Browsing by Author "DiMicco, Joseph A."

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    Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus
    (Society for Neuroscience, 2006-09-06) Shekhar, Anantha; Johnson, Philip L.; Sajdyk, Tammy J.; Fitz, Stephanie D.; Keim, Stanley R.; Kelley, Pamela E.; Gehlert, Donald R.; DiMicco, Joseph A.; Psychiatry, School of Medicine
    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.e., anxiety, tachycardia, hypertension, and tachypnea). In the present study, previous injections of the angiotensin-II (A-II) type 1 receptor antagonist losartan and the nonspecific A-II receptor antagonist saralasin into the DMH of "panic-prone" rats blocked the anxiety-like and physiological components of lactate-induced panic-like responses. In addition, direct injections of A-II into the DMH of these panic-prone rats also elicited panic-like responses that were blocked by pretreatment with saralasin. Microinjections of saralasin into the DMH did not block the panic-like responses elicited by intravenous infusions of the noradrenergic agent yohimbine or by direct injections of NMDA into the DMH. The presence of the A-II type 1 receptors in the region of the DMH was demonstrated using immunohistochemistry. Thus, these results implicate A-II pathways and the A-II receptors in the hypothalamus as putative substrates for sodium lactate-induced panic-like responses in vulnerable subjects.
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    Characterization of the relationship between spontaneous locomotor activity and cardiovascular parameters in conscious freely moving rats
    (Elsevier, 2016-02) Zaretsky, Dmitry V.; Zaretskaia, Maria V.; DiMicco, Joseph A.; Department of Emergency Medicine, IU School of Medicine
    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. After examining data for individual rats, we found that the relationship between Act and HR could be approximated by the negative exponential function HR(Act)=HRmax-(HRmax-HRmin)∗exp(-Act/Acte), where HRmax, HRmin, and Acte are constants. These constants were calculated separately for light and dark periods by non-linear curve fitting. HR corresponding to maximal locomotion was similar during the light and dark phases, while HR at rest during the dark phase was higher than during the light phase. The range of HR variability associated with Act during the dark phase was similar in young and older animals, but minimal HR was significantly lower in older rats. The relationship between Act and BP was approximated with a similar function. We have found no differences between BP at rest and at maximal locomotion between light and dark and between 10-week and 16-week-old rats. Our results indicate that in rats, cardiovascular parameters are coupled to locomotion to a high degree; however both the HR and the BP reach maximal values when locomotor activity is relatively low. We also found that the phase of daily cycle affects HR in conscious rats independent of locomotor activity.
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    Independent of 5-HT1A receptors, neurons in the paraventricular hypothalamus mediate ACTH responses from MDMA
    (Elsevier, 2013-10-25) Zaretsky, Dmitry V.; Zaretskaia, Maria V.; DiMicco, Joseph A.; Durant, Pamela J.; Ross, Christian T.; Rusyniak, Daniel E.; Emergency Medicine, School of Medicine
    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. We sought to determine if the PVH and 5-HT1A receptors were also involved in mediating HPA responses to MDMA. Rats were pretreated with either saline or a 5-HT1A antagonist, WAY-100635 (WAY), followed by a systemic dose of MDMA (7.5mg/kg i.v.). Animals pretreated with WAY had significantly lower plasma ACTH concentrations after MDMA. To determine if neurons in the PVH were involved, and if their involvement was mediated by 5-HT1A receptors, rats implanted with guide cannulas targeting the PVH were microinjected with the GABAA receptor agonist muscimol, aCSF, or WAY followed by MDMA. Compared to aCSF, microinjections of muscimol significantly attenuated the MDMA-induced rise in plasma ACTH (126 vs. 588pg/ml, P=<0.01). WAY had no effect. Our data demonstrates that neurons in the PVH, independent of 5-HT1A receptors, mediate ACTH responses to MDMA.
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    The role of ionotropic glutamate receptors in the dorsomedial hypothalamus in the increase in core body temperature evoked by interoceptive and exteroceptive stresses in rats
    (2010-03-03T16:56:49Z) Moreno, Maria; DiMicco, Joseph A.; Queener, Sherry F.; Rusyniak, Daniel E.; Vasko, Michael R.
    Brain responds to an array of diverse challenges that are defined as either exteroceptive stress, involving cognitive processing of sensory information from the external environment and or interoceptive stress, detected through sensory neural or chemical cues from the internal environment. The physiological response to most stresses consists of autonomic responses that are essential for animal survival in the face of a threatening circumstance. However, it is known that exposition to continuous situations of stress is involved in the development of a series of diseases such as hypertension, myocardial infarction and panic syndrome. Several studies have shown that cells in a specific area of the brain, the dorsomedial hypothalamus (DMH), are involved in the response produced during emotional stress. However, the role of glutamatergic transmission in the DMH in the increase in body temperature induced by experimental stress has not been examined. Research findings thus far indicate that neurons in the DMH play a role in thermoregulation and that local glutamate receptors may be involved. The hypothesis of this thesis is that activity at ionotropic glutamate receptors in the DMH is necessary for the thermogenic response induced by experimental stress. In the present work, microinjections of kynurenate, an excitatory amino acid antagonist, NBQX (2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione), an AMPA/kainate receptor antagonist, DL-2-amino-5-phosphonovaleric acid (APV), an NMDA receptor antagonist, and a mixture of NBQX and APV, were delivered to the DMH before exposure to experimental stress. The stress paradigms used include models for exteroceptive stress and interoceptive stress. The results show that inhibition of both NMDA and non-NMDA receptors is necessary to abolish the thermogenic response produced by all stress paradigms tested. Furthermore, there appears to be a difference in the degree of attenuation of the thermogenic response produced by either inhibition of NMDA receptors or non-NMDA receptors. Together these results support a definite role for ionotropic glutamate receptors within DMH region in the thermogenic response to stress. These results also finally show that the DMH is involved in all the major physiological stress responses including increase in plasma ACTH, increase in heart rate, blood pressure and now temperature as well.
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    Role of the Dorsomedial Hypothalamus in Responses Evoked from the Preoptic Area and by Systemic Administration of Interleukin-1β
    (2009-06-23T21:35:36Z) Hunt, Joseph L.; DiMicco, Joseph A.; Cummins, Theodore R.; Rusyniak, Daniel; Vasko, Michael R.
    Recent studies in anesthetized rats suggest that autonomic effects relating to thermoregulation that are evoked from the preoptic area (POA) may be mediated through activation of neurons in the dorsomedial hypothalamus (DMH). Disinhibition of neurons in the DMH produces not only cardiovascular changes but also increases in plasma adrenocorticotropic hormone (ACTH) and locomotor activity mimicking those evoked by microinjection of muscimol, a GABAA receptor agonist and neuronal inhibitor, into the POA. Therefore, I tested the hypothesis that all of these effects evoked from the POA are mediated through neurons in the DMH by assessing the effect of bilateral microinjection of muscimol into the DMH on the changes evoked by microinjection of muscimol into the POA in conscious rats. In addition, I tested the hypothesis that neurons in the DMH mediate a specific response that is thought to signal through the POA, the activation of the HPA axis evoked by systemic administration of the inflammatory cytokine IL-1β. After injection of vehicle into the DMH, injection of muscimol into the POA elicited marked increases in heart rate, arterial pressure, body temperature, plasma ACTH and locomotor activity and also increased Fos expression in the hypothalamic paraventricular nucleus (PVN), a region known to control the release of ACTH from the adenohypophysis, and the raphe pallidus, a medullary region known to mediate POA-evoked sympathetic responses. Prior microinjection of muscimol into the DMH produced a modest depression of baseline heart rate, arterial pressure, and body temperature but completely abolished all changes evoked from the POA. Microinjection of muscimol just anterior to the DMH had no effect on POA-evoked autonomic and neuroendocrine changes. Inhibition of neuronal activity in the DMH only partially attenuated the increased activity of the HPA axis following systemic injections of IL-1β. Thus, neurons in the DMH mediate a diverse array of physiological and behavioral responses elicited from the POA, suggesting that the POA represents an important source of inhibitory tone to key neurons in the DMH. However, it is clear that the inflammatory cytokine IL-1β must employ other pathways that are DMH-, and possibly POA-, independent to activate the HPA axis.
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    'S' is for ... John Steinbeck (1902-1968)
    (IU Conscience Project, 2024) DiMicco, Joseph A.
    In Steinbeck’s EAST OF EDEN one character is dark: Cathy. Referring to her, Steinbeck writes: “There are monsters born.” No conscience-- but Cathy has perspectives-- on others’ weaknesses and inadequacies and exploits them in self-interest. One of the criticisms made of Steinbeck’s novel is that Cathy is unbelievable-she can’t be real. Steinbeck’s counterargument would be if you believe in saints, you must also believe in the possibility of a Cathy.
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    Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1 mg/kg.
    (Elsevier, 2015-10-08) Zaretsky, Dmitry V.; Zaretskaia, Maria V.; DiMicco, Joseph A.; Rusyniak, Daniel E.; Department of Emergency Medicine, IU School of Medicine
    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. In this report we characterized dose-dependent autonomic and behavioral effects of yohimbine and its interaction with an antagonist of 5-HT1A receptors, WAY 100635. In low doses (0.5 – 2 mg/kg i.p.) yohimbine induced locomotor activation which was accompanied by a tachycardia and mild hypertension. Increasing the dose to 3–4.5 mg/kg reversed the hypertension and locomotor activation and induced profound hypothermia. The hypothermia as well as the suppression of the locomotion and the hypertension could be reversed by the blockade of 5-HT1A receptors with WAY 100635. Our data confirm that yohimbine possesses 5-HT1A properties, and demonstrated that in doses above 1 mg/kg significantly activate these receptors.