General mental ability: prediction and intervention.
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Developmental Disabilities↗
Biomedical subjects
R B McCall
Publications and source records attributed to R B McCall.
5-HT2 receptor agonists increase spontaneous sympathetic nerve discharge.
The selective 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced a marked increase in spontaneous sympathetic nerve discharge recorded from the inferior cardiac nerve in chloralose anesthetized cats. DOI (0.01-1.0 mg/kg i.v.) increased sympathetic nerve discharge to a maximum of 1750% of control values. The increase in sympathetic nerve discharge produced by DOI was reversed by the 5-HT2 antagonists ketanserin and LY 53857. In addition, pretreatment with ketanserin, but not prazosin, completely prevented the increase in sympathetic nerve discharge produced by DOI. These data are discussed in relationship to the role of serotonin in the regulation of activity in central sympathetic pathways.
Amphetamines↗
Effects of putative neurotransmitters on sympathetic preganglionic neurons.
Epinephrine, substance P, and glutamate have all been hypothesized as primary chemical mediators in the descending pathway from the brain stem "vasomotor center" to SPNs. Interestingly, lesions of or antagonists to epinephrine, substance P, glutamate, and 5-HT neurons all abolish sympathetic activity and reduce blood pressure to a level similar to that in a spinal-transected animal. However, it is unlikely that all these substances are primary mediators of sympathetic information carried from the brain stem to the spinal cord. How then do we resolve these findings? A plausible explanation is that monoamines and neuropeptides act in the IML, as in other areas of the central nervous system, as neuromodulators, setting the level of excitability of SPNs rather than relaying sympathetic information over a functionally specific pathway from brain stem sympathetic neurons to the IML. For example, the time course of the norepinephrine-mediated slow EPSPs and IPSPs in SPNs is consistent with a gain-setting function. Likewise, the depolarization of SPNs by 5-HT is similar to the depolarization elicited in myenteric and celiac ganglion cells. In these ganglia, 5-HT appears to mediate a slow excitatory potential that enhances incoming fast synaptic potentials. A similar gain-enhancing effect of 5-HT has been demonstrated in facial motoneurons. By analogy, epinephrine is likely to act as a neuromodulator in the IML rather than to serve as the primary mediator of sympathetic information descending from the brain stem. Similarly, it is difficult to imagine that an agent with such a long duration of excitatory action as substance P could serve as the primary descending transmitter in a system where moment to moment changes in activity are essential. It is more likely that substance P aids in setting the excitability of SPNs. Pharmacological antagonism of any of the excitatory neuromodulators (i.e. gain setters) might act to decrease, at least temporarily, the excitability of SPNs to the point where primary sympathetic activity from the brain stem could not excite SPNs. This accounts for the wide variety of pharmacological agents that act to eliminate sympathetic activity and drastically reduce blood pressure. On the basis of the above arguments, the most logical candidate for a transmitter mediating primary excitatory sympathetic information from brain stem "vasomotor centers" would be an excitatory amino acid. Fast EPSPs in SPNs appear to be mediated by glutamate and excitatory amino acid antagonists markedly inhibit sympathetic activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
GABA-mediated inhibition of sympathoexcitatory neurons by midline medullary stimulation.
The present investigation determined whether the effects of electrical stimulation of depressor sites in midline medullary raphe nuclei were a result of inhibition of sympathoexcitatory medullospinal neurons in the rostral ventrolateral medulla of anesthetized cats. Electrical stimulation of the raphe inhibited inferior cardiac sympathetic activity. Microinjections of glutamate mimicked the effects of electrical stimulation. Electrical stimulation inhibited sympathoexcitatory neurons in the rostral ventrolateral medulla. The onset of the sympathoinhibition recorded from the inferior cardiac nerve (72 ms) was equal to the sum of the onset latency of the sympathoexcitatory response elicited from the rostral ventrolateral medulla (49 ms) plus the conduction time in the raphe to rostral ventrolateral sympathoinhibitory pathway (23 ms). Raphe stimulation excited a second set of neurons in the rostral ventrolateral medulla with an onset of 21 ms. Microiontophoretically applied bicuculline increased the discharge of sympathoexcitatory neurons and blocked the raphe-evoked inhibition. Iontophoretic glutamate excited sympathoexcitatory neurons but failed to antagonize raphe-elicited inhibition. These data suggest that neuronal elements in medullary raphe nuclei tonically inhibit sympathoexcitatory medullospinal neurons in the rostral ventrolateral medulla by activating closely adjacent gamma-aminobutyric acid (GABA) interneurons.
Action Potentials↗
Cardiovascular depressant effects of the kappa opioid receptor agonists U50488H and spiradoline mesylate.
The cardiovascular effects of the selective kappa opioid receptor agonists U50488H and spiradoline mesylate were examined in pentobarbital-anesthetized mongrel dogs and chloralose-anesthetized cats. In the dog studies, U50488H (0.01-3.0 mg/kg, i.v.) produced a dose-related depression in mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular dp/dt, and heart rate. These effects were completely reversed by a 1 mg/kg i.v. dose of the opioid receptor antagonist naloxone. A second kappa agonist, spiradoline mesylate, also produced a naloxone-reversible cardiovascular depression. Furthermore, the compound did not interfere with the positive inotropic or hypertensive effects of norepinephrine (1 microgram/kg, i.v.), showing that the cardiovascular depressant effects of the kappa agonist are unrelated to interference with alpha- or beta-adrenergic receptor mechanisms. In normal cats anesthetized with chloralose, which produces less depression of sympathetic tone than does pentobarbital, spiradoline mesylate did not decrease the MAP in i.v. doses up to 1.0 mg/kg. However, a dose-related increase in sympathetic nerve discharge (SND) was observed (+290% at 1.0 mg/kg). In contrast, in baroreceptor-denervated cats, spiradoline mesylate caused a dose-related hypotensive effect with no change in SND. These results show that the cardiovascular effects of the kappa agonists are peripherally mediated and that reflex sympathetic activity, if uncompromised, can produce a full compensation.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Sympathetic alterations after midline medullary raphe lesions.
The present study was designed to determine the functional importance of the midline medullary raphe nuclei in the autonomic regulation of the cardiovascular system in the anesthetized cat. Baroreceptor and somatosympathetic reflexes as well as the effects of electrical stimulation of vagal afferents and pressor and depressor sites in the hypothalamus and spinal trigeminal tract were determined before and after midline medullary lesions that extended from 2 to 7 mm rostral to the obex. Midline medullary lesions failed to affect baroreceptor reflexes as judged by the lack of effect on the sympathoinhibition associated with the pressor response to phenylephrine and the degree of slow-wave locking of sympathetic activity to the cardiac cycle. However, the lesion did significantly increase spontaneous sympathetic activity recorded from the inferior cardiac nerve. Blood pressure and heart rate were not altered by midline lesions. In addition, the computer-summed sympathoexcitatory response to electrical stimulation of somatic afferents in the sciatic nerve and the sympathoinhibitory response to stimulation of vagal afferent fibers were not affected by midline lesions. In contrast, the decrease in blood pressure and inhibition of sympathetic nerve activity elicited by electrical stimulation of the spinal trigeminal tract were completely abolished by the lesion. Depressor responses evoked from the anteroventral third ventricle region of the hypothalamus but not pressor responses elicited from the posterior hypothalamus were eliminated following midline medullary lesions. Finally, the sympathoinhibitory actions of the serotonin antagonist methysergide were blocked by medullary raphe lesions. These data indicate that neural elements in the medial medullary area function to provide a tonic inhibition of sympathetic nerve activity that is of nonbaroreceptor origin. Depressor responses evoked from the anterior hypothalamus and the spinal trigeminal tract also are mediated through this area of the medulla. Finally, the data support our contention that medullary serotonergic neurons have a sympathoexcitatory function.
Animals↗
Effects of serotonin1 and serotonin2 receptor agonists and antagonists on blood pressure, heart rate and sympathetic nerve activity.
Previous studies indicate that serotonin (5-HT) neurons provide a tonic excitatory input to central sympathetic neurons. The purpose of the present study was to utilize a number of 5-HT agonists in order to provide insights into the general function of the serotonergic system in the regulation of central sympathetic pathways. The 5-HT1A agonists 8-hydroxy-dipropylaminotetralin and p-aminophenyl-ethyl-m-trifluoromethylphenyl piperazine produced a dose-related inhibition of sympathetic nerve discharge (SND) recorded from either the postganglionic inferior cardiac nerve or the preganglionic splanchnic nerve in chloralose-anesthetized cats. The sympatholytic effects of 8-hydroxy-dipropylaminotetralin and p-aminophenyl-ethyl-m-trifluoromethylphenyl piperazine were accompanied by hypotension and bradycardia. The effects of 5-HT1A agonists were reversed by the 5-HT1A antagonist spiperone. In contrast, spiperone alone produced decreases in blood pressure, heart rate and SND. The 5-HT1B agonists 1[3(trifluoromethyl) phenyl]-piperazine, 1-(3-chlorophenyl) piperazine and 1-(2-methoxyphenyl) piperazine all produced variable effects on SND. In some experiments, SND was increased by these agents, whereas it was decreased in others. The 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane produced a marked increase in SND. A second 5-HT2 agonist, MK212, produced similar effects. The role of 5-HT receptor subtypes in mediating the 5-HT excitation of sympathetic neurons is discussed. It is suggested that 5-HT1A agonists inhibit SND through a process of disfacilitation by inhibiting the firing rate of 5-HT neurons. Possible mechanisms by which 5-HT2 agonists increase SND are proposed.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Characterization of the central sympathoinhibitory action of ketanserin.
The present study was designed to determine whether the central sympatholytic effects of ketanserin result from the ability of the drug to block serotonin2 or alpha-1 adrenergic receptors. Ketanserin produced a dose-related inhibition of sympathetic nerve discharge recorded from the inferior cardiac nerve in chloralose-anesthetized cats. Administration of a large dose of prazosin (1 mg/kg i.v.) decreased arterial blood pressure and inhibited sympathetic activity for several hours. Additional doses of prazosin failed to further inhibit sympathetic nerve discharge. Pretreatment with prazosin (1 mg/kg i.v.) also blocked the ability of ketanserin to inhibit sympathetic activity. Conversely, pretreatment with ketanserin blocked the central sympatholytic action of prazosin. In contrast, the alpha-2 adrenergic agonist clonidine inhibited sympathetic activity in animals pretreated with prazosin. The highly selective serotonin2 antagonist, LY 53857, failed to affect arterial blood pressure, heart rate or sympathetic activity recorded from the inferior cardiac nerve. These data, along with earlier results from our laboratory, provide strong evidence to indicate that ketanserin produces a centrally mediated inhibition of sympathetic nerve discharge as a result of the ability of the drug to block alpha-1 adrenergic receptors.
Animals↗
Roundtable: what is temperament? Four approaches.
4 current approaches to understanding temperament are discussed in the roundtable. In an introductory overview, Goldsmith outlines some of the major convergences and divergences in the understanding of this concept. Theorists representing 4 positions--Goldsmith, Buss and Plomin, Rothbart, and Thomas and Chess--outline their views by responding to each of 6 questions: How do you define temperament and explain the boundaries of the concept? What are the elements of temperatment? How does the construct of temperament permit you to approach issues or organize data in ways that are possible only if this construct is invoked? How does temperament develop? To what extent do you consider temperament to be a personological versus a relational or an interactional construct? and How does your approach deal with issues of temperamental "difficulty"? In 2 commentaries on the theorists' answers, Hinde highlights differences among their positions and indicates issues that current theories of temperament must take into consideration, and McCall draws on common aspects to propose a synthesizing definition that draws on all 4 approaches.
Arousal↗
GABA-serotonergic interactions in the regulation of central sympathetic pathways.
Methysergide, a serotonin antagonist, and clonidine, an alpha 2-adrenoceptor agonist, lowered arterial blood pressure, heart rate and inferior cardiac sympathetic nerve activity in the anesthetized cat. Picrotoxin, a GABA antagonist, caused a reduction in the inhibition of sympathetic activity produced by methysergide. In contrast, picrotoxin did not effect the reduction of sympathetic nervous discharge resulting from administration of clonidine. These observations suggest that an interaction exists between GABAergic and serotonergic neurons which regulates central sympathetic pathways, possibly by a tonic GABAergic inhibition of serotonergic sympathoexcitatory pathways.
Animals↗
Effects of hallucinogenic drugs on serotonergic neuronal systems.
Studies indicate that hallucinogens markedly suppress the discharge of serotonin containing neurons in the dorsal raphe nucleus. Forebrain neurons receiving a major serotonergic input are relatively insensitive to hallucinogens. These actions of hallucinogens are not sufficient to explain the psychoactive effects of these drugs. Evidence is presented to indicate that hallucinogens sensitize serotonin and norepinephrine receptors in the facial nucleus. This receptor sensitizing effect is common to all, and specific for, hallucinogens. It is suggested that a mechanism of receptor sensitization might account for the altered perceptual reactivity produced by hallucinogens.
Animals↗
Lack of involvement of GABA in baroreceptor-mediated sympathoinhibition.
The purpose of the present investigation was to determine if gamma-aminobutyric acid (GABA) mediates the baroreceptor-induced inhibition of sympathetic nerve discharge (SND) in dialurethan-anesthetized cats. The GABA antagonists picrotoxin and bicuculline produced marked elevations in arterial blood pressure and inferior cardiac SND. The inhibition of SND observed during pressor responses was occasionally slightly depressed after picrotoxin or bicuculline. Midcollicullar transection blocked or reversed the increase in blood pressure and SND produced by GABA antagonists. Under these conditions, baroreceptor inhibition of SND was not affected by picrotoxin. Microinjections of picrotoxin into the rostral ventrolateral medulla produced increases in arterial blood pressure and SND but failed to affect baroreceptor-induced sympathoinhibition. GABA antagonists given intravenously also failed to affect the baroreceptor-induced inhibition of sympathetically related neurons recorded in the rostral ventrolateral medulla. However, intravenous picrotoxin did antagonize the inhibitory affect of microiontophoretically applied GABA on these neurons. These data provide no evidence to support the contention that GABA mediates the baroreceptor-induced inhibition of SND. The role of GABA in regulating SND is discussed.
Animals↗
Evidence for GABA mediation of sympathetic inhibition evoked from midline medullary depressor sites.
GABA antagonists blocked, and diazepam potentiated, inhibition of spontaneous sympathetic activity elicited by electrical stimulation of classic midline medullary depressor sites. Picrotoxin often converted inhibitory effects of raphe stimulation into sympathoexcitatory responses. Serotonin antagonists blocked these sympathoexcitatory responses. The midline medullary raphe complex is heterogeneous in respect to autonomic function with sympathoinhibitory elements mediated at least in part by GABA and sympathoexcitatory pathways mediated by serotonin.
Animals↗
Evidence for gamma-aminobutyric acid mediation of the sympathetic nerve inhibitory response to vagal afferent stimulation.
The involvement of gamma-aminobutyric acid (GABA) in the vagal-stimulated reflex inhibition of sympathetic nerve discharge (SND) was investigated in the cat. Computer summation was used to assess the sympathoinhibitory response to vagal afferent stimulation and the resultant changes seen with agents known to effect GABAergic neurotransmission. The GABA antagonists picrotoxin and bicuculline at 0.25 to 1.0 mg/kg i.v. attenuated the vagal sympathetic inhibitory response, but increased the 1:1 locking of SND to the arterial pulse. Conversely, the GABA agonist diazepam at 0.3 mg/kg i.v. potentiated the vagal sympathoinhibition, reduced total SND and diminished SND locking to the arterial pulse. Picrotoxin also blocked the vagal sympathoinhibitory response in midcollicular transected cats and when applied topically to the dorsal brain stem. Midcollicular transection forestalled the irregular SND spiking normally seen with picrotoxin in the intact cat, thus resulting in improved 3 cycle/sec SND periodicity. None of these drug-induced changes effected the SND shutoff response to vasopressor tests, however. These results suggest that GABA plays a role in the SND inhibitory response to vagal afferent stimulation in the brain stem, independent of the sinoarterial baroreceptors, and may also be involved in the entrainment of SND to the arterial pulse.
Afferent Pathways↗
Evidence for a serotonergically mediated sympathoexcitatory response to stimulation of medullary raphe nuclei.
The cardiovascular role of serotonin (5-HT) containing neurons in the midline medullary raphe nuclei was studied in anesthetized cats. High frequency electrical stimulation of nucleus (n.) raphe (r.) pallidus, n.r. obscurus and n.r. magnus produced both pressor and depressor responses. Single shock stimulation of pressor sites produced an excitatory evoked potential of sympathetic nervous discharge (SND) recorded from the inferior cardiac nerve. Conversely, single shock stimulation of vasodepressor sites resulted in a computer-summed inhibition of SND. The mean conduction velocity in the sympathoexcitatory medullo-spinal pathway to sympathetic preganglionic neurons was calculated to be 1.24 m/s. The 5-HT antagonists methysergide and metergoline blocked the excitation of sympathetic activity evoked from medullary raphe nuclei. In contrast, these agents failed to alter the sympathoexcitatory response to electrical stimulation of lateral medulla pressor sites or the sympathoinhibitory response elicited by raphe stimulation. The 5-HT uptake inhibitor chlorimipramine increased the duration of the sympathoexcitatory response evoked from the raphe but not from the lateral medulla. Finally, mid-collicular transection did not effect the excitation of sympathetic activity elicited by stimulation of medullary raphe nuclei. These data suggest that serotonergic neurons in the midline medullary raphe nuclei provide an excitatory input to sympathetic neurons in the spinal cord.
Animals↗
Evidence that L-glutamic acid mediates baroreceptor function in the cat.
The possible role of L-glutamic acid (L-glu) as a neurotransmitter of baroreceptor afferent neurons was investigated in the cat by monitoring the changes in three indices of baroreceptor function seen with the L-glu antagonists L-glutamic acid diethyl ester (GDEE) and 1-hydroxy-3-amino-pyrrolidone-2-(HA-966). Baroreceptor function was determined from a) the computer summed inhibition of sympathetic nerve discharge (SND) evoked by electrical stimulation of vagal baroreceptor afferent pathways, b) the locking of SND to the cardiac cycle, and c) the sympathoinhibitory response to i.v. pressor doses of phenylephrine. Direct bilateral microinjections of GDEE (20 micrograms) and HA-966 (4 micrograms) into the region of the nucleus tractus solitarii (NTS) resulted in immediate, marked reductions in the SND inhibitory response to vagal stimulation, a loss in SND locking to the cardiac cycle, a shift in the arterial pulse/SND phase relation, and a diminished sympathoinhibitory response to phenylephrine. Control microinjections of isotonic saline (1 mu 1/NTS) were devoid of these effects. The vagal induced sympathoinhibitory response was restored after NTS microinjections of GDEE by increasing the intensity of the vagal stimulus, or by directly stimulating the NTS injection site, suggesting that the impairment in baroreceptor function seen with this L-glu antagonist was independent of mechanical or local anesthetic effects. These data strongly suggest that L-glu may act as a neurotransmitter of baroreceptor afferent neurons in the NTS of the cat.
Afferent Pathways↗
Evidence for an alpha-1 receptor-mediated central sympathoinhibitory action of ketanserin.
The effect of the serotonin receptor antagonist ketanserin on sympathetic nervous discharge recorded from the inferior cardiac and splanchnic nerves was studied in the baroreceptor-denervated cat. Intravenous ketanserin (0.05-0.8 mg/kg) produced dose-dependent decreases in mean arterial pressure, heart rate and sympathetic nervous discharge, with maximal decreases of 41, 7 and 55% of control, respectively. The decrease in mean arterial pressure could not be disassociated from a decrement in the pressor response to i.v. phenylephrine. The central sympatholytic effect of ketanserin was augmented in serotonin-depleted animals. In contrast, the centrally mediated reduction in sympathetic nervous discharge produced by ketanserin was blocked completely in catecholamine-depleted cats. In addition, the central sympatholytic action of the alpha-1 adrenergic receptor antagonist prazosin was blocked in catecholamine-depleted animals. These data indicate that ketanserin acts at central alpha-1 adrenergic receptors to reduce sympathetic outflow from the central nervous system. Central serotonergic pathways do not appear to be involved in the sympatholytic action of ketanserin. The nature of the interaction between central noradrenergic neurons and neurons involved in the genesis of sympathetic nerve activity is discussed.
Animals↗
Serotonergic excitation of sympathetic preganglionic neurons: a microiontophoretic study.
The effects of microiontophoretically applied serotonin on the extracellularly recorded discharges of sympathetic preganglionic neurons (SPNs) were studied in anesthetized cats. Thoracic SPNs were identified on the basis of constancy of antidromic activation and collision. Low ejecting currents of serotonin (5-30 nA) invariably excited spontaneously active SPNs. Serotonin also excited the vast majority of quiescent SPNs, as well as neurons brought to discharge threshold by the excitatory amino acid L-glutamate. A population of SPNs was identified which was insensitive to the excitatory effects of both serotonin and L-glutamate. Iontophoretic or intravenous administration of the putative serotonin antagonists methysergide and metergoline blocked the excitatory effects of serotonin on SPNs. The blockade of the serotonin-induced excitation was not associated with a local anesthetic action of methysergide or metergoline. Methysergide and metergoline also reduced the firing rate of SPNs in intact but not in spinal animals. These data provide strong evidence to support the contention that serotonergic neurons provide a tonic excitatory input to SPNs.
Animals↗