Differential expression of two α2-adrenergic receptor subtype mRNAs in human tissues

Perälä, Merja; Hirvonen, Harri; Kalimo, Hannu; Ala-Uotila, Sari; Regan, John W.; Åkerman, Karl E.O.; Scheinin, Mika

doi:10.1016/0169-328x(92)90193-f

Cited by 33 publications

(10 citation statements)

References 14 publications

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“…In the rat brain, α 2B ‐adrenoceptors are exclusively localised in the thalamus (Scheinin et al , 1994), an area which is involved in psychotic processes in man (Buchsbaum, 1995), and in sensorimotor gating and catalepsy in rats (Young et al , 1995). On the other hand, α 2C receptors are found in high density in the caudate nucleus of many species, including man (Ordway et al , 1993; Perälä et al , 1992) and α 2C ‐adrenoceptor ‘knock‐out’ mice display altered dopamine turnover in the brain (Sallinen et al , 1997). Interestingly, clozapine displays somewhat higher affinity for the human α 2B and α 2C receptor subtypes (pK D values of 7.7 and 8.0, respectively) than for human α 2A receptors (pK D = 7.3; Schotte et al , 1996).…”

Section: Discussionmentioning

confidence: 99%

The role of α₂‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

Kalkman

Neumann

Hoyer

et al. 1998

British J Pharmacology

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1 The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat. 2 The close structural analogues of clozapine, loxapine (0.1 mg kg 71 s.c.) and iso-clozapine (1 and 3 mg kg 71 s.c.) induced catalepsy in rats. In contrast, clozapine and the regio-isomer of loxapine, isoloxapine (up to 10 mg kg 71 s.c.) did not produce catalepsy, but at a dose of 1 mg kg 71 signi®cantly inhibited catalepsy induced by loxapine (0.3 mg kg 71 s.c.). 3 Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D 2 /5-HT 1A , D 2 /5-HT 1B/1D and D 2 /a 2 -receptor a nity (K D ) ratios: i.e. 30 ± 100-fold higher ratios were calculated for loxapine and iso-clozapine, whereas the ratios were less than 1 for clozapine and isoloxapine. The ratios of a nities for D 2 to 5-HT 2A , 5-HT 2C or D 1 did not re¯ect the grouping of cataleptic and non-cataleptic compounds. 4 Co-treatment with the a 2 -adrenoceptor antagonists, yohimbine (1 ± 10 mg kg 71 s.c.), RX 821002 (1 ± 10 mg kg 71 s.c.) and MK-912 (0.3 and 1 mg kg 71 s.c.) dose-dependently inhibited the cataleptic response to loxapine (0.3 mg kg 71 ). Yohimbine (1 ± 10 mg kg 71 s.c.) also dose-dependently inhibited the cateleptic response to haloperidol (0.3 mg kg 71 s.c.). The a 2 -adrenoceptor antagonists had no e ect per se. 5 Neither yohimbine (10 mg kg 71 ) nor RX821002 (3 mg kg 71 ) altered the cataleptic response to the D 1 receptor antagonist, SCH 23390 (1 mg kg 71 s.c.), while, like clozapine, both compounds abolished the response to the 5-HT 2A receptor antagonist, MDL 100,151 (3 mg kg 71 s.c.). 6 The present data strongly implicate a 2 -adrenoceptor blockade in the anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side e ects in the clinic may also be a consequence of this property.

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Section: Discussionmentioning

confidence: 99%

The role of α₂‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

Kalkman

Neumann

Hoyer

et al. 1998

British J Pharmacology

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“…Based upon PCR (Eason & Liggett, 1993) and RNase protection assays (Perälä et al ., 1992), all three cloned α 2 ‐adrenoceptor subtypes are expressed at the mRNA level in the human prostate. Studies at the protein level have sometimes been performed using immunohistochemistry (Slater et al ., 2000) and receptor autoradiography (James et al ., 1989; Felsen et al ., 1994), but in most cases have relied upon radioligand‐binding experiments with tissue homogenates.…”

Section: Prostatementioning

confidence: 99%

α₁‐, α₂‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

Michel

Vrydag

2006

British J Pharmacology

409

320

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1 We have systematically reviewed the presence, functional responses and regulation of a 1 -, a 2 -and b-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes. 2 a 1 -Adrenoceptors are only poorly expressed and play a limited functional role in the detrusor. a 1 -Adrenoceptors, particularly their a 1A -subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates. a 1 -Adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate. 3 a 2 -Adrenoceptors, mainly their a 2A -subtype, are expressed in bladder, urethra and prostate. They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans. Their overall post-junctional function in the lower urinary tract remains largely unclear. 4 b-Adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate. The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the b 3 -and b 2 -subtypes are important in the human bladder and urethra, respectively. b 3 -Adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder. 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence. Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment.

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“…According to available data of previous studies (Petrash and Bylund, 1986;Meana et al ., 1989;De Vos et al, 1992) and unpublished results from the present laboratories, the population of human brain a2-adrenoceptors in the hippocampus and frontal cortex visualized in this study appears to belong to the predominant a2A subtype, the receptor subtype that is also the presynaptic inhibitory autoreceptor on brain noradrenergic terminals (Limberger et al, 1991 ;Raiteri et al ., 1992) . The a,, subtype is also expressed (a2-C4 mRNA) in the hippocampus and frontal cortex (Perälä et al, 1992;Nicholas et al ., 1993), but the lack of selective drugs makes the quantitation of this a2adrenoceptor subtype difficult (Ordway et al ., 1993) . In contrast, the presence of the a2B subtype through gene expression (a2-C2 mRNA) has not been reported in the human brain, but in the rat brain the mRNA encoding the a2B subtype is poorly expressed and only in the diencephalon (Zeng and Lynch, 1991 ;Nicholas et al, 1993).…”

Section: Subjects and Suicide Victims With Rnojor Depression Or Othermentioning

confidence: 99%

Autoradiographic Demonstration of Increased α₂‐Adrenoceptor Agonist Binding Sites in the Hippocampus and Frontal Cortex of Depressed Suicide Victims

González

Pascual

Meana

et al. 1994

Journal of Neurochemistry

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To examine directly in the brain the status of α2‐adrenoceptors in major depression, the specific binding of the agonist [3H]UK 14304 was measured by quantitative receptor autoradiography in the hippocampus and frontal cortex of suicide victims (n = 17) with a retrospective diagnosis of depression (n = 7) or other psychiatric disorders (n = 10) as well as of matched control subjects (n = 9). In suicide victims, a significant increase in the number of α2‐adrenoceptors was found in the CA1 field (40%) and dentate gyrus (20%) of the hippocampus and in the external layers I (33%) and II (31%) of the frontal cortex, compared with that in matched controls. In depressed suicide victims, the increase in α2‐adrenoceptors in the CA1 field (57%) was significantly greater (24%, p < 0.05) than that observed in the group of suicide victims with other diagnoses (26%). In the same depressed suicide victims, the increase in cortical α2‐adrenoceptors was restricted to layer I (34%) and it was equivalent to that found in layer I (33%) of suicide victims with other diagnoses. The results indicate that suicide is associated with increases in the high‐affinity state of brain α2‐adrenoceptors and that there is a pronounced localized increase of this inhibitory receptor in the hippocampus of depressed suicide victims.

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Differential expression of two α2-adrenergic receptor subtype mRNAs in human tissues

Cited by 33 publications

References 14 publications

The role of α₂‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

The role of α₂‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

α₁‐, α₂‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

Autoradiographic Demonstration of Increased α₂‐Adrenoceptor Agonist Binding Sites in the Hippocampus and Frontal Cortex of Depressed Suicide Victims

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Differential expression of two α2-adrenergic receptor subtype mRNAs in human tissues

Cited by 33 publications

References 14 publications

The role of α2‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

The role of α2‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

α1‐, α2‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

Autoradiographic Demonstration of Increased α2‐Adrenoceptor Agonist Binding Sites in the Hippocampus and Frontal Cortex of Depressed Suicide Victims

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Product

Resources

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The role of α₂‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

The role of α₂‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

α₁‐, α₂‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

Autoradiographic Demonstration of Increased α₂‐Adrenoceptor Agonist Binding Sites in the Hippocampus and Frontal Cortex of Depressed Suicide Victims