Effect of clonidine on the human acoustic startle reflex

Kumari, Veena; Cotter, Paul A.; Corr, Philip J.; Gray, Jeffrey A.; Checkley, Stuart

doi:10.1007/bf02246646

Cited by 41 publications

(49 citation statements)

References 19 publications

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“…These studies show that lack of ␣ 2C AR expression is associated with increased startle reactivity, reduced prepulse inhibition of the startle reflex, and isolation-induced attack latency, whereas overexpression of ␣ 2C AR produces the opposite effects. Consistent with these data, in humans, the ␣ 2 AR agonist clonidine and the ␣ 2 AR antagonist idazoxan reduce and facilitate the acoustic startle response, respectively (31,32). The role of ␣ 2C AR in modulating working memory has also been characterized (4).…”

Section: Resultsmentioning

confidence: 60%

“…Briefly, membranes (ϳ20 g) were incubated with 27 M phosphoenolpyruvate, 0.6 M GTP, 0.1 mM cAMP, 0.12 mM ATP, 50 g/ml myokinase, 0.05 mM ascorbic acid, and 2 Ci of [␣- 32 P]ATP in a buffer containing 40 mM HEPES, pH 7.4, 1.6 mM MgCl 2 , and 0.8 mM EDTA for 30 min at 37°C. These conditions minimize the stimulation of adenylyl cyclase, which is observed at high agonist concentrations (16,17).…”

Section: Methodsmentioning

confidence: 99%

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A Four Amino Acid Deletion Polymorphism in the Third Intracellular Loop of the Human α2C-Adrenergic Receptor Confers Impaired Coupling to Multiple Effectors

Small

Forbes

Rahman

et al. 2000

Journal of Biological Chemistry

177

166

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The ␣ 2 -adrenergic receptors (␣ 2 ARs) play a critical role in modulating neurotransmitter release in the central and peripheral sympathetic nervous systems. A polymorphism of the ␣ 2 AR subtype localized to human chromosome 4 (the pharmacologic ␣ 2C AR subtype) within an intracellular domain has been identified in normal individuals. The polymorphism (denoted Del322-325) is because of an in-frame 12-nucleic acid deletion encoding a receptor lacking Gly-Ala-Gly-Pro in the third intracellular loop. To delineate the functional consequences of this structural alteration, Chinese hamster ovary cells were permanently transfected with constructs encoding wild-type human ␣ 2C AR and the polymorphic receptor. The Del322-325 variant had decreased high affinity agonist binding (K H ‫؍‬ 7.3 ؎ 0.95 versus 3.7 ؎ 0.43 nM; %R H ‫؍‬ 31 ؎ 4 versus 49 ؎ 4) compared with wild-type indicating impaired formation of the agonist-receptor-G protein complex. The polymorphic receptor displayed markedly depressed epinephrine-promoted coupling to G i , inhibiting adenylyl cyclase by 10 ؎ 4.3% compared with 73 ؎ 2.4% for wild-type ␣ 2C AR. This also was so for the endogenous ligand norepinephrine and full and partial synthetic agonists. Depressed agonist-promoted coupling to the stimulation of MAP kinase (ϳ71% impaired) and inositol phosphate production (ϳ60% impaired) was also found with the polymorphic receptor. The Del322-325 receptor was ϳ10 times more frequent in African-Americans compared with Caucasians (allele frequencies 0.381 versus 0.040). Given this significant loss of function phenotype in several signal transduction cascades and the skewed ethnic prevalence, Del322-325 represents a pharmacoethnogenetic locus and may also be the basis for interindividual variation in cardiovascular or central nervous system pathophysiology.The ␣ 2 -adrenergic receptors (␣ 2 AR) 1 are cell surface receptors for catecholamines, which couple to the G i /G o family of G proteins. ␣ 2 AR are expressed at multiple sites within the central and peripheral sympathetic nervous systems and may also be expressed at noninnervated sites of peripheral tissues as well. In the central nervous system presynaptic ␣ 2 AR act to inhibit the release of neurotransmitters such as norepinephrine, serotonin, and dopamine. As such, a number of responses have been ascribed to activation of these receptors by endogenous catecholamines or exogenously administered agonists. These include modulation of blood pressure, sedation, analgesia, opiate withdrawal, and multiple complex cognitive and behavioral parameters (1-5).Three human ␣ 2 AR subtypes have been cloned and characterized and are denoted as the ␣ 2A , ␣ 2B , and ␣ 2C subtypes (6 -8). Based on chromosomal localization, these have previously been denoted as ␣ 2 C10, ␣ 2 C2, and ␣ 2 C4, respectively. Recent studies including those with genetically engineered mice have shown that the ␣ 2C subtype plays specific roles in modulation of the acoustic startle reflex, prepulse inhibition, isolation-induced aggression, spatial...

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Section: Resultsmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

A Four Amino Acid Deletion Polymorphism in the Third Intracellular Loop of the Human α2C-Adrenergic Receptor Confers Impaired Coupling to Multiple Effectors

Small

Forbes

Rahman

et al. 2000

Journal of Biological Chemistry

177

166

View full text Add to dashboard Cite

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“…Earlier studies have shown that the a 2 -AR agonist clonidine decreases startle after systemic administration in humans (Kumari et al, 1996) and rats (Davis et al, 1977), and after spinal (Davis and Astrachan, 1981) or intra-amygdaloid (Schulz et al, 2002) administration in rats. The almost totally abolished startle reflex of WT mice after Dex 10 and especially 30 mg/kg was likely due to its sedative effect.…”

Section: Discussionmentioning

confidence: 96%

“…The a 2 -AR agonist clonidine attenuates (Kumari et al, 1996) and the antagonist yohimbine enhances (Morgan et al, 1993) the startle response in humans, but the receptor subtype(s) mediating these effects is unclear. a 2 -ARdependent modulation of PPI has also been reported.…”

Section: Introductionmentioning

confidence: 99%

Alpha2A-Adrenoceptors are Important Modulators of the Effects of D-Amphetamine on Startle Reactivity and Brain Monoamines

Lähdesmäki

Sallinen

MacDonald

et al. 2004

Neuropsychopharmacol

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Amphetamines are commonly used to treat attention-deficit hyperactivity disorder, but are also widely abused. They are employed in schizophrenia-related animal models as they disrupt the prepulse inhibition (PPI) of the acoustic startle response. The behavioral effects of amphetamines have mainly been attributed to changes in dopamine transmission, but they also involve increases in the synaptic concentrations of norepinephrine (NE). a 2 -Adrenoceptors (a 2 -ARs) regulate the excitability and transmitter release of brain monoaminergic neurons mainly as inhibitory presynaptic auto-and heteroreceptors. Modulation of acoustic startle and its PPI by the a 2A -AR subtype was investigated with mice lacking the a 2A -AR (a 2A -KO) and their wild-type (WT) controls, without drugs and after administration of the a 2 -AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the a 2 -AR-noradrenergic neuronal system in modulating startle reactivity and in regulating brain monoamine metabolism was assessed as the behavioral and neurochemical responses to D-amph alone, or to the combination of D-amph and dexmedetomidine or atipamezole. a 2A -KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of a 2A -KO mice were depleted by D-amph, revealing the a 2A -AR as essential in modulating the actions of D-amph. Also, increased startle responses and more pronounced disruption of PPI were noted in D-amph-treated a 2A -KO mice. a 2A -AR also appeared to be responsible for the startlemodulating effects of a 2 -AR drugs, since the startle attenuation after the a 2 -AR agonist dexmedetomidine was absent in a 2A -KO mice, and the a 2 -AR antagonist atipamezole had opposite effects on the startle reflex in a 2A -KO and WT mice.

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“…Indeed, it has been reported that the EMG startle reflex amplitude can be reduced by sedative drugs of different classes, for example, benzodiazepines (diazepam: Scaife et al, 2005), 5HT 2 receptor antagonists (ketanserin: Graham et al, 2002), a 2 -adrenoceptor agonists (clonidine: Kumari et al, 1996;Abduljawad et al, 1997Abduljawad et al, , 2001, tricyclic antidepressants (amitriptyline: Phillips et al, 2000a), and atypical antipsychotics (clozapine and quetiapine: Graham et al, 2001Graham et al, , 2004. In contrast to the EMG startle response, the AEP is relatively resistant to sedative drugs, with only the benzodiazepines reducing N1/P2 amplitude consistently (Lader, 1977;Bond et al, 1983;Pooviboonsuk et al, 1996;Curran et al, 1998;Abduljawad et al, 2001;Scaife et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

Samuels

Hou

Langley

et al. 2007

Neuropsychopharmacol

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A sudden loud sound evokes an electromyographic (EMG) response from the orbicularis oculi muscle in humans together with an auditory evoked potential (AEP) and an increase in skin conductance (SC). Startle responses are inhibited by weak prepulses (prepulse inhibition, (PPI)) and may also be modified by the level of alertness. We compared the sedative drug clonidine and the alerting drug modafinil on sound-evoked EMG, AEP, and SC responses, on the PPI of these responses and on level of arousal and autonomic functions. Sixteen healthy male volunteers participated in four weekly sessions (clonidine 0.2 mg, modafinil 400 mg, their combination, placebo) in a double-blind, cross-over, balanced design. Responses were evoked by sound pulses of 115 and 85 dB (PPI) for 40 ms and recorded conventionally. Level of alertness, autonomic functions (pupil diameter, blood pressure, heart rate, salivation, temperature) and the plasma levels of the hormones prolactin, thyroid-stimulating hormone and growth hormone were also measured. Data were analyzed with analysis of variance with multiple comparisons. Both prepulses and clonidine attenuated all three startle responses and modafinil antagonized clonidine's effects on the EMG and AEP responses. None of the drugs affected PPI. Clonidine showed sedative and sympatholytic effects, and modafinil showed alerting and sympathomimetic effects. In conclusion, startle responses were susceptible not only to PPI but also to the level of arousal. Keywords: acoustic startle response; auditory evoked potential; skin conductance; prepulse inhibition; clonidine; modafinil INTRODUCTIONThe startle response involves rapid involuntary contractions of facial and skeletal musculature in response to a sudden intense stimulus. In the case of the acoustic startle response, this reaction occurs in response to a sudden loud sound and is measurable in humans as an electromyographic (EMG) response from the orbicularis oculi muscle (eyeblink startle response). This response is believed to be mediated via a pathway below the level of the diencephalon consisting of between three and five central synapses, originating from the sensory receptors and terminating on the motor neurons, where the principal relay is the caudal pontine reticular nucleus (Davis et al, 1982; for review, see Yeomans and Frankland, 1996;Koch, 1999). In addition to this muscular response, changes in electroencephalographic (EEG) activity can be observed in response to the auditory stimulus, and these changes are termed auditory evoked potentials (AEP). In particular, the N1/P2 component of the AEP is measurable following the presentation of the acoustic startle stimulus (for examples, see Abduljawad et al, 1999Abduljawad et al, , 2001 Phillips et al, 2000a, b;Graham et al, 2001Graham et al, , 2004Scaife et al, 2005Scaife et al, , 2006. Both the muscular and the AEP responses are fast responses; longer-latency responding to the startle stimulus can be observed in autonomic activity, in particular in sympathetically mediated skin conductance...

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Effect of clonidine on the human acoustic startle reflex

Cited by 41 publications

References 19 publications

A Four Amino Acid Deletion Polymorphism in the Third Intracellular Loop of the Human α2C-Adrenergic Receptor Confers Impaired Coupling to Multiple Effectors

A Four Amino Acid Deletion Polymorphism in the Third Intracellular Loop of the Human α2C-Adrenergic Receptor Confers Impaired Coupling to Multiple Effectors

Alpha2A-Adrenoceptors are Important Modulators of the Effects of D-Amphetamine on Startle Reactivity and Brain Monoamines

Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

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