Review
a 1 -Adrenergic receptor subtypes in the central nervous system: insights from genetically
engineered mouse models
Irena Nalepa, Grzegorz Kreiner, Adam Bielawski, Katarzyna Rafa-Zab³ocka, Adam Roman
Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland
Correspondence: Irena Nalepa, e-mail: nfnalepa@cyf-kr.edu.pl
Abstract:
a1-Adrenergic receptors (a1-ARs) are important players in peripheral and central nervous system (CNS) regulation and function and in mediating various behavioral responses. The a1-AR family consists of three subtypes, a1A, a1Band a1D, which differ in their sub- cellular distribution, efficacy in evoking intracellular signals and transcriptional profiles. All three a1-AR subtypes are present at relatively high densities throughout the CNS, but the contributions of the individual subtypes to various central functions are cur- rently unclear. Because of the lack of specific ligands, functionally characterizing the a1-ARs and discriminating between the three subtypes are difficult. To date, studies using genetically engineered mice have provided some information on subtype-related func- tions of the CNS a1-ARs. In this mini-review, we discuss several CNS processes where the a1-ARs role has been delineated with pharmacological tools and by studies using mutated mice strains that infer specific a1-AR subtype functions through evaluation of behavioral phenotypes.
Key words:
a1Aadrenergic receptor, a1Badrenergic receptor, a1Dadrenergic receptor, genetic models, noradrenergic, antidepressant, phenotype
Abbreviations: AR – adrenergic receptor, CAM – constitu- tively active mutant, cAMP – cyclic adenosine monophos- phate, CMS – chronic mild stress, CNS – central nervous sys- tem, CRF/CRH – corticotropin releasing factor/hormone; ECS – electroconvulsive shock, FST – forced swim test, GPCR – G-protein-coupled receptor, GRK – G-protein-coupled recep- tor kinase, HPA – hypothalamic-pituitary-adrenocortical, KO – knockout, MSA – multiple system atrophy, PCA – p-chloro- -amphetamine, PKA – protein kinase A, PKC – protein kinase C, PLC – phospholipase Cb, TCA – tricyclic antidepressant drug, TGFb – transforming growth factor b3, TST – tail sus- pension test, WT – wild-type
Introduction
Noradrenaline is a neurotransmitter that plays an es- sential role in behavior and the regulation and func- tion of the peripheral and central nervous system (CNS). The noradrenergic system modulates cogni- tive functions, such as arousal, attention, learning and memory [41]. Dysregulation of noradrenergic neuro- transmission and abnormalities in brain adrenergic re-
Pharmacological Reports 2013, 65, 14891497 ISSN 1734-1140
Copyright © 2013 by Institute of Pharmacology Polish Academy of Sciences
(ADHD); stress- and/or anxiety-related disorders (e.g., posttraumatic stress disorder [PTSD] and de- pression) and drug abuse [1].
Physiological responses to noradrenaline and adrenaline are mediated by adrenergic receptors (AR), which are seven-transmembrane-spanning receptors that belong to the large G-protein-coupled receptor (GPCR) superfamily. The AR family is presently di- vided into three distinct receptor subclasses, b-, a2- and a1-AR, and each subclass comprises several sub- types. All three a1-AR subtypes, a1A, a1Band a1D, are coupled to Gq/11 and phospholipase Cb (PLC), which stimulate phosphoinositide hydrolysis to produce two second messengers, diacylglycerol and inositol trisphosphate, followed by protein kinase C (PKC) activation and increased mobilization of intracellular Ca2+. The a1-ARs function as stimulatory receptors, and each subtype is encoded by a separate gene lo- cated on different chromosomes, has a distinct phar- macological profile and amino acid sequence and is differentially distributed [8, 37, 38].
The physiological responses mediated by a1-ARs in the cardiovascular and peripheral nervous systems have been well studied. These receptors are involved in smooth muscle contraction, growth and differentia- tion. The a1-AR subtypes are important for the modu- lation of vasoconstriction, blood pressure control and urinary tract contractility and have been previously characterized [4, 8, 15, 46] but are beyond the scope of this current review.
Central a1-ARs modulate a large number of posi- tive motivated behaviors and mediate aversive behav- iors [44]. These receptors influence motor and ex- ploratory activity, and in mice, central a1-AR neuro- transmission is required for behavioral activation to environmental changes and may act on sensorimotor and motivational processes [45]. The a1-ARs mediate corticotropin releasing factor (CRF) secretion, can modulate the activity of the hypothalamic-pituitary- adrenocortical (HPA) axis and regulate behavioral stress responses. However, because subtype-selective pharmacological tools are absent, the contributions of each a1-AR subtype to various central functions are currently unclear.
In this review, we briefly examine the different regulatory and cellular characteristics of a1-ARs (in vitro studies using recombinant systems and trans-
mice).
a1-Adrenoceptor signaling regulation and cellular function
The regulation of GPCR signaling occurs via a variety of dynamic control mechanisms, including phospho- rylation and desensitization, protein-protein interac- tions, protein trafficking, and transcription. Because of GPCR desensitization, the intensity of a biological response wanes over time (reviewed in [26]). Similar to other GPCRs, the a1-ARs may undergo homolo- gous (phosphorylation by G-protein-coupled receptor kinases [GRKs]) or heterologous desensitization (phosphorylation by second messenger-activated pro- tein kinases, such as PKC and protein kinase A [PKA]), arrestin-related internalization and endocyto- is into clathrin-coated vesicles. Although such mechanisms are responsible for the regulation of a1-AR signaling intensity, a1-AR subtypes display di- vergent regulatory properties, and as demonstrated through previous work utilizing various recombinant systems, the rate of phosphorylation, desensitization and internalization in response to agonists differs be- tween the receptor subtypes [5]. Such diversity may be linked, at least in part, with differential cellular lo- calization of receptor subtypes and their access to agonists acting at the cell surface. The a1B-AR, which is localized mainly on the plasma membrane, under- goes rapid desensitization and internalization in re- sponse to adrenergic agonists, but the a1A-AR, which is localized both on the cell surface and intracellu- larly, displays a slower rate of internalization com- pared with the a1B-AR. By contrast, the a1D-AR is lo- calized predominantly in intracellular vesicles, and the intracellular localization of a1D-AR in unstimu- lated cells may be linked with its continuous internali- zation stemming from its constitutive activity [3, 38].
Therefore, these studies implicate the existence of ad- ditional mechanism(s) to regulate a1D-AR function.
Interestingly, the a1-AR subtypes have been shown to form both homo- and hetero-oligomers. Hetero- dimerization, in particular, seems to regulate a1D-AR function, as co-expression of a1D-AR with the
a1B-AR rescued surface a1D-AR expression [18].
Such an interaction modified the pharmacological profile of a1D-AR, and the a1D/a1Bdimer displayed an increased response to noradrenaline compared with either monomer alone. The above-described study and other studies [5, 15] suggest heterodimerization as an additional mechanism to regulate the physiological response mediated by a1-AR subtypes. However, to date, this phenomenon has not been explored in vivo.
In addition, although the three a1-AR subtypes ac- tivate the same Gq/11 signaling pathway, they may in- teract with different protein binding partners, and in the overall a1-adrenergic response, various signaling pathways may participate (e.g., AC/cAMP, modula- tion of ion channels, activation of ERK1/2) [3, 15, 38]. Not surprisingly, these interactions may result in a multitude of transcriptional responses. Using an oli- gonucleotide microarray technique and Rat-1 fibro- blasts transfected with a1-ARs, Gonzalez-Cabrera et al. [16] identified 29 different genes with ³ 2-fold changes after adrenaline stimulation in cells expres- sing each individual a1-AR subtype. For instance, all subtypes showed increased gene expression of IL-6, a proinflammatory cytokine, suggesting that some re- dundancy exists among the a1-AR subtypes. Con- versely, the individual subtypes differed in the regula- tion of IL-6 signaling pathway members. Only the ac- tivation of the a1A- and a1D-AR subtypes was associated with increases in gp-130 expression (a high affinity IL-6 receptor) and STAT3 (a prototypical IL- 6-stimulated transcription factor), but the a1B-AR subtype did not. Other changes in gene expression also occurred that were unique to each a1-AR sub- type. Interestingly, in the a1B-AR-transfected cells, most of the modified genes were associated with neu- rodegeneration and apoptosis, including t protein ki- nase, synuclein, transforming growth factor b3 (TGFb) and caspase-6 [16]. The a1B-AR-specific modulation of t and TGFb genes was corroborated using the brains of transgenic mice overexpressing the a1B-AR [51].
a1-Adrenoceptor subtypes distribution in the CNS
The a1-ARs are widely distributed in the CNS and present on neurons in a number of brain regions. The a1-ARs are expressed in glial cells and thus may in-
fluence many brain functions via non-neuronal mechanisms. In situ hybridization analysis of a1-AR subtype mRNAs distribution in rat brain showed high levels of a1A-AR expression in several regions such as the olfactory system, several hypothalamic nuclei, and regions of the brainstem and spinal cord, particu- larly in areas related to motor function. However, the a1B-AR was abundant in the pineal gland, most thal- amic nuclei, the lateral nucleus of the amygdala and dorsal and median raphe nuclei [6]. In turn, our study has shown that a1B-AR mRNA expression, as as- sessed by northern blot analysis, was similarly and poorly expressed in the thalamus and prefrontal cor- tex but undetectable in the hippocampus [23]. The a1D-AR distribution was the most discrete among the three receptor subtypes and was strongly expressed in the olfactory bulb, cortical layers II–V, the hippocam- pus, the reticular thalamic nucleus, regions of the amygdala, the motor nuclei of the brainstem and the spinal cord [6]. The distinct mRNA distribution of the three a1-AR subtypes suggests their unique functional roles; however, at the protein level, both the a1A- and a1B-ARs were expressed in similar brain regions but each to a different extent. The a1A-AR was more abundant in the hippocampus, midbrain, and hind- brain compared with the a1B-AR [37].
The role of a1-adrenoceptor subtypes in depression
Depression is generally recognized as and represents a multifactorial disorder involving many brain circuits (monoaminergic systems, CRF, HPA axis and corti- costeroids, cytokines and growth factors) and neu- ronal processes (neuronal atrophy, neurogenesis) (reviewed in [25, 35, 43]). Noradrenaline has been implicated in depression since the 1960s, when biolo- gical depression hypotheses were developed that stated that brain monoaminergic transmission deficits play an important role in depression etiology. Much later, the adrenergic receptors (b, a2 and a1 classes) were shown to undergo changes after antidepressant drug treatment (reviewed in [30]].
Impaired brain a1-adrenergic neurotransmission has been implicated in some depressive illness symp- toms, and CNS a1-AR blockade induced depression- related behaviors in a mouse model of depression
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Repetitive imipramine and other tricyclic antidepres- sant (TCA) treatments have been reported to increase the a1-AR density in different brain areas of both mice and rats (reviewed in [13, 48]). However, the mechanism by which the individual a1-AR subtypes mediate these antidepressant effects is still not well understood.
The specific involvement of one a1-AR subtype, a1A-AR, in antidepressant action was suggested by our study that showed that chronic imipramine and electro- convulsive shock (ECS) treatments increased a1A-AR (but not the a1B-AR) mRNA levels and receptor den- sity in the rat cerebral cortex and hippocampus [29]. As such an effect was not caused by chronic administra- tion of the selective serotonin reuptake inhibitor citalo- pram [22], the up-regulation of a1A-AR seemed de- pendent on the noradrenergic component of the phar- macological action of antidepressants. In fact, our recent study utilizing DSP4 (a neurotoxin selective for noradrenergic nerve terminals) found that the nor- adrenergic component of antidepressant agents played an essential role in the above-described modulation of a1A-AR [24]. Therefore, our results suggested that the a1Areceptor subtype is involved in the mechanism of action of antidepressant drugs.
Interestingly, a recent study by Doze et al. has shown that increased a1A-AR expression following chronic use of noradrenaline-related antidepressants or electroconvulsive shock may mediate the antide- pressant effects of these therapies [9]. The study in the model of transgenic mice engineered to express a con- stitutively active mutant (CAM) form of a1A-AR (CAM–a1AAR) or a1B-AR (CAM–a1BAR) demon- strated that these two receptors differentially modu- late antidepressant-like behaviors. Only a1A-AR sig- naling promoted antidepressant-like behavior in the tail suspension (TST) and forced swim (FST) tests, but CAM–a1BAR mice manifested pro-depressant- like behavior. Furthermore, the antidepressant-like phenotype of CAM–a1AAR mice was reversed by prazosin administration and, in wild-type (WT) ani- mals, was mimicked by chronic cirazoline administra- tion (an a1A-AR agonist) [9]. Together, the a1A- and a1B-ARs may have separate and distinct CNS func- tions, even with overlapping brain distribution [9].
Such an assumption is also supported by two other findings that indicate that CAM–a1AAR expression
tion [53]. These two phenomena may be associated with and underlie the aforementioned antidepressant- like behavior in CAM–a1AAR mice and the pro- depressant-like behavior in the CAM–a1BAR mice [9].
Furthermore, a1B-AR signaling may be involved in depression in animals, as suggested by our studies using the chronic mild stress (CMS) model of depres- sion. This model causes a decrease in sensitivity to re- ward, and depressive animal behavior manifests as consumption anhedonia for a palatable sucrose solu- tion [50]. Our preliminary results showed that 3 weeks of CMS procedure caused an increase in rat hippocampal a1B-AR mRNA expression, but the other two a1-AR subtypes were not altered [2]. This in- creased expression was observed only in animals that developed anhedonia for sucrose consumption, and because a1B-AR expression was unchanged in CMS- resistant rats, CMS action produced a specific a1B-AR response. In addition, the decrease in receptor density after a prolonged 8-week CMS procedure suggests an a1B-AR vulnerability to prolonged stressful events and a role in depression [2]. The association of a1B-AR with the HPA axis, which is critical to an ani- mal’s stress response, was demonstrated by Day et al., who observed a1B-AR mRNA expression in CRH- containing, stress-responsive cells of the PVN and high sensitivity to circulating corticosterone [7].
Consequences of chronic a1B-AR activation
a1B-AR signaling may participate in neurodegenera- tive processes, as suggested by transgenic mouse models that overexpressed either WT or constitutively active forms of a1B-AR (CAM–a1BARs). Such chronic overactive a1B-AR signaling led to an extensive apop- totic neurodegeneration, and mice displayed symp- toms and degenerative histology that share similari- ties with a Parkinson’s plus syndrome called multiple system atrophy (MSA). These mice experienced a grand mal seizure disorder, which appeared as a possible multifocal epilepsy [53]. The molecular ba- sis of this phenotype was further investigated by oli- gonucleotide microarray analysis. Gene expression changes between transgenic and normal mice were
observed, which involved glutamate and calcium regulation, apoptosis and neurodegeneration, cell growth and synaptic vesicle transport. Interestingly, in transgenic mouse brains, the expression of excitatory N-methyl-D-aspartate (NMDA) receptors increased, and inhibitory GABAA receptors decreased. Thus, chronic activation of a1B-AR can lead to seizures through NMDA and GABA receptor dysregulation, and a glutamate imbalance has been suggested to cause the epileptic seizures observed in mutant mice overexpressing a1B-AR [51].
The role of a1-adrenoceptor subtypes in cognitive function and behavioral activation
Noradrenaline has been shown to influence a variety of cognitive processes in the brain; however, the func- tion of the a1-ARs in learning and memory is contro- versial. Depending on the animal model, a1-AR stimulation has been reported to either inhibit or fa- cilitate learning and memory (reviewed in [41]).
Recent studies by Doze et al. with CAM–a1AAR mice revealed the significance of the a1A-AR in learn- ing and memory [10]. Long-term stimulation of the a1A-AR enhanced learning and memory in behavioral tests (Barnes, Morris water and multi-T mazes). In contrast, a1AAR-KO mice displayed poor cognitive function. Interestingly, aged CAM–a1AAR mice dem- onstrated enhanced synaptic plasticity in the hippo- campus compared with WT mice. Moreover, the life- span of CAM–a1AAR mice was 10% longer than the lifespan of WT mice. Additionally, as mentioned above, long-term a1A-AR activation improved mood.
Together, these results suggest that long-term a1A-AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity [10].
Some evidence indicates that the a1B- and a1D-ARs may be involved in the modulation of memory func- tions and exploratory activity; however, the data are not completely straightforward. Knauber and Müller [21] reported that in passive avoidance procedures, a1BAR-KO mice showed a tendency towards de- creased short-term-latency and a significant decline in long-term-latency. Furthermore, a1BAR-KO mice ex- hibited low levels of open field activity, as measured by a lower initial exploratory activity (square entries)
and a reduced number of rears, compared with WT mice. Thus, the authors proposed that the a1B-AR is involved in the modulation of memory consolidation and fear-motivated exploratory activity [21]. Addi- tionally, Spreng et al. [42] have demonstrated that a1BAR-KO mice have selectively reduced learning capacities, which were reflected by impaired spatial learning in the water maze but increased reaction to novelty.
Studies by Sadalge et al. [40] examining a1D-AR’s functional role suggested that this receptor is not criti- cal for learning and memory. No differences were ob- served in spatial and emotional learning or in cued and contextual fear conditioning, when comparing a1DAR-KO and WT mice [40]. However, Mishima et al. [27] demonstrated in the Y-maze (requiring work- ing memory or attention) that a1DAR-KO mice dis- played impaired spontaneous alternation perfor- mance. Thus, a1D-AR appears to play an important role in attention or working memory but is not associ- ated with reference memories.
The a1D-AR receptor seems to mediate behavioral activation and motor coordination. Mishima et al. [27]
demonstrated that when comparing a1DAR-KO and WT mice, locomotor activity was similar, but a1DAR-KO possessed better motor coordination at the highest speeds of the rotarod and stronger muscle tone meas- ured by a traction meter [27]. Sadalge et al. [40] dem- onstrated that the wheel-running activity of a1DAR- KO mice was significantly reduced during the subjec- tive night, or in the active phase. Additionally, mutant mice showed a reduction in exploratory rearing be- havior in a novel cage environment. Thus, in contrast to a1BAR-KO mice, a1DAR-KO mice manifested a significantly reduced reactivity to novel environ- ments. These data clearly indicate a role for a1D-AR in mediating behavioral activation and suggest that the receptor is important for facilitating selective at- tention to environmental cues [40].
a1-Adrenoceptor subtypes and effects of drugs of abuse
Psychostimulants (e.g., cocaine or amphetamine) and opiates (e.g., morphine or heroin) are addictive in hu- mans, and in rodents, they induce locomotor hyperac- tivity and trigger behavioral sensitization after re-
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consequent enhanced interaction between dopamine and postsynaptic dopamine receptors. However, most psychostimulants increase noradrenaline release, and numerous studies have indicated an interaction be- tween dopaminergic and noradrenergic neurons medi- ated through a1-AR [36]. Over a decade of evidence indicates the important role of noradrenaline and its a1-AR in stimulant-evoked effects. Drouin et al. per- formed behavioral studies that demonstrated the blockade of a1-ARs by the a1-AR antagonist prazosin reduced the locomotor effects of acute cocaine and amphetamine and blocked behavioral sensitization in- duced by repeated drug injections [11]. Thus, the a1-ARs may play a permissive role for dopamine- induced behavioral effects. Moreover, prazosin ad- ministration reduced reinstatement of drug-seeking behavior [52], which demonstrated the importance of a1-adrenoceptors in cocaine self-administration.
The involvement of a1-AR in cocaine’s mechanism of action was supported by our earlier studies demon- strating that a single cocaine injection enhances a1-AR responsiveness to noradrenaline, as measured by changes in inositol phosphate accumulation [49].
Furthermore, we demonstrated that cocaine sensitiza- tion produced significant alterations in a1-AR density, as assessed by autoradiographic analysis of [3H]-pra- zosin binding [34]. The changes were dependent on the withdrawal period length and were observed mainly in the brain structures known to be involved in the priming-induced reinstatement of cocaine seeking.
Our data indicate that, in addition to cocaine-induced behavioral effects and modulation of the dopaminer- gic system, drug administration results in biochemical changes in cerebral a1-ARs, and the behavioral phe- nomenon of cocaine sensitization may be partially due to modified a1-ARs signaling [34].
Evidence from mutant mice suggests that at least two a1-AR subtypes, the a1B- and a1D-ARs, are impli- cated in drug-induced locomotor hyperactivity.
Drouin et al. [12] have demonstrated that the locomo- tor effects of acute D-amphetamine, cocaine, and morphine and drug-induced behavioral sensitization were dramatically reduced in a1BAR-KO mice. Fur- thermore, in a1BAR-KO mice, the rewarding effects of cocaine and morphine in an oral preference test and morphine in conditioned place preference were elimi- nated. Compared with WT mice, a1BAR-KO mice
critical role in the vulnerability to addiction was pro- posed [12].
Along with its dopaminergic effects, the a1B-AR has been postulated to engage in reciprocal interaction with the 5-HT2Aserotonin receptor that could mutu- ally control serotonergic and noradrenergic neuro- transmission, as suggested by several Tassin group publications (reviewed in [47]). a1BAR-KO mice exhibited an increased response to p-chloro-amphet- amine (PCA), a compound that causes serotonin re- lease, when administered in the prefrontal cortex, and PCA-induced locomotor activity and cortical sero- tonin levels were significantly higher in the a1BAR- KO mice compared with the WT mice. Moreover, in mice lacking the 5-HT2Areceptor, D-amphetamine in- creased locomotor activity and cortical noradrenaline release. Thus, Tassin proposed that noradrenergic and serotonergic neurons inhibit each other through a1B-AR and 5-HT2Areceptor stimulation, and further- more, this mechanism may be disrupted as a conse- quence of repeated administration of drugs of abuse, which leads to stable sensitization of noradrenergic and serotonergic neurons [47].
Although the above-cited evidence suggests a spe- cial role of the a1Breceptor mediating the effects of stimulant drugs, Sadalge et al. demonstrated that mice lacking the a1D-AR displayed decreased hyperloco- motion after acute amphetamine administration (but not after cocaine). However, the rewarding effects of amphetamine, cocaine and morphine were not ob- served in a1DAR-KO mice [40]. Thus, the functional involvement of the a1D receptor in mediating psy- chostimulant action should be considered with cau- tion, as its role may be limited to motor activity modulation and hyperlocomotive effects of ampheta- mine.
a1D-Adrenoceptors in nociception
The involvement of the noradrenergic system in pain and analgesia is well documented [14]. However, most studies examining noradrenaline-mediated ef- fects in pain have focused on the antinociceptive role of a2-AR, and the studies evaluating a1-AR participa- tion are based mostly on behavioral data. In some of
these studies, the activation of supraspinal a1-ARs has been considered pronociceptive [20]. Our study employing quantitative autoradiography of the [3H]-prazosin binding sites provided the first descrip- tion of changes at the level of central a1-AR binding during formalin-evoked pain in mice [33]. The formalin-evoked pain induced changes in a1-AR binding that occurred specifically in the CNS areas in- volved in pain signaling or processing. These changes were often lateralized, differed in the early and late pain phases, and included a1-AR subtypes. These re- sults suggested a role for the a1B-AR subtype in the acute phase of formalin-evoked pain, which was evi- denced by decreased receptor density in the somato- sensory cortex that contained projections from the hind limbs and secondary motor cortex. Conversely, changes in a1-ARs in the late pain phase were attrib- uted mostly to AR subtypes other than the a1B. There- fore, we postulated that the a1-ARs were down- regulated to reduce both pain signaling processing in the spinal cord (in the early phase of formalin-evoked pain) and pain perception in the sensorimotor cortex (in both the early and late phases) [33].
In mice lacking a1D-AR, responses to various nox- ious stimuli were studied by Harasawa et al. [19] us- ing the following behavioral tests: tail-flick, hot-plate (hindpaw-licking and jumping), tail-pinch and formalin-evoked pain. Mechanical and chemical no- ciception was not altered in a1DAR-KO mice, and mutants were relatively insensitive to noxious heat stimuli compared with WT littermates. Compared with WT mice, a1DAR-KO mice showed longer tail- flick and hindpaw-licking latencies, but their jumping latency in the hot plate test was reduced. The authors postulated that spinal cord a1D-ARs contribute to thermal pronociception and that the observed heat- avoiding jump behavior is inhibited via the supraspi- nal a1D-ARs [19]. However, the other a1-AR subtypes were not investigated.
Summary and conclusion
Adrenergic receptors play key roles in the modulation of CNS activity; however, the functional roles of a1-ARs and their subtypes are the least understood among the adrenergic receptor family members. Be- cause most currently available drugs are not selective
enough to differentiate between the a1-AR subtypes, it is difficult to characterize the cloned a1-ARs or to determine which subtypes modulate behavior in vivo.
The recent development of transgenic animal models in which a1-AR subtypes have been deleted or over- expressed provide excellent tools to investigate the chronic effects of signaling through different receptor subtypes. Recent evidence derived from the models reviewed here demonstrates the importance of all three a1-AR subtypes in the regulation of various as- pects of CNS activity. Several conclusions about their subtype-related functions can be drawn: the a1A-AR is important in the modulation of learning and mem- ory, and the a1B-AR appears to play a critical role in vulnerability to addiction, but a1D-AR modulates no- ciception. Interestingly, the individual a1-AR sub- types can possess opposing roles in some neuronal ac- tivities. For example, the positive association of a1A-AR function with an enhanced synaptic plasticity, antidepressant-like behavior and improved longevity opposes a1B-AR overactivity, which leads to neurode- generation and a pro-depressive phenotype. Although genetically engineered animal models are not devoid of limitations, they provide new insights into the physiological and subtype-specific functions of CNS a1-ARs, which suggest the a1-AR subtypes as poten- tial therapeutic targets for the treatment of mood dis- orders, cognitive impairments and other neurological disturbances.
Acknowledgment:
This work was supported by grant No. POIG.01.01.02-12-004/09-00 financed by the European Regional Development Fund.
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Received: September 3, 2013; accepted: September 20, 2013.
a1-Adrenergic receptor subtypes in the CNS
Irena Nalepa et al.
