Arousal attention and sleep

Centrally acting a1-adrenoceptor agonists often potentiate motor stimulation or arousal produced by other pharmacological (Holz et al. 1982) or behavioural (Astrachan et al. 1983a,b) challenges, and will increase vigilance when administered alone (Nozulak et al. 1992). a1-Adrenoceptor agonists can reverse sedation induced by norepinephrine depletion produced by a dopamine ^-hydroxylase inhibitor (Nozulak et al. 1992). Likewise, they can reverse cataplexy in a genetic canine model of narcolepsy (Renaud et al. 1991). Based on studies in rats and primates, modafinil, now marketed for the treatment of narcolepsy, may act through the activation of central a1-adrenoceptors (Duteil et al. 1990), although based on its structure and peripheral pharmacological effects, this drug would not be expected to be an a-adrenoceptor agonist. The precise functional roles of each individual a1 -adrenoceptor subtype within the CNS are not yet known. It has been proposed that both a1B- and a2A-adrenoceptors are present on cell bodies of presympathetic ganglionic neurons in the intermediolateral cell column of the thoracic spinal cord, mediating an excitatory and inhibitory action, respectively (Nicholas etal. 1995). This reciprocal action is consistent with the observation that central a1-adrenoceptor stimulation will attenuate the sedative actions of an a2-adrenoceptor agonist in the rat (Guo etal. 1991). Mice lacking the a1b-adrenoceptor show different behavioural effects from wild-type mice, in which enhanced reactivity to new situations is observed. Correlation of affinity for recombinant a1 -adrenoceptors with their activity in the canine narcolepsy model suggests that the ability of a1 -adrenoceptor agonists to reverse cataplexy in this model results from a1B-adrenoceptor activation (Nishino etal. 1993).

Table 12.1 a1-, a2-, and ß-adrenoceptors

a1 -Adrenoceptors

a1A

a1B

a1D

Alternative names

a1a. a1c

a1b

a1d' a1a/d

Structural information (Accession no.)

h 466 aa(P3 5348)AS r 466 aa(P43140)AS m 466 aa (P97718)

h 519 aa (P35368) r 515 aa (P1 5823) m 514 aa (P97717)

h 572 aa (P25100) r 561 aa (P23944) m 562 aa (P97714)

Chromosomal location

8

5q33

20p13

Selective agonists

oxymetazoline, SKF89748, A61603

Selective antagonists

SNAP5089, SNAP5272, Ro70004, RS17053, KMD3213

(+)-Cyclazosin, L765314

BMY7378, SKF105854

Radioligands

[3H]-Prazosin, [125I]-HEAT, [125I]-L762459

[3H]-Prazosin, [125I]-HEAT

[3H]-Prazosin, [125I]-HEAT

G protein coupling

Gq/G11

Gq/G11

Gq

Expression profile

olfactory system, hypothalamus, brainstem, spinal cord, prostate, vas deferens, heart, blood vessels

cerebral cortex, thalamus, raphe, motor neurons, pinieal gland, spleen, kidney, heart, blood vessels

cerebral cortex, hippocampus, dentate gyrus, thalamus, motor neurons, inferior olivary complex, olfactory bulb, aorta, large blood vessels

Physiological function

smooth muscle and myocardial contraction

smooth muscle contraction

smooth muscle contraction

Knockout phenotype

decreased vasocontrictor response, selective learning deficits

Disease relevance

attention disorders, narocolepsy, feeding disorders, Parkinson's disease, cognitive decline

neurodegenerative diseases, epilepsy, attention disorders, narocolepsy, feeding disorders, Parkinson's disease, cognitive decline

attention disorders, narocolepsy, feeding disorders, Parkinson's disease, cognitive decline

.^-Adrenoceptors

a2A

a2B

a2C

Alternative names

a2-C10, RG20, a2D (rat)

a2-C2, RNG

a2-C4

Structural information (Accession no.)

h 450 aa (P08913) r 450 aa (P22909) m 450 aa (Q01338)

h 451 aa (P18089) r 453 aa (P19328) m 455 aa (P30545)

h 461 aa (P18825) r 458 aa (P22086) m 458 aa (Q01337)

Chromosomal location

10q23-25

2

4

Selective agonists

oxymetazoline (partial), guanfacine

Selective antagonists

BRL44408, BRL48962

imiloxan, rauwolscine

MK912

Radioligands

[3H]-Rauwolscine, [3H]-RX821002

[3H]-Rauwolscine, [3H]-RX821002

[3H]-Rauwolscine, [3H]-RX821002

G protein coupling

Gi/Go

Gi/Go

Gi/Go

Expression profile

Physiological function

cerebral cortex, hippocampus, locus coeruleus, amygdala, hypothalamus, spinal cord, platelets, adipocytes, aorta, kidney, spleen major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves, hypotension, analgesia, sedation, anaesthesia

thalamus, cerebellum, septum, striatum, olfactory tubercle, liver, spleen, heart, kidney, neonatal lung regulation of the sympathetic nervous system, vasoconstriction

cerbral cortex, cerebellum, hipocampus, striatum, olfactory bulb, islands of Cajella, heart, lung, aorta, kidney regulation of the sympathetic nervous system

Knockout phenotype

increase in sympathetic activity with resting tachycardia, depletion of cardiac tissue norepinephrine concentration, down-regulation of cardiac p receptors

decreased vascular response to agonists

decreased hypothermic response, reduced behavioural despair, increased startle response

Disease relevance

depression, pain, addiction, attention deficit hyperactivity disorder, hypertension, intra-ocular pressure in glaucoma

Table 12.1 (Continued)

ß-Adrenoceptors

01

02

03

Alternative names

Structural information (Accession no.)

h 477 aa (P08588) r 466 aa (P18090) m 466 aa (P34971)

h 413 aa (P07550) r 418 aa (P10608) m 418 aa (P18762)

h 408 aa (P13945)AS r 400 aa (P26255)AS m 400 aa (25962)AS

Chromosomal location

10q24-26

5q31-32

8p11-12

Selective agonists

norepinephrine, T0509, denopamine, xamoterol (partial)

procaterol, salbutamol, fenoterol

BRL37344, CL316243, SB226552

Selective antagonists

CGP20712A, betaxolol, atenolol, bisoprolol, practolol

ICI1 18551, butoxamine, a-methylpropranolol

SR58894, SR59230A

Radioligands

[125I]-I-iodoncyanopindolol, [3H]-CGP12177, [3H]-dihydroalprenolol

[125I]-I-iodoncyanopindolol, [3H]-CGP12177, [3H]-dihydroalprenolol

[125I]-I-iodoncyanopindolol, [3H]-CGP12177, [3H]-dihydroalprenolol

G protein coupling

Gs

Gs

Gs

Expression profile

widely expressed in brain inculding cerebral cortex, hippocampus, diencephalon, cerebellum, caudate

cerebral cortex, piriform cortex, hippocampus, cerebellum, caudate, diencephalon, olfactory bulb

adipose, gall bladder, small intestine, stomach, prostate, atrium, bladder

Physiological function

increased heart rate and force of contraction

smooth muscle relaxation

lipolysis, cardioinhibition

Knockout phenotype

decreased cardiac response to agonists

increased exercise capacity

increased fat accumulation

Disease relevance

hypertension, congestive heart failure, myocardial infarction, angina, cardial arrhythmia

same as P1 but may also be useful for the treatment of asthma

same as P1 but may also be useful for the treatment of diabetes and obesity

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