The non-peptide CRH1-antagonist CP-154,526 elicits a paradoxical route-dependent activation of the HPA axis.

The corticotropin-releasing hormone (CRH) plays an important role in mediating physiological response to stress and is thought to be involved in the development of various psychiatric disorders. In this paper, we compare the differences between the effect of intraperitoneal (i.p.

Characterization of the relationship between spontaneous locomotor activity and cardiovascular parameters in conscious freely moving rats.

In freely behaving rats, variations in heart rate (HR) and blood pressure (BP) are coupled closely with changes in locomotor activity (Act). We have attempted to characterize this relationship mathematically. In 10- and 16-week-old rats, HR, BP and Act were recorded telemetrically every minute for 2 days under 12h:12h light-dark cycling.

Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1 mg/kg.

Yohimbine is a prototypical alpha2-adrenergic receptor antagonist. Due to its relatively high selectivity, yohimbine is often used in experiments whose purpose is to examine the role of these receptors. For example, yohimbine has been employed at doses of 1-5 mg/kg to reinstate drug-seeking behavior after extinction or to antagonize general anesthesia, an effects presumably being a consequence of blocking alpha2-adrenergic receptors.

Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA.

Acute and chronic complications from the substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) are linked to activation of the hypothalamic-pituitary-adrenal (HPA) axis. How MDMA activates the HPA axis is not known. HPA responses to stress are known to be mediated through the paraventricular (PVH) hypothalamus and to involve serotonin-1a (5-HT1A) receptors.

Contribution of infralimbic cortex in the cardiovascular response to acute stress.

The infralimbic region of the medial prefrontal cortex (IL) modulates autonomic and neuroendocrine function via projections to subcortical structures involved in the response to stress. We evaluated the contribution of the IL to the cardiovascular response evoked by acute stress. Under anesthesia (80 mg/kg ketamine-11.

The orexin-1 receptor antagonist SB-334867 decreases sympathetic responses to a moderate dose of methamphetamine and stress.

We recently discovered that inhibiting neurons in the dorsomedial hypothalamus (DMH) attenuated hyperthermia, tachycardia, hypertension, and hyperactivity evoked by the substituted amphetamine 3, 4-methylenedioxymethamphetamine (MDMA). Neurons that synthesize orexin are also found in the region of the DMH. As orexin and its receptors are involved in the regulation of heart rate and temperature, they would seem to be logical candidates as mediators of the effects evoked by amphetamines.

Stress-free microinjections in conscious rats.

Microinjections are a major tool in modern neuroscience. Microinjection techniques in conscious animals typically involve four steps: (1) animal adapts to experimental setup; (2) injection system is filled and the microinjector is carefully inserted; (3) a drug solution is injected; (4) 1-2 min later the microinjector is carefully removed. Steps 2 and 4 are difficult to perform in rodents without disturbing the animal.

The role of orexin-1 receptors in physiologic responses evoked by microinjection of PgE2 or muscimol into the medial preoptic area.

The medial preoptic area (mPOA) of the hypothalamus has long been thought to play an important role in both fever production and thermoregulation. Microinjections of prostaglandin E2 (PgE2) or the GABA(A) agonist muscimol into the mPOA cause similar increases in body temperature, heart rate, and blood pressure. Microinjections of these compounds however evoke different behavioral responses with muscimol increasing and PgE2 having no effect on locomotion.

The dorsomedial hypothalamus and the central pathways involved in the cardiovascular response to emotional stress.

Psychological stress elicits increases in sympathetic activity accompanied by a marked cardiovascular response. Revealing the relevant central mechanisms involved in this phenomenon could contribute significantly to our understanding of the pathogenesis of stress-related cardiovascular diseases, and the key to this understanding is the identification of the nuclei, pathways and neurotransmitters involved in the organization of the cardiovascular response to stress. The present review will focus specifically on the dorsomedial hypothalamus, a brain region now known to play a primary role in the synaptic integration underlying the cardiovascular response to emotional stress.

Increase in plasma ACTH induced by urethane is not a consequence of hyperosmolality.

Although anesthetic doses of urethane increase plasma levels of ACTH, the exact mechanism through which this occurs is unclear. We theorized that these increases might be a consequence of an increased systemic osmolality owing to the large doses of urethane usually employed. To evaluate this possibility, we measured plasma osmolality and ACTH in a total of six rats after graded infusions of urethane (N=3 rats) or equimolar amounts of mannitol (N=3 rats).

Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder.

Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.

Dorsomedial hypothalamus mediates autonomic, neuroendocrine, and locomotor responses evoked from the medial preoptic area.

Previous studies suggest that sympathetic responses evoked from the preoptic area in anesthetized rats require activation of neurons in the dorsomedial hypothalamus. Disinhibition of neurons in the dorsomedial hypothalamus in conscious rats produces physiological and behavioral changes resembling those evoked by microinjection of muscimol, a GABA(A) receptor agonist and neuronal inhibitor, into the medial preoptic area. We tested the hypothesis that all of these effects evoked from the medial preoptic area are mediated through neurons in the dorsomedial hypothalamus by assessing the effect of bilateral microinjection of muscimol into the DMH on these changes.

Cardiovascular and thermal responses evoked from the periaqueductal grey require neuronal activity in the hypothalamus.

Stimulation of neurons in the lateral/dorsolateral periaqueductal grey (l/dlPAG) produces increases in heart rate (HR) and mean arterial pressure (MAP) that are, according to traditional views, mediated through projections to medullary autonomic centres and independent of forebrain mechanisms. Recent studies in rats suggest that neurons in the l/dlPAG are downstream effectors responsible for responses evoked from the dorsomedial hypothalamus (DMH) from which similar cardiovascular changes and increase in core body temperature (T(co)) can be elicited. We hypothesized that, instead, autonomic effects evoked from the l/dlPAG depend on neuronal activity in the DMH.

Microinjection of muscimol into the periaqueductal gray suppresses cardiovascular and neuroendocrine response to air jet stress in conscious rats.

Microinjection of the neuronal inhibitor muscimol into the dorsomedial hypothalamus (DMH) suppresses increases in heart rate (HR), mean arterial pressure (MAP), and circulating levels of adrenocorticotropic hormone (ACTH) evoked in air jet stress in conscious rats. Similar injection of muscimol into the caudal region of the lateral/dorsolateral periaqueductal gray (l/dlPAG) reduces autonomic responses evoked from the DMH, leading to the suggestion that neurons in the l/dlPAG may represent a descending relay for DMH-induced increases in HR and MAP. Here, we examined the role of neuronal activity in the caudal l/dlPAG on the increases in MAP, HR, and plasma ACTH seen in air jet stress in rats.

Microinjection of muscimol into the dorsomedial hypothalamus suppresses MDMA-evoked sympathetic and behavioral responses.

When given systemically to rats and humans, the drug of abuse 3,4 methylenedioxymethamphetamine (ecstasy, MDMA) elicits hyperthermia, hyperactivity, tachycardia, and hypertension. Chemically stimulating the dorsomedial hypothalamus (DMH), a brain region known to be involved in thermoregulation and in stress responses, causes similar effects. We therefore tested the hypothesis that neuronal activity in the DMH plays a role in MDMA-evoked sympathetic and behavioral responses by microinjecting artificial CSF or muscimol, a neuronal inhibitor, into the DMH prior to intravenous infusion of saline or MDMA in conscious rats.

Induction of Fos-immunoreactivity in the rat brain following disinhibition of the dorsomedial hypothalamus.

Activation of neurons in the dorsomedial hypothalamus (DMH) appears to play an important role in signaling the excitation of brain regions responsible for experimental fever and for many of the physiological and behavioral changes seen in experimental stress or anxiety in rats. Here, we examined the effect of disinhibition of the DMH by unilateral microinjection of bicuculline methiodide (BMI) on Fos expression in selected regions of the brain that have been implicated in anxiety and responses to stress and fever in rats. Disinhibition of the DMH resulted in dramatic increases in local Fos expression and also increased the numbers of Fos-positive neurons in the lateral septal nucleus and in both the parvocellular and magnocellular subdivisions of the paraventricular nucleus, with greater increases ipsilateral to the injection site in the DMH.

Stress- and lipopolysaccharide-induced c-fos expression and nNOS in hypothalamic neurons projecting to medullary raphe in rats: a triple immunofluorescent labeling study.

Neurons in the rostral raphe pallidus (rRP) have been proposed to mediate experimental stress-induced tachycardia and fever in rats, and projections from the dorsomedial hypothalamus (DMH) may signal their activation in these settings. Thus, we examined c-fos expression evoked by air jet/restraint stress and restraint stress or by systemic administration of lipopolysaccharide (10 microg/kg and 100 microg/kg) as well as the distribution of the neuronal nitric oxide synthase (nNOS) in neurons retrogradely labeled from the raphe with cholera toxin B in key hypothalamic regions. Many neurons in the medial preoptic area and the dorsal area of the DMH were retrogradely labeled, and approximately half of those in the medial preoptic area and moderate numbers in the dorsal DMH were also positive for nNOS.

3,4-Methylenedioxymethamphetamine- and 8-hydroxy-2-di-n-propylamino-tetralin-induced hypothermia: role and location of 5-hydroxytryptamine 1A receptors.

The popular drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has complex interactions with thermoregulatory systems, resulting in either hyperthermia or hypothermia. MDMA induces hypothermia when given to animals housed at a low ambient temperature. In this study we report that MDMA (7.

The dorsomedial hypothalamus: a new player in thermoregulation.

Neurons in the dorsomedial hypothalamus (DMH) play key roles in physiological responses to exteroceptive ("emotional") stress in rats, including tachycardia. Tachycardia evoked from the DMH or seen in experimental stress in rats is blocked by microinjection of the GABA(A) receptor agonist muscimol into the rostral raphe pallidus (rRP), an important thermoregulatory site in the brain stem, where disinhibition elicits sympathetically mediated activation of brown adipose tissue (BAT) and cutaneous vasoconstriction in the tail. Disinhibition of neurons in the DMH also elevates core temperature in conscious rats and sympathetic activity to least significant difference interscapular BAT (IBAT) and IBAT temperature in anesthetized preparations.

Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus.

Intravenous sodium lactate infusions or the noradrenergic agent yohimbine reliably induce panic attacks in humans with panic disorder but not in healthy controls. However, the exact mechanism of lactate eliciting a panic attack is still unknown. In rats with chronic disruption of GABA-mediated inhibition in the dorsomedial hypothalamus (DMH), achieved by chronic microinfusion of the glutamic acid decarboxylase inhibitor L-allylglycine, sodium lactate infusions or yohimbine elicits panic-like responses (i.

Microinjection of muscimol into caudal periaqueductal gray lowers body temperature and attenuates increases in temperature and activity evoked from the dorsomedial hypothalamus.

Microinjection of the neuronal inhibitor muscimol into the midbrain lateral/dorsolateral periaqueductal gray (l/dlPAG) suppresses increases in heart rate (HR) and mean arterial pressure (MAP) evoked by microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) into the dorsomedial hypothalamus (DMH) in rats. Injection of BMI into the DMH also increases body temperature (Tco) and motor activity. Here, our goal was to extend previous findings by examining the effect of microinjection of muscimol into the PAG on these thermogenic and behavioral responses in conscious freely moving rats.

Stress-induced cardiac stimulation and fever: common hypothalamic origins and brainstem mechanisms.

Our past results provide considerable evidence that activation of neurons somewhere in the region of the dorsomedial hypothalamus (DMH) plays a key role in the generation of many of the effects typically seen in "emotional" stress in rats, including activation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine hallmark of the generalized response to stress, and sympathetically mediated tachycardia. More recently, we demonstrated that (1) the tachycardia resulting either from chemical stimulation of the DMH or from experimental stress is markedly attenuated by microinjection of the GABAA receptor agonist muscimol, a neuronal inhibitor, into the medullary raphe pallidus (RP); and (2) the specific subregion of the DMH mediating stimulation-induced tachycardia corresponds to the dorsal hypothalamic area (DHA), a site where neurons projecting to the RP are densely concentrated. Thus, the pathway from neurons in the DHA to sympathetic premotor neurons in the RP may constitute a key relay mediating the increases in heart rate seen in emotional stress--a role that had never been proposed previously for either of these regions.

Microinjection of prostaglandin E2 and muscimol into the preoptic area in conscious rats: comparison of effects on plasma adrenocorticotrophic hormone (ACTH), body temperature, locomotor activity, and cardiovascular function.

The preoptic area (POA) is thought to play an important role in thermoregulation and fever. Local application of prostaglandin E2 (PGE2) to this region elicits increases in core body temperature, heart rate, and plasma levels of adrenocorticotrophic hormone (ACTH). Similar effects on body temperature and heart rate have also been reported after local application of the GABAA receptor agonist muscimol to the preoptic area.

Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons.

Disinhibition of neurons in the region of the dorsomedial hypothalamus (DMH) elicits sympathetically mediated tachycardia in rats through activation of the brain stem raphe pallidus (RP), and this same mechanism appears to be largely responsible for the increases in heart rate (HR) seen in air jet stress in this species. Neurons projecting to the RP from the DMH are said to be concentrated in a specific subregion, the dorsal hypothalamic area (DA). Here, we examined the hypothesis that the location of RP-projecting neurons in the DA correspond to the sites at which microinjection of bicuculline methiodide (BMI) evokes the greatest increases in HR.