg dose improved behavioral habituation and object memory recognition. Dose-dependent effects of methylene blue on brain oxygen consumption revealed that low concentrations increased brain oxygen consumption in vitro and 24 h after in vivo administration. Therefore, methylene blue doses that increase brain oxygen consumption also facilitate memory retention.

Analysis of Variance↗

PubMed2005

Construct validity of an operant signal detection task for rats.

Many psychoactive drugs produce simultaneous effects on a variety of psychological processes. Behavioral measures in tasks designed to assess cognitive processes in rodents should be able to characterize and dissociate these multiple influences. The present study evaluated how error measures in a classic two-choice operant spatial signal detection paradigm were affected by procedural manipulations of the motivational state of the rat, stimulus properties, and alterations of the inter-trial interval. The experiments were conducted in a two lever operant chamber in which a cue lamp was mounted over each lever. The rats were trained to respond quickly to a short illumination of one of the cue lamps at one of three durations (100, 300 or 1000 ms), presented in a random order. The procedural manipulations were (1) to allow pre-session water access to the normally water-restricted subjects, (2) to vary the intertrial interval (ITI) between sessions, (3) to reduce the intensity of the discriminative stimuli, and (4) to manipulate the variability of the ITI within a session. Stimulus duration-dependent decreases of detection accuracy were observed following pre-session water access and when the intertrial interval was decreased. A reduction of stimulus intensity resulted in decreased accuracy at all stimulus durations. Varying the ITI within the session produced stimulus duration-independent alterations of detection accuracy but no change in the frequency of errors of omission. These findings show that distinct patterns of performance deficits result from manipulating different components of this task and that errors of omission and commission often co-vary and raise questions about the definitions of vigilance and sustained attention as these constructs apply to signal detection tasks that present spatially distinct stimuli.

Animals↗

PubMed2005

Assessment of new functional roles for galanin in the CNS.

There is considerable evidence that galanin plays an important role in food intake, nociception, stress reactivity, sexual behavior, and learning. However, its involvement in other important behavioral processes, especially higher cognition, has not been systematically investigated. This review summarizes our recent efforts to explore the role of galanin in executive processes as well as in fundamental motivational and motor productive processes that are essential to the behavioral assessment of cognitive constructs in rodents. Our work points to a role in reward processes and physiological water balance regulation, and argues against a role for galanin in fine motor production and maintenance, simple visual discrimination, and perseveration.

Animals↗

PubMed2005

One for all or one for one: does co-transmission unify the concept of a brain galanin "system" or clarify any consistent role in anxiety?

Galanin (GAL) is a potential target for novel antidepressant or anti-anxiety drug development. However, no integrated role for a "brain galanin system" in anxiety has yet emerged. It is possible that such a function may be revealed by examining the interaction of GAL with norepinephrine (NE), with which it is prominently co-localized. We showed previously that enhancing stress-activation of the NE system by yohimbine (YOH) pretreatment induced the release of GAL in central amygdala (CeA) to exert an anxiolytic effect on the elevated plus-maze. However, it remained to be demonstrated conclusively that GAL was co-released from NE terminals in CeA in this context, or if a multi-synaptic circuit activated GAL release from another afferent to CeA, or from local GAL neurons in the vicinity of CeA. In studies presented at the Third International Symposium on Galanin and Its Receptors, we utilized a combination of behavioral pharmacological approaches, testing the effects of YOH on the behavioral response to stress on the plus-maze after lesioning NE afferents to CeA with 6-OHDA, and anatomical approaches to identify GAL afferents to CeA that are activated in the context of stress with yohimbine pretreatment, to address these alternatives. Our results suggest that GAL was not co-released from noradrenergic terminals innervating CeA to exert an anxiolytic influence when noradrenergic activation was amplified by yohimbine pretreatment. Rather, it most likely originated from GAL neurons immediately adjacent to CeA that were activated by a non-noradrenergic afferent arising from elsewhere in the brain, itself activated by increasing NE activity. Thus, any role for brain GAL in anxiety remains region-specific, pathway specific, response specific and context-specific, which is likely to continue to present challenges to the development of novel agents targeting brain GAL for treatment of depression or anxiety.

Animals↗

PubMed2004

Regulation of feeding by galnon.

Galanin is a neuropeptide that has been implicated in multiple bioactivities, inter alia eating disorders. In this study, we have examined the effects of galnon, a novel low molecular weight galanin receptor ligand. Previous studies have shown that galnon acts as a systemically active, blood-brain barrier crossing agonist on galanin signaling both in vitro and in vivo, inhibiting pentylenetetrazole-induced seizures. Here, intracerebroventricular (10-20 microg) and intraperitoneal (1.5-5 mg/kg) administration of galnon induced a strong, dose-dependent reduction of food intake in rats and mice. This reduction in feeding occurred without reducing general activity and was shown to be attenuated by an intracerebroventricular administration of M35, a peptide galanin antagonist. These data demonstrate that galnon is a promising tool for studies of the involvement of galanin in feeding disorders and other behavioral processes.

Animals↗