Does the brain noradrenaline network mediate the effects of the CO2 challenge?

The inhalation of carbon dioxide (CO2) is commonly used in patients and volunteers as a means of producing anxiety or panic. It is generally believed that patients with panic disorder are more vulnerable to the effects of CO2 than patients with other anxiety disorders or healthy volunteers and there is speculation and debate as to the mechanism for this apparent sensitivity. Recent work from our group has shown that a single inhalation of 35% CO2 activates the hypothalamic-pituitary-adrenocortical (HPA) axis, increases blood pressure (BP) and increases subjective fear responses in healthy volunteers. Correlation analyses reveal a relationship between the changes in BP and the cortisol increase. These findings led us to postulate that a common mechanism may mediate these and the subjective responses to inhalation of CO2. We propose that the noradrenergic system, particularly the locus coeruleus (LC), but including the A1 and A2 cell groups, may be a key mediator of these responses. This article examines the evidence and discusses the results of studies from our laboratory in relation to a neuroanatomical model centring on the LC.     

Analysis of the 2×2 crossover design with subsampling

Subsampling can be used in experimental design to investigate extraneous sources of variability. One useful strategy is to make independent replicate measurements of the response variate. This can be achieved in clinical studies, for example,by dividing a blood or urine specimen from each of a sample of subjects into aliquots and processing these through a chemistry laboratory in such a way that the replicate determinations are independent. This procedure can be used to increase design efficiency. This paper addresses considerations in the design and analysis of the 2×2 crossover plan with this type of subsampling.     

COX-2 expression in atherosclerosis: the good, the bad or the ugly?

Cyclooxygenase (COX) is the rate limiting enzyme catalyzing the conversion of arachidonic acid into prostanoids, lipid mediators critically implicated in a variety of physiological and pathophysiological processes, including inflammation, vascular and renal homeostasis, and immune responses. Since the early 1990s it has been appreciated that two isoforms of COX exist, referred to as COX-1 and COX-2. Although structurally homologous, COX-1 and COX-2 are regulated by two independent and quite different systems and have different functional roles. In the setting of acute ischemic syndromes it has been recognized that COX pathway plays an important role; however, whereas the function of platelet COX-1 in acute ischemic diseases is firmly established, the role of COX-2 in atherothrombosis remains controversial. The complex role of COX-2 in this setting is also confirmed by the unexpected cardiovascular side effects of long-term treatment with COX-2 inhibitors. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, the effects of the variable expression of upstream and downstream enzymes in the prostanoid biosynthesis on COX-2 expression and inhibition.     

Presynaptic α2-autoreceptors in brain cortex: α2D in the rat and α2A in the rabbit

Summary Presynaptic ₂-autoreceptors in rat and rabbit brain cortex were compared by means of antagonists and agonists. Brain cortex slices were preincubated with [³H]-noradrenaline and then superfused and stimulated by 3 (rat) or 4 (rabbit) pulses at a frequency of 100 Hz.The ₂-adrenoceptor agonist bromoxidine (UK 14 304) reduced the electrically evoked overflow of tritium with EC₅₀ values of 4.5 nmol/l in the rat and 0.7 nmol/l in the rabbit. The antagonists phentolamine, 2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole (BRL 44408), rauwolscine, 1,2-dimethyl-2,3,9,13b-tetrahydro-1H-dibenzo(c,f)imidazo(1,5-a)azepine (BRL 41992), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), 6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-1H-2,3,4, 5-tetrahydro-3-benzazepine (SKF 104078), imiloxan, prazosin and corynanthine did not per se increase the evoked overflow of tritium but shifted the concentration-inhibition curve of bromoxidine to the right in a manner compatible with competitive antagonism. Up to 4 concentrations of each antagonist were used to determine its dissociation constant K_D. The K_D values correlated only weakly between the rat and the rabbit. Dissociation constants K_A of bromoxidine were calculated from equieffective concentrations in unpretreated brain slices and slices in which part of the ₂-adrenoceptors had been irreversibly blocked by phenoxybenzamine. The K_A value was 123 nmol/l in the rat and 7.2 nmol/l in the rabbit.The results confirm the species difference between rat and rabbit brain presynaptic ₂-autoreceptors. Comparison with data from the literature indicates that the rat brain autoreceptors can be equated with the _2D subtype as defined by radioligand binding, whereas the rabbit brain autoreceptors conform to the _2A subtype. For example, the antagonist affinities for the rat autoreceptors correlate with their binding affinities for the gene product of ₂-RG20, the putative rat _2D-adrenoceptor gene (r = 0.97; P<0.01), but not with their binding affinities for the gene product of ₂-C10, the putative human _2A-adrenoceptor gene. Conversely, the rabbit autoreceptors correlate with the ₂-C10 (r = 0.98; P<0.001) but not with the ₂-RG20 gene product. Since presynaptic ₂-autoreceptors are also _2D in rat submaxillary gland and perhaps vas deferens and _2A in rabbit pulmonary artery, the possibility arises that the majority of ₂-autoreceptors generally are _2D in the rat and _2A in the rabbit. Moreover, receptors of the _2A/D group generally may be the main mammalian ₂-autoreceptors.Correspondence to: N. Limberger at the above address     

Is pannexin the pore associated with the P2X7 receptor?

The P2X7 receptor (P2X7R), an ATP-gated cation channel, is expressed predominantly in leukocytes. Activation of P2X7R has been implicated in the formation of a cytolytic pore (i.e., a large conductance channel) that allows the passage of molecules up to 900 Da in macrophages. At least two hypotheses have been presented to explain the conversion of a nonselective cation channel to a cytolytic pore. One hypothesis suggests that the pore is a separate molecular structure activated by P2X7R, and the second asserts that this is an intrinsic property of P2X7R (pore dilation). Based on connexin knockout and hemichannel antagonist studies, some groups have concluded that connexins and pannexins, the hemichannel-forming proteins in vertebrates, are fundamental components of the large conductance channel associated with P2X7R. Dye uptake and electrophysiology experiments were used to evaluate the efficacy and specificity of some hemichannel antagonists under conditions known to open the large conductance channel associated with P2X7R. Hemichannel antagonists and interference RNA (RNAi) targeting pannexin-1 did not affect P2X7R macroscopic currents [ATP, 1,570?±?189 pA; ATP?+?100 μM carbenoxolone (CBX), 1,498?±?100 pA; ATP?+?1 mM probenecid (Prob), 1,522?±?9 pA] or dye uptake in a FACS assay (ATP, 63?±?5 %; ATP?+?100 μM CBX, 51.51?±?8.4 %; ATP?+?1 mM Prob, 57.7?±?4.3 %) in mouse macrophages. These findings strongly suggest that the high-permeability pore evident after prolonged P2X7R activation does not occur through connexin or pannexin hemichannels in murine macrophages. Another membrane protein may be involved in P2X7R pore formation.     

Stereoselectivity at the β2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of β2-agonists

Previous research has shown that beta-adrenoceptor (beta-AR) agonists have potent anti-inflammatory capabilities, e.g. represented by suppression of release of the proinflammatory cytokines. Aim of this research was to determine whether the effects of beta-agonists on LPS-induced TNFalpha and IL-10 release are influenced by their different stereochemistry. In addition, the role of the beta-AR subtypes was studied. The effect of two stereoisomers of the selective beta2-AR agonist TA2005 [(R,R)- and (S,S)-] on the LPS-induced TNFalpha and IL-10 release by U937 macrophages was compared. The (R,R)-stereoisomer was 277 times more potent in inhibiting the TNFalpha release than the (S,S)-form. The (R,R)-stereoisomer also appeared to be more potent in increasing the IL-10 release. In radioligand binding studies the affinity of (R,R)-TA2005 for the beta-adrenoceptor was 755 times higher than the (S,S)-TA2005 stereoisomer. In addition, the elevation of intracellular cAMP in U937 cells appeared to be stereoselective: (R,R)-TA2005 was more potent in elevating intracellular cAMP. The effect of both stereoisomers on the LPS-induced TNFalpha release could almost completely be antagonized by preincubation with the selective beta2-AR-antagonist ICI-118551. Further evidence that the effect of the beta-agonists is mediated via the beta2-adrenoceptor subtype exclusively was acquired by incubation of U937 cells with selective beta1- and beta3-agonists. None of these receptor subtype agonists showed significant suppressive effect on TNFalpha release. This study provides additional proof that the anti-inflammatory effects of beta2-agonists are mediated via the beta2-adrenoceptor and indicates that these effects are highly dependent on the stereoselectivity of the ligand.     

Molecular mechanisms for the persistent bronchodilatory effect of the β2-adrenoceptor agonist salmeterol

Background:

β₂-adrenoceptor agonists are effective bronchodilators. In vitro studies demonstrated long-lasting airway smooth muscle relaxation by salmeterol after washout, the quick disappearance of this effect in presence of antagonists and its recovery after antagonist removal. Current explanations invoke salmeterol accumulation in the membrane (‘diffusion microkinetic’ model) or the existence of salmeterol-binding ‘exosites’. An alternative model based on ‘rebinding’ of a dissociated ligand to the receptor molecules also produces an apparent decrease in the ligand''s dissociation rate in the absence of competing ligands.

Purpose and approach:

Computer-assisted simulations were performed to follow the receptor-occupation by a salmeterol-like ligand and a competing ligand as a function of time. The aptness of the models to describe the above in vitro findings was evaluated.

Key results:

The ‘diffusion microkinetic’ model is sufficient to explain a long-lasting β₂-adrenoceptor stimulation and reassertion as long as the membrane harbors a high concentration of the agonist. At lower concentration, ‘rebinding’ and, in second place, ‘exosite’ binding are likely to become operational.

Conclusions and implications:

The ‘rebinding’ and ‘exosite’ binding mechanisms take place at a sub-cellular/molecular scale. Pending their demonstration by experiments on appropriate, simple models such as intact cells or membranes thereof, these mechanisms remain hypothetical in the case of salmeterol. Airway smooth muscle contraction could also be governed by additional mechanisms that are particular to this macroscopic approach.     

Exploring the pharmacology of the pro-convulsant effects of α2-adrenoceptor antagonists in mice

The effects of selective and specific ₂-adrenoceptor antagonists on electroshock seizure threshold in mice were investigated. Idazoxan, at low doses, efaroxan, RX811059 and RX821002 significantly lowered seizure threshold. The ₁-agonist St 587 and the -agonist isoprenaline were also pro-convulsant. On the other hand the ₂-agonists clonidine and UK 14,304 produced small increases in seizure threshold. Anticonvulsant effects were also produced by low doses of the noradrenaline uptake inhibitor desipramine. This compound increases levels of noradrenaline in the synaptic cleft which could subsequently act at post-synaptic ₂-adrenoceptors. The pro-convulsant action of ₂-adrenoceptor antagonists could be explained in terms of two mechanisms: a) blockade of endogenous noradrenaline which may normally exert a tonic anti-convulsant influence on seizure threshold, through post-synaptic ₂-receptors and/or b) increased activation of ₁- and -adrenoceptors by elevated synaptic noradrenaline levels following blockade of pre-synaptic ₂-adrenoceptors. Of the ₂-antagonists tested, idazoxan was unusual in that high doses were not pro-convulsant; this difference may be explained by ₁-adrenoceptor mediated actions or be related to its recently described affinity at a non-adrenoceptor site — a function for which is currently unknown.     

β2-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart

Endogenous catecholamines released during myocardial ischemia have been considered both to aggravate cell injury and exacerbate arrhythmias and to exert a protective action on the post-ischemic contractile function. The present work was addressed to look for evidence to explain this controversy. The effects of cardiac catecholamine depletion and of α- and β-adrenoceptor (AR) blockade on the post-ischemic contractile dysfunction, as well as its possible relationship with cardiac oxidative stress, were studied in isolated and perfused rat hearts submitted to 20 min of ischemia and 30 min of reperfusion (stunning). Catecholamine depletion improves the contractile recovery in the stunned heart. This mechanical effect was associated with decreased levels of lipid peroxidation. A similar enhancement of the contractile function during reperfusion was detected after the simultaneous blockade of α₁- and β-ARs with prazosin plus propranolol. To ascertain which specific AR pathway was involved in the effects of catecholamines on the stunned heart, selective AR blockers, prazosin (α₁-blocker), atenolol (β₁-blocker), ICI 118,551 (β₂-blocker) and selective inhibitors of G_i-PI3K pathway (pertussis toxin and wortmannin) were alternatively combined. The results indicate that catecholamines released during ischemia exert a dual action on the contractile behavior of the stunned heart: a deleterious effect, related to the activation of the β₂-AR-G_i-PI3K-pathway, which was counteracted by a beneficial effect, triggered by the stimulation of α₁-AR. Neither the depression nor the enhancement of the post-ischemic contractile recovery were related with the increase in ROS formation induced by endogenous catecholamines.     

Evidence for the existence of two forms of α2A-adrenoceptors in the rat

Summary The _2A-adrenoceptors in rat spleen, kidney, spinal cord and cerebral cortex were studied using [³H]-RX821002 radioligand binding. In the spleen, spinal cord and cerebral cortex, the ligand bound to saturable sites with a K _d of about 1 nmol/l and capacities of 134, 240 and 290 fmol/mg protein, respectively. Computer modelling competition curves for 39 drugs, including those for _2A-, _2B- or _2C-adrenoceptor selective drugs, indicated that the sites labelled by [³H]-RX821002 in the spleen consisted of a single population of _2A-adrenoceptors. However, the competition curves for guanoxabenz were definitely biphasic and resolved into two site fits, indicating that guanoxabenz was binding to both high affinity (K _d = 35 nmol/1) and low affinity (K _d = 8900 nmol/1) _2A-adrenoceptor sites in the proportions 57% and 43%, respectively. The K _d ^Sfor a number of ₂-adrenoceptor subtype selective drugs, measured in competition with [³H]-RX821002 in cerebral cortex and spinal cord, were highly correlated with those obtained in the spleen indicating their _2A-adrenoceptor nature. However, by contrast to the results with the spleen, the guanoxabenz competition curves for the spinal cord and cerebral cortex were monophasic and resolved only into one site fits, the K _d of guanoxabenz being about 4000 nmol/l for both tissues. Drug K _d ^Sfor kidney _2A-adrenoceptors were also determined using [³H]-RX821002. For nearly all drugs tested, the K _d ^Swere highly correlated with those found for the _2A-adrenoceptors in the other rat tissues. However, for guanoxabenz, the data indicated that it competed with [³H]-RX821002 at a single _2A-adrenoceptor site with a K _d of 39 nmol/1. When the rat _2A-adrenoceptor gene RG20 was transiently expressed in COS-7 cells and its ligand binding properties probed using [³H]-RX821002, the drug K _d ^Sobtained were also highly correlated with those found for the _2A-adrenoceptors in the spleen, cerebral cortex, spinal cord and kidney of the rat. For the RG20 encoded receptor, the guanoxabenz competition curves were steep and monophasic and modelled best into one site fits, with the Kd of guanoxabenz being 5200 nmol/1.It is suggested that guanoxabenz can differentiate between two forms of _2A-adrenoceptors in the rat: _2A1 and _2A2. The _2A1-form is present in the spleen and kidney where it shows a high apparent affinity for guanoxabenz. The _2A2-form shows a low apparent affinity for guanoxabenz and is present in the spleen, cerebal cortex and spinal cord. The _2A2-form of the rat ₂-adrenoceptor appears to be encoded by the RG20 gene. The _2A, and _2A2-adrenoceptor forms do not represent high and low affinity receptor forms for agonists because assays included EDTA, Gpp(NH)p and Na⁺, which eliminated the high affinity receptors for agonists.     

α2-Adrenoceptors inhibit the cholera-toxin-induced intestinal fluid accumulation

Summary The effects of adrenoceptor agonists and antagonists on the cholera-toxin-induced intestinal fluid accumulation and the mucosal levels of cAMP were investigated in vivo. Cholera toxin produced a marked fluid accumulation. Adrenaline inhibited the effect of the toxin in a dose-dependent manner. An ₁-adrenoceptor blocking agent yohimbine antagonized the effect of adrenaline. The ₁-adrenoceptor blocking agents prazosin and phenoxybenzamine failed to antagonize the effect of adrenaline. A high dose of a -adrenoceptor blocking agent pindolol did not antagonize the effect of adrenaline. Yohimbine or pindolol alone did not produce any effects on the toxin-induced fluid accumulation. However, prazosin and phenoxybenzamine per se inhibited the toxin-induced fluid accumulation. An ₂-selective agonist clonidine was slightly more potent than adrenaline, and was about 100-fold more potent than the ₁-selective agonist methoxamine in inhibiting the cholera-toxin-induced intestinal secretion. Clonidine, adrenaline and methoxamine failed to reduce the mucosal levels of cAMP, while these -adrenoceptor agonists inhibited the toxin-induced fluid accumulation in the same preparations. These results suggest that the stimulation of ₂-adrenoceptors inhibit the cholera-toxin-induced intestinal secretion without reducing the whole mucosal levels of cAMP.     

Contraction-mediating α2-adrenoceptors in the mouse vas deferens

Summary The question of the existence of postjunctional, contraction-mediating ₂-adrenoceptors, in addition to the known ₁-adrenoceptors, was studied in the mouse isolated vas deferens. Both the ₁-selective agonist phenylephrine and the ₂-selective agonist 5-bromo-6-(2imidazolin-2-ylamino)-quinoxaline (UK 14,304) caused contraction of the vas deferens. In the presence of the ₁-selective antagonist prazosin (added in order to prevent an ₁ component in the effect of high concentrations of UK 14,304), the ₂-selective antagonists yohimbine and idazoxan shifted the concentration—response curve of UK 14,304 to the right in a manner compatible with competitive antagonism and with dissociation constants K_B indicating the involvement of ₂-adrenoceptors. The maximal contraction elicited by UK 14,304 (in the presence of prazosin) was much lower than the maximal contraction elicited by phenylephrine. The effect of UK 14,304 was not changed by the P₂-purinoceptor agonist ,-methylene-ATP and was reduced by neuropeptideY, but was markedly enhanced by relatively low concentrations of phenylephrine. When the sympathetic fibres of the vas deferens were stimulated by trains of ten widely spaced (0.5 Hz) electric pulses, the tissue responded with ten separate twitches in which purinergic and adrenergic components were isolated by prazosin and suramin, respectively. Prazosin reduced the first adrenergic twitch in these trains at concentrations close to its K_B value at ₁-adrenoceptors, whereas yohimbine and idazoxan reduced the first adrenergic twitch at concentrations far lower than their K_B values at ₁-adrenoceptors. The results indicate that the smooth muscle of the mouse vas deferens possesses contraction-mediating ₂-adrenoceptors. They are activated by UK 14,304 and probably also by noradrenaline of neural origin. Responses mediated by the ₂-adrenoceptors are enhanced by simultaneous ₁-receptor activation, an interaction that may increase the contribution of the ₂-adrenoceptors to the adrenergic phase of neurogenic contractions. Send offprint requests to R. Bültmann at the above address     

Investigation of the role of organic cation transporter 2 (OCT2) in the renal transport of guanfacine,a selective α2A-adrenoreceptor agonist

Abstract

1.?Guanfacine is a selective α_2A-adrenoreceptor agonist primarily excreted as its unchanged form through urine in human. This study was to investigate the involvement of organic cation transporter 2 (OCT2) in the renal tubular secretion of guanfacine.

2.?Transport of guanfacine was characterized using human embryonic kidney (HEK293) cells expressing human OCT2 (hOCT2). The inhibitory effect of cimetidine on guanfacine uptake was also examined. In addition, in vivo pharmacokinetic study was conducted in rats to assess the effects of cimetidine on the pharmacokinetics of guanfacine.

3.?The accumulation of guanfacine in hOCT2-transfected HEK293 cells was both time- and concentration-dependent, and markedly higher than that in mock cells. The apparent K_m and V_max values of guanfacine uptake by hOCT2 were 96.19?±?7.49?μM and 13.03?±?0.49?nmol/mg protein/min, respectively. Guanfacine transport mediated by hOCT2 was significantly inhibited by a typical OCT2 inhibitor cimetidine with an IC₅₀ value of 93.82?±?1.13?μM. Co-administration of cimetidine significantly decreased the plasma clearance (CL_p) as well as the renal clearance (CL_r) of guanfacine in rats in a dose-dependent manner, resulting in a noticeable increase in the systemic exposure of guanfacine.

4.?These results indicated that OCT2 may be involved in the renal disposition of guanfacine.     

Are the α2-adrenoceptors in the noradrenaline cell body region of physiological significance?

Summary Preganglionic stimulation of the cervical sympathetic increased the content of 3,4-dihydroxyphenylacetic acid (DOPAC) in the superior cervical ganglion of rats treated with the dopamine -hydroxylase inhibitor FLA-63. It also increased and decreased the concentrations of dopamine and noradrenaline, respectively, in the salivary gland. The effects were partially inhibited by the ₂-adrenoceptor agonist clonidine via a yohimbine-sensitive mechanism. The ₂-adrenoceptor antagonist yohimbine by itself did not enhance the stimulation-evoked increase in ganglionic DOPAC, but it markedly potentiated the stimulation-evoked changes in dopamine and noradrenaline in the salivary gland. The results indicate that there are inhibitory ₂-adrenoceptors both in the somatodendritic and in the axon terminal region of the noradrenaline neurons but that only the ₂-receptors of the axon terminals are physiologically stimulated. Send offprint requests to N. E. Anden at the above address     

Action of prostaglandin,PGF2α, on the uterus of the pregnant rat

Summary The effects of prostaglandin F₂ (PG) have been studied on the transmembrane potentials and contractions in isolated myometrial strips from pregnant rats. The results showed that: 1. The sensitivity of the myometrium to exogenous PG increases from day 19 to day 22 of gestation. 2. The electrical response to PG, at maximally effective doses (10^–6 to 10^–5 M) consists of a slow depolarization which upon reaching threshold initiates spike discharge. 3. These actions are most pronounced t term (day 22) and are due to a direct action of PG on the myometrical cells. 4. D-600 (a methoxy derivative of verapamil) abolishes spike discharge and the phasic contractions induced by PG but has no effect on the slow depolarization and the accompanying increase in tonic tension. 5. The slow depolarization is dependent upon the presence of sodium in the external environment and is unaffected by the removal of calcium. 6. The spikes (and phasic contractions) are dependent upon the presence of calcium in the external environment.This study was supported by USPHS Grant HD-06963-9     

Alpha-2 agonists: can they modify the outcomes in the Postanesthesia Care Unit?

While most patients recover uneventfully from the effects of anesthesia and surgery, for a small percentage of patients the immediate postoperative period can be a period of significant physiological stress. Hence the goal for a Post Anesthesia Care Unit (PACU) is to provide a safe environment for a patient to recover, while avoiding the undesirable side effects of pain, nausea, vomiting and shivering, and to monitor for potentially life threatening hemodynamic and respiratory complications that may require admission into the intensive care unit (ICU). Anesthetic techniques in the operating room are extremely important as these may have significant bearing on the post-operative course. The type of surgery, the patients' co morbid conditions, anticipated extubation and recovery of the patient, as well as the sophistication of the PACU and the expertise of its staff, all influence the choice of anesthetic technique. These agents, however, may themselves contribute to some of the complications and unpleasant events encountered in the PACU. Therefore, evaluation of newer and safer agents, which promote a smoother PACU transition, are warranted. Alpha 2 agonists are increasingly being used as adjuvant therapeutic agents in the perioperative period because of their ability to block the sympathetic stress response, complete with their anesthetic and analgesic sparing properties, lack of respiratory depression and low and predictable side effect profile.     

Association between the 1291-C/G polymorphism in the adrenergic α-2a receptor and the metabolic syndrome

The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic α-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an association between the α-2a 1291-C/G polymorphism and antipsychotic induced weight gain, with conflicting results between whites and Asians. No studies have been published investigating the association between the 1291-C/G polymorphism and the metabolic syndrome. The primary objective of this cross-sectional study was to investigate the association between the ADRA2A 1291-C/G polymorphism and the metabolic syndrome in 470 patients using antipsychotic drugs. There was no significant association between carriership of the variant 1291-G allele and prevalence of the metabolic syndrome (odds ratio, 0.73; 95% confidence interval, 0.49-1.15). Exploratory analysis showed an association between carriership of the variant 1291-G allele and a reduced prevalence of the metabolic syndrome in patients not currently using antipsychotics (odds ratio, 0.05; 95% confidence interval, 0.003-0.97; P = 0.048). In conclusion, this study shows that the ADRA2A 1291-C/G polymorphism does not seem to be a strong predictor for long-term occurrence of the metabolic syndrome in antipsychotic using patients. Studies investigating this association using a prospective, or retrospective, design, as well as studies investigating this association in a nonpsychiatric population, are warranted.