Biomedical subjects

R M Sullivan

Publications and source records attributed to R M Sullivan.

At least 37 records · Page 2Linked to original sources

PubMed1999

Neonatal ventral hippocampal lesions attenuate the nucleus accumbens dopamine response to stress: an electrochemical study in the adult rat.

Neonatal damage to the ventral hippocampus (VH) can lead, during adulthood, to behaviours that are believed to reflect enhanced mesocorticolimbic dopamine (DA) transmission. In the present study, the effects of neonatal excitotoxic lesions to the VH on spontaneous locomotor activity and stress-elicited increases in extracellular nucleus accumbens (NAcc) DA levels were examined in adult rats. Male pups received, on postnatal day 7, bilateral injections of either an ibotenic acid solution (lesioned) or vehicle (sham-lesioned) into the VH. At 3-4 months of age, animals were assessed during five daily sessions for changes in spontaneous locomotor activity associated with habituation to a novel environment. Voltammetry was used in separate groups of sham- and VH-lesioned animals to monitor the NAcc DA response to each of five once-daily exposures to tail-pinch stress. The results indicate that while VH-lesioned animals seem to habituate to novelty, they remain hyperactive relative to sham-lesioned controls. In contrast, however, stress consistently elicited in VH-lesioned animals smaller and shorter-lasting increases in NAcc DA than in sham-lesioned controls. These data suggest that neonatal excitotoxic damage to VH leads to changes in DA function that persist into adulthood. The blunted response to stress seen in VH-lesioned animals indicates that one consequence of such damage is a functional hyporeactivity in meso-NAcc DA neurons. The fact that these animals are spontaneously more active suggests compensatory changes in DA function that are efferent to DA terminals in NAcc.

Animals↗

PubMed1999

Norepinephrine and associative conditioning in the neonatal rat somatosensory system.

Neonatal rats, aged postnatal days 3-4, were trained in a somatosensory associative conditioning task involving temporal correlation of facial vibrissa stimulation and aversive shock. This training resulted in a subsequent conditioned behavioral activation/arousal response to vibrissa stimulation alone, compared to non-learning control pups trained with random vibrissa-shock presentations. The acquisition of the conditioned response was blocked by systemic injections of the NE beta-receptor antagonist propranolol in a dose-dependent manner. In a second study, vibrissa stimulation was paired with systemic injections of the NE beta-receptor agonist isoproterenol. Association of vibrissa stimulation with beta-receptor activation resulted in subsequent conditioned responses to vibrissa stimulation alone, in a dose-dependent manner. Together, these results suggest that early associative somatosensory conditioning requires and involves NE in a manner similar to that previously demonstrated for early olfactory learning.

Adrenergic beta-Agonists↗

PubMed1999

Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats.

The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function.

Adrenal Glands↗

PubMed1999

Respiratory airflow pattern at the rat's snout and an hypothesis regarding its role in olfaction.

Respiratory airflow outside the external nares of the rat was mapped by monitoring temperature fluctuations with a thermistor and simultaneous piezoelectric monitoring of respiration-associated chestwall movement. The results demonstrated that both exhalation and inhalation airflow were directed laterally. Relatively little air exchange occurred anterior to the nares. These results suggest that the two nares of the rat take independent, bilateral samples of the odor environment. Combined with recent descriptions of laterally specific, spatial receptive fields in piriform cortical neurons, an hypothesis is outlined describing a mechanism of odor orientation in the rat involving comparisons of timing or intensity of bilateral odor stimulation.

Animals↗

PubMed1998

Relationships between stress-induced increases in medial prefrontal cortical dopamine and plasma corticosterone levels in rats: role of cerebral laterality.

In the present study, in vivo voltammetry was used to monitor changes in dopamine levels in the left and right medial prefrontal cortex of rats exposed to mild physical and psychological stress. These were 2 min of tail-pinch and 15 min exposure to cat odour, respectively. Fourteen male Long Evans rats with bilateral carbon fibre recording electrodes were tested on four consecutive days, and records obtained in each medial prefrontal cortex for each stressor. A week later, animals underwent a 20 min restraint stress, with plasma samples taken at 0, 20 and 80 min to determine stress-induced corticosterone responses. It was found that dopamine responses to tail-pinch were significantly longer-lasting in the left hemisphere than in the right, while this asymmetry was not present for the dopamine response to cat odour. Stress-induced dopamine increases elicited by the two stressors were significantly correlated only in the right medial prefrontal cortex. Restraint stress-induced increases in plasma corticosterone were positively correlated with dopaminergic responses to tail-pinch, but were only related to dopamine cat odour responses when individual asymmetries favoured the right medial prefrontal cortex. The data suggest that asymmetric mesocortical dopamine activation depends on the type of stress, and that regulation of dopamine responses to both types of stress is most tightly coupled in the right hemisphere. While neuroendocrine and dopaminergic stress responses are positively linked, this relationship is only asymmetrical for the psychological stressor, suggesting a specialized role for right cortical mechanisms in the integration of emotional and physiological responses to stressful situations. A preliminary report of this work was presented at the Society for Neuroscience meeting in Washington DC, November, 1996.

Amphetamine↗

PubMed1998

Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats.

The present study examined post mortem changes in central dopaminergic terminal regions following acute or chronic treatment regimens with the dopamine D2/D3 receptor agonist quinpirole, a psychomotor stimulant which induces pronounced behavioural sensitization when given chronically. Drug-induced changes in nucleus accumbens, striatum and amygdala were bilateral in nature, while in prefrontal cortex (medial prefrontal and anterior cingulate combined), left and right brain regions responded differentially to quinpirole. Acute drug treatment increased dopamine tissue levels in nucleus accumbens and right prefrontal cortex, while the dopamine metabolite 3,4-dihydroxyphenylacetic acid, was decreased in amygdala. In contrast, sensitization to quinpirole was associated with decreased dopamine levels in left prefrontal cortex, and increases in 3,4-dihydroxyphenylacetic acid levels in subcortical structures, particularly striatum and amygdala. Additionally, the increase in striatal 3,4-dihydroxyphenylacetic acid in chronic quinpirole animals was independent of drug treatment on the final day of injections. In summary, quinpirole induces a variety of simultaneous, regional changes in dopaminergic function, with the sensitized condition being primarily associated with an up-regulation of subcortical dopamine activity. While the nucleus accumbens and striatum play a well known role in motor activation and sensitized behaviour, it is concluded that the amygdala and prefrontal cortex have significant modulatory influences on these processes, with the role of the prefrontal cortex being asymmetrical in nature. Given the suggested relevance of behavioural sensitization to psychopathological states in humans, parallels are drawn between the present data and clinical findings, particularly in relation to obsessive-compulsive disorder.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Clinical usefulness of maternal odor in newborns: soothing and feeding preparatory responses.

This study assessed the responsiveness of newborn breast- and bottle-fed infants to presentations of maternal odor. Maternal odor was presented for 1 min to crying, sleeping or awake newborns. The odors were: (1) own mother's odor - presentation of a hospital gown worn by the baby's mother, (2) other mother's odor - presentation of a hospital gown of another newborn baby's mother, (3) clean gown - presentation of a clean hospital gown and (4) no gown - no gown presented. The results indicated that crying babies stopped crying when either own mother or other mother odor was presented. Awake babies responded specifically to their own mother's odor by increasing mouthing. These results suggest that the practice of presenting the mother's odor to a distressed infant is of clinical usefulness since it was capable of attenuating crying. The results also characterized a role for maternal odor with respect to feeding since presentation of the infant's own mother odor increased mouthing. Thus, presentation of maternal odor may also be useful in enhancing nipple acceptance and feeding in newborns.

Crying↗

PubMed1996

NMDA-receptor modulation of lateral inhibition and c-fos expression in olfactory bulb.

Olfactory bulb primary output neurons, mitral/tufted cells, are glutamatergic and excite inhibitory interneurons, granule cells, by activation of both alpha-amino-3-hydroxy-5-methyl-ioxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors. The data presented here demonstrate that the NMDA antagonists MK-801 and CGP39551, but not ketamine, significantly enhanced expression of c-fos mRNA by mitral cells as measured by in situ hybridization. All three antagonists significantly reduced mitral/tufted cell excitation of granule cells as measured with extracellular field potentials following antidromic stimulation of the lateral olfactory tract (LOT). In turn, the NMDA antagonists significantly reduced granule cell mediated feedback inhibition of mitral/tufted cells, as measured with field potential recordings of paired-pulse LOT stimulation, suppression of mitral/tufted cell single-unit spontaneous activity following LOT stimulation, and intracellularly recorded IPSP amplitude in mitral/tufted cells following LOT stimulation. While there was not a perfect correlation between the effects of the NMDA antagonists on c-fos mRNA expression and on inhibition, the results suggest that disinhibition of mitral/tufted cells accounts for the observed enhancement in c-fos mRNA expression induced by NMDA receptor antagonists.

2-Amino-5-phosphonovalerate↗

PubMed1996

Early locus coeruleus lesions increase the density of beta-adrenergic receptors in the main olfactory bulb of rats.

Norepinephrine is supplied to both deep and superficial layers of the olfactory bulb through dense projections from the locus coeruleus. Beta-adrenergic receptors are located in nearly all bulb laminae, with high-density foci of beta-1 and beta-2-adrenoceptors present in the glomerular layer. Early olfactory experiences that increase norepinephrine levels in the bulb also decrease the density of beta-1- and beta-2-adrenoceptors, as well as the number of high-density glomerular foci of beta-2-receptors. Changes in bulb norepinephrine levels, therefore, may affect the density of beta-adrenoceptors in the bulb. In the current study, we test this hypothesis by performing unilateral lesions of the locus coeruleus with 6-hydroxydopamine on postnatal day 4, and examining the density of beta-1- and beta-2-adrenergic receptors in the main olfactory bulb of the rat using 125I-labeled iodopindolol receptor autoradiography on postnatal day 19. Locus coeruleus destruction resulted in a statistically significant increase in the density of adrenergic receptors in the ipsilateral bulb compared to the contralateral bulb. Both beta-1- and beta-2-adrenoceptor subtypes increased in density with this manipulation, although the number of glomerular layer high-density beta-2 foci was not significantly different between the two bulbs. These results are consistent with the hypothesis that changes in olfactory bulb norepinephrine can regulate the density of beta-adrenergic receptors in the bulb.

Animals↗

PubMed1995

Dissociation of behavioral and neural correlates of early associative learning.

Wistar rat pups were trained in an olfactory associative conditioning task on postnatal Day 6, 12, or 20. The training consisted of 20 pairings of a novel odor (peppermint) with footshock (1.5 mA, 1 s) with an intertrial interval of 3 min. Additional pups were trained in either unpaired or naive control conditions. On the day following training, pups were either tested for their behavioral response to the conditioned odor in a two-odor choice test, or injected with 14C-2-deoxyglucose and exposed to the odor for examination of olfactory bulb neural responses to the odor. The results demonstrate that, although pups at all ages learned to avoid the odor, only pups trained during the first postnatal week had a modified olfactory-bulb glomerular-layer response to the odor. These results suggest that although olfactory memory is correlated with modification of olfactory bulb glomerular layer function in newborns, these changes are not required for normal memory in older pups.

Aging↗

PubMed1995

Asymmetrical influence of mesocortical dopamine depletion on stress ulcer development and subcortical dopamine systems in rats: implications for psychopathology.

The effects of left, right or bilateral depletion of the mesocortical dopamine innervation (medial prefrontal and anterior cingulate) with 6-hydroxydopamine were examined in male Sprague-Dawley rats tested for susceptibility to cold restraint-induced gastric stress pathology. All three types of lesions tended to potentiate the development of stress pathology (i.e. ulceration) in comparison to restrained shams, but only right cortical dopamine depletion produced a highly significant increase. The results support a protective role for mesocortical dopamine in helping the organism cope with stressful situations, and extend previous findings suggesting that dopamine activation in the right cortex is preferentially associated with uncontrollable stress. The right cortex is hypothesized to be at the top of a hierarchy in the processing of such stressful inputs, and endogenous dopaminergic modulation facilitates adaptive responses. Subcortical dopamine terminal regions were also examined for dopamine content and turnover. In addition to depleting cortical dopamine, the three lesion groups showed highly specific alterations in the status of subcortical dopamine systems, compared to either restrained or non-restrained shams. Left brain lesions resulted in significant bilateral increases in amygdala dopamine turnover. Right cortical lesions induced significant bilateral reductions of striatal dopamine content. Bilateral lesions increased dopamine content in the left amygdala and decreased dopamine in the right nucleus accumbens. Also in this group, dopamine turnover was increased in the right nucleus accumbens and decreased in the right amygdala. The data suggest that increases in stress vulnerability induced by cortical lesions may be related, in part, to neurochemical alterations in subcortical structures previously shown to modulate gastric stress pathology. The results also indicate that brain organization is inherently asymmetrical with respect to the regulation of responses to stress, which may be of significance for human psychopathology and its exacerbation by stress.

Amygdala↗

PubMed1995

The D2 antagonist spiperone mimics the effects of olfactory deprivation on mitral/tufted cell odor response patterns.

Wistar rats had a single nare occluded on postnatal day 30, depriving the ipsilateral olfactory bulb of odor stimulation. The deprivation lasted for either 1-2 months (short-term) or 12 months (long-term). As previously reported, deprivation greatly reduced tyrosine hydroxylase immunoreactivity (the rate limiting enzyme for dopamine synthesis) in the glomerular layer of the ipsilateral olfactory bulb. The nare was then reopened and odor response patterns of mitral/tufted cells were examined. The proportion of mitral/tufted cell single-units responding to a single odor was enhanced by deprivation. Furthermore, the proportion of mitral/tufted cells responding to more than one odor was increased by deprivation, suggesting a decrease in discrimination. Finally, in undeprived bulbs, the dopamine D2 receptor antagonist spiperone mimicked the effects of deprivation on mitral/tufted cell odor response patterns. The results are interpreted as an activity-dependent dopamine modulation of lateral and feedback inhibition in the olfactory bulb, and are compared with similar events in the dark-adapted retina.

Animals↗

PubMed1994

Bilateral 6-OHDA lesions of the locus coeruleus impair associative olfactory learning in newborn rats.

On postnatal day 4 (PN4) Wistar rat pups were anesthetized and received bilateral infusions of 6-OHDA into the locus coeruleus or received vehicle infusions. On PN6 pups were trained in a classical conditioning paradigm with intra-oral milk infusions as the UCS and citral odor as the CS. Pups were trained in either 'paired', 'odor-only', 'milk-only' or 'backward' (milk then odor) conditions. On PN7 acquisition of a learned odor preference to the CS was tested in a two-odor choice test. HPLC analysis showed that locus coeruleus lesions significantly reduced olfactory bulb NE content but had no effect on olfactory bulb DA or 5-HT levels compared to controls. Pups receiving locus coeruleus lesions did not differ in behavioral response patterns during training compared to their littermate, vehicle controls. However, locus coeruleus lesions impaired acquisition of conditioned odor preferences. These results suggest that NE output from the locus coeruleus is critical for early olfactory learning.

Analysis of Variance↗

PubMed1994

Left/right nigrostriatal asymmetry in susceptibility to neurotoxic dopamine depletion with 6-hydroxydopamine in rats.

Male Sprague-Dawley rats were investigated for the existence of a left/right hemispheric population asymmetry in the extent of striatal dopamine depletion following unilateral lesions with 6-hydroxydopamine (6-OHDA) in the left or right substantial nigra. Four doses of 6-OHDA were employed (with left and right lesion groups at each dose). Analysis of striatal dopamine depletion revealed significant main effects not only for dose of 6-OHDA, but also for side of lesion, with right-lesioned rats having greater dopamine depletion across doses. In a group of non-lesioned rats, randomly selected from this population, striatal dopamine turnover showed a significant right-sided bias. It is suggested that the latter functional asymmetry may have been responsible for the neurotoxic depletion asymmetry seen in lesioned animals, and that side of lesion should be considered when attempting to produce consistent and maximal dopamine depletion in large scale studies with the unilateral 6-OHDA lesion paradigm.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Striatal G-proteins: effects of unilateral 6-hydroxydopamine lesions.

To investigate the molecular mechanisms of denervation-induced dopamine receptor supersensitivity, levels of striatal G-proteins were examined in 6-hydroxydopamine (6-OHDA)-lesioned rats. Increased levels of the alpha-subunits of Gs and G(olf), as measured by immunoblotting, were observed 8 days postlesion and remained elevated up to day 28 (25-45% over the time course). G(i) levels were significantly increased only on day 8 (20%) and G(o) levels remained unaltered. These results suggest that stimulatory G-proteins may be involved in the long-term maintenance of dopamine receptor supersensitivity following denervation.

Animals↗

PubMed1994

Asymmetrical orientation to edges of an openfield: modulation by striatal dopamine and relationship to motor asymmetries in the rat.

Rats with unilateral 6-hydroxydopamine (6-OHDA, 4 or 8 micrograms) or sham lesions of the substantia nigra were examined (undrugged) for asymmetrical orientation to edges of a large openfield. Lesioned rats preferentially aligned with the edge such that the intact striatum was contralateral to the edge. The magnitude of this asymmetry was greatest in rats lesioned with the highest dose of 6-OHDA. There was no population left/right hemispheric asymmetry in the extent to which unilateral striatal dopamine (DA) depletion produces this behavioral bias. In sham-lesioned rats, endogenous imbalances in striatal DA activity (DOPAC/DA) were related to the direction of edge orientation, such that the more active striatum tended to be contralateral to the edge. Also in shams, the direction of this orientational asymmetry was not significantly related to the direction of motor bias measured as amphetamine- and apomorphine-induced turning behavior in rotometers (having no edges). However, the magnitudes of sensorimotor (edge behavior) and motor (turning) asymmetries were negatively correlated. The results extend previous findings that asymmetrical edge behavior is a sensitive index of imbalances in striatal DA activity, not only in DA-depleted rats, but in intact rats as well. Furthermore, sensorimotor and motor asymmetries, while both under DAergic influence, are largely independent processes.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Effects of dose and interdose interval on locomotor sensitization to the dopamine agonist quinpirole.

To assess whether the interval between injections affects the course of locomotor sensitization to quinpirole, groups of rats were injected every 2, 4, or 8 days with quinpirole (0, 0.025, 0.25, 0.5, and 2.5 mg/kg; n = 222) and their locomotor activity monitored after each injection for a total of 10 tests. Results indicate that the number of drug injections, rather than the interval between them, predominantly controls the development of locomotor sensitization to quinpirole. It is suggested that this may reflect a rapid induction but slow decay time for a response-enhancing factor stimulated by each injection of quinpirole, and that the effects of this putative factor are cumulative but saturable.

Animals↗

PubMed1994

The locus coeruleus, norepinephrine, and memory in newborns.

Use of learned odor cues by newborn rats is critical for pup survival. Rat pups acquire approach responses to maternal odors through an associative conditioning mechanism. This learned behavioral response is accompanied by a modification of olfactory bulb neural response patterns to the learned odor. Both the behavioral and neural response changes involved and require norepinephrine release in the olfactory bulb. The source of this norepinephrine is the locus coeruleus. It is proposed that the unique response properties of the locus coeruleus during the early postnatal period in the rat may facilitate acquisition of these critical early memories.

Animals↗