Interaction of hypothalamic GABA\u3csub\u3eA\u3c/sub\u3e and excitatory amino acid receptors controlling heart rate in rats

We have previously shown that microinjection of drugs that impair gamma-aminobutyric acid (GABA)-mediated synaptic inhibition into the dorsomedial hypothalamus (DMH) of rats generates cardiovascular and behavioral changes that mimic the response to stress. The purpose of this study was to examine the role of excitatory amino acid (EAA) receptors in the DMH in generating the cardiovascular changes caused by withdrawal of local GABAergic inhibition in urethan-anesthetized rats. Local treatment of the DMH with the nonselective EAA antagonist kynurenic acid blocked or reversed the increases in heart rate and blood pressure caused by microinjection of the GABAA antagonists bicuculline methiodide (BMI) or picrotoxin into the same region. Conversely, similar injection of xanthurenic acid, a structural analogue of kynurenic acid without significant effects on EAA receptors, did not significantly alter the cardiovascular changes produced by either GABAA antagonist. The tachycardic effects of BMI were also attenuated by injection of either the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid or the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. When the two EAA receptor antagonists were combined, their effects to suppress the BMI-induced tachycardia were additive. These findings suggest that the cardiovascular effects caused by blockade of GABAergic inhibition in the DMH of the rat are dependent on activation of local NMDA and non-NMDA EAA receptors

Hypothalamic excitatory amino acid receptors mediate stress-induced tachycardia in rats

The role of hypothalamic excitatory amino acid (EAA) receptors in mediating the cardiovascular response to stress was examined using conscious chronically instrumented rats. Microinjection of the EAA agonists N-methyl-D-aspartic acid (NMDA; 1-10 pmol), alpha-amino-3-hydroxy-5-methyl-4-isooxazolepropionic acid (AMPA; 0.3-3.0 pmol), or kainic acid (0.1-1.0 pmol) into the dorsomedial hypothalamus (DMH) elicited dose-related increases in heart rate and modest elevations in arterial pressure. Local microinjection of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (AP5; 100 pmol) selectively blocked NMDA-induced cardiovascular changes, whereas the non-NMDA EAA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 pmol) selectively blocked the responses to AMPA and kainic acid. In the stress trials, microinjection of the nonselective EAA antagonist kynurenic acid (1-10 nmol) into the DMH blocked air stress-induced tachycardia in a dose-related manner. Similar injection of kynurenic acid at sites lateral or posterior to the DMH or injection of xanthurenic acid (a structural analogue of kynurenic acid with no antagonistic properties at EAA receptors) into the DMH failed to influence air stress-induced cardiovascular changes. Injection of either AP5 or CNQX into the DMH at doses shown to be selective for their respective EAA receptor subtypes also attenuated air stress-induced tachycardia. Thus activity at EAA receptors in the DMH appears to be necessary for the generation of stress-induced changes in heart rate

GABA\u3csub\u3eA\u3c/sub\u3e and excitatory amino acid receptors in dorsomedial hypothalamus and heart rate in rats

We have previously shown that microinjection of drugs that interfere with the function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into the hypothalamus produces cardiorespiratory and behavioral changes resembling those seen in emotional stress. The purpose of this study was to determine whether excitatory amino acids (EAAs) can produce a cardiovascular response similar to that caused by the GABAA receptor antagonist bicuculline methiodide (BMI) when microinjected at the same hypothalamic site in urethan-anesthetized rats and to clarify the precise locus of action of these agents. N-methyl-D-aspartic acid (NMDA, 0.68-6.8 pmol/50 nl) and kainic acid (KA, 0.47-4.7 pmol/50 nl) produced dose-related increases in heart rate and blood pressure when injected at sites in the dorsomedial hypothalamus reactive to BMI (20 pmol/50 nl). Higher doses of NMDA (68 pmol), however, failed to elicit consistent increases in heart rate and blood pressure when injected at these same sites. The effects of NMDA were selectively blocked by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid, whereas the effects of KA were selectively blocked by the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These results demonstrate that 1) blockade of inhibitory amino acid receptors or stimulation of EAA receptors in the dorsomedial nucleus of the hypothalamus produces tachycardic and pressor responses in urethan-anesthetized rats and 2) use of high doses of EAAs may be an unreliable method of evoking local neuronal excitation in certain regions of the central nervous system

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. 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

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. 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

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. 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

'S' is for ... John Steinbeck (1902-1968)

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