Adrenergic Mechanisms Research Articles

Desipramine increases cardiac parasympathetic activity via α2-adrenergic mechanism in rats.

Desipramine (DMI) is a blocker of neuronal norepinephrine (NE) uptake transporter. Although intravenous DMI has been shown to cause centrally-mediated sympathoinhibition and peripheral NE accumulation, its parasympathetic effect remains to be elucidated. We hypothesized that intravenous DMI activates the cardiac vagal nerve via an α2-adrenergic mechanism. Using a cardiac microdialysis technique, changes in myocardial interstitial acetylcholine (ACh) levels in the left ventricular free wall in response to intravenous DMI (1mg·kg-1) were examined in anesthetized rats. In rats with intact vagi (n=7), intravenous DMI increased ACh from 1.67±0.43 to 2.48±0.66nM (P<0.01). In rats with vagotomy (n=5), DMI did not significantly change ACh (from 0.92±0.16 to 0.85±0.23nM). In rats with intact vagi pretreated with intravenous yohimbine (2mg·kg-1), DMI did not significantly change ACh (from 1.25±0.23 to 1.13±0.15nM). In conclusion, while DMI is generally considered to be an agent that predominantly affects sympathetic neurotransmission, it can activate the cardiac vagal nerve via α2-adrenergic stimulation in experimental settings in vivo.

Injections of the of the α1-adrenoceptor antagonist prazosin into the median raphe nucleus increase food intake and Fos expression in orexin neurons of free-feeding rats

Previously, we showed that the blockade of α1-adrenoreceptors in the median raphe nucleus (MnR) increased food intake in free-feeding rats, indicating that adrenergic mechanisms in the MnR participate in the regulation of food intake. However, the impact of such a pharmacological manipulation on other neural circuits related to food intake remains unknown. In the current study, we sought to identify forebrain regions which are responsive to α1-adrenergic receptor blockade and presumably involved in the modulation of the feeding response. For this purpose, we examined the induction of c-Fos immunoreactivity in forebrain structures following injections of the α1-adrenoceptor antagonist prazosin into the MnR of free-feeding rats. To determine the chemical identity of hypothalamic c-Fos-positive cells, we then conducted double-label immunohistochemistry for Fos/orexin (OX) or Fos/melanin-concentrating hormone (MCH). Finally, we combined anterograde tracing from the MnR with immunohistochemical detection of orexin. Prazosin injections into the MnR significantly increased food intake. The ingestive response was accompanied by an increase in Fos expression in the basolateral amygdala (BLA) and lateral hypothalamic area (LHA). In the LHA, Fos expression occurred in neurons expressing OX, but not MCH. Combined anterograde tracing experiments revealed that LHA OX neurons are prominently targeted by MnR axons. These findings suggest that intra-MnR injection of prazosin, via activation of orexinergic neurons in the LHA and non-orexinergic neurons in the BLA, evoked a motivational response toward food intake.

New actions of an old friend: perivascular adipose tissue's adrenergic mechanisms.

This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

ПСИХОТРОПНІ ВЛАСТИВОСТІ ПОТЕНЦІЙНОГО АНТИКОНВУЛЬСАНТА 1-(4-МЕТОКСИФЕНІЛ)-5-{2-[4-(4-МЕТОКСИФЕНІЛ)ПІПЕРАЗИН-1-ІЛ]-2-ОКСОЕТИЛ}- 1,5-ДИГІДРО-4H-ПІРАЗОЛО[3,4-D]ПІРИДИН-4-ОНУ

Вивчено психотропні властивості та взаємодію з речовинами пригнічувального типу нового похідного піримідину - 1-(4-метоксифеніл)-5-{2-[4-(4-метокси-феніл)піперазин-1-іл]-2-оксоетил}-1,5-дигідро-4Н-піразоло [3,4- D]піридин-4-ону в дозі 200 мг/кг, який в попередніх дослідженнях виявив протисудомну дію на рівні вальпроату натрію (300 мг/кг). Встановлено, що сполука чинить виразну седативну дію, виявляє антиамнестичні властивості та слабкий анксіолітичний ефект. Крім того, досліджувана сполука не впливає на депресивну поведінку, не чинить негативного впливу на тонус скелетних м'язів та координацію рухів, а також не потенціює депримуючий вплив етанолу.

Pharmacological evidence of α-adrenergic receptors in the hypotensive effect of Chamaemulum nobile L.

This study aims to evaluate the underlying mechanism of action involved in the hypotensive effect of Chamaemulum nobile L. (Cn) aqueous extract and in anesthetized Wistar rats. Lyophilized aqueous extract was administered in the jugular vein, arterial blood pressure and heart rate were measured in the carotide artery over 120 min of injection throughout an invasive direct blood pressure measuring procedure. Intravenous bolus injection of aqueous Cn extract at the doses of 50, 100 and 200 mg/kg produced a dose dependent reduction in arterial blood pressure and heart rate (p<0.001). Specific receptor antagonists (Phentolamine, Terazosin and Atropine) and pharmacological agents (N(omega)-Nitro-L-Arginine Methyl Ester and Captopril) were used for determining the underlying mechanism involved in the hypotensive effect of Cn. Only Phentolamine treatment (2 mg/kg) reduced significantly the hypotensive effect of aqueous Cn extract at a dose of 200 mg/kg. Intravenous perfusion of aqueous Cn extract caused a significant reduction of arterial blood pressure (p<0.01) and reduced the hypertensive effect of intravenous injection of norepinephrine at a dose of 1 &#181;g/kg. We conclude that aqueous Cn extract exhibits a hypotensive effect which may be probably due to an alpha adrenergic receptor blockade mechanism.

Effects of Caffeine on Salivation

Background: Caffeine is a methylxanthine which may decrease salivation through adrenergic mechanisms. Few studies have formally tested whether caffeine actually decreases saliva production. Methods: Eleven volunteers collected unstimulated 1-minute saliva production (1-MSP) after an overnight fast, followed shortly by a stimulated 1-MSP while chewing a stick of chewing gum. We then asked them to drink a beverage randomly selected to contain either regular or decaffeinated instant coffee. Caffeine content was doubleblinded. 1-MSP, both unstimulated and stimulated were then collected 30, 60, 90, and 120 minutes later. The following morning the subject followed the same protocol but drank the other kind of beverage. We used a mixedeffects linear model to analyze our data. Results: The adjusted mean difference between decaffeinated and caffeinated 1-MSP was -0.14 ml (p<0.05). Stimulation with chewing gum caused an unadjusted increase of 2.02 ml (p<0.001) and an adjusted increase of 2.01 ml (p<0.05). Variation for the unstimulated 1-MSP was much lower (SD 0.4 ml) than the stimulated 1-MSP (SD 1.01 ml), whereas variation for caffeinated 1-MSP (SD 1.29 ml) was similar to decaffeinated 1-MSP (SD 1.25 ml). Conclusion: Caffeine modestly but significantly decreased both Unstimulated and stimulated saliva production. The effect of caffeine was approximately 6.5% that of stimulation. The effect from caffeine was consistent across both stimulated and unstimulated samples. Additionally, caffeine did not increase the variability of saliva production either within or between individuals, in contrast to the effect from stimulation

Anti-nociceptive activity of a few structurally related trimethoxy flavones and possible mechanisms involved.

The present study was designed to investigate the anti-nociceptive activity of a few structurally related trimethoxy flavones (7,2',3'-TMF, 7,2',4'-TMF, 7,3',4'-TMF and 7,5,4'-TMF) and the possible mechanisms involved. Anti-nociceptive activity was evaluated in mice by employing acetic acid-induced writhing, formalin-induced nociception and hot water tail immersion methods. The involvement of opioid, GABAergic, tryptaminergic, adrenergic and dopaminergic mechanisms and K+ATP channels in the anti-nociceptive activity of trimethoxy flavones was investigated using suitable interacting chemicals. Trimethoxy flavones exhibited a significant and dose-dependent inhibition of acetic acid writhing. The paw-licking response time was reduced both in the early and late phases of formalin nociception in a dose-dependent manner by trimethoxy flavones. A significant increase in tail withdrawal latency time was also observed after trimethoxy flavones treatment. These observations revealed the potential anti-nociceptive action of the investigated trimethoxy flavones. Pretreatment with naloxone and bicuculline significantly attenuated the reduction of abdominal constrictions produced by all the tested trimethoxy flavones indicating a definite role of opioid and GABAergic mechanisms in the anti-nociceptive effect of trimethoxy flavones. The anti-nociceptive action elicited by various trimethoxy flavones was differently modulated by glibenclamide, ondansetron, yohimbine and sulpiride. The investigated trimethoxy flavones exhibited promising anti-nociceptive activity in various nociceptive models, and multiple mechanisms are involved in the anti-nociceptive activity of these compounds.

Adrenergic DNA damage of embryonic pluripotent cells via β2 receptor signalling

Embryonic pluripotent cells are sensitive to genotoxicity though they need more stringent genome integrity to avoid compromising multiple cell lineages and subsequent generations. However it remains unknown whether the cells are susceptible to adrenergic stress which can induce somatic cell genome lesion. We have revealed that adrenergic stress mediators cause DNA damage of the cells through the β2 adrenergic receptor/adenylate cyclase/cAMP/PKA signalling pathway involving an induction of intracellular reactive oxygen species (ROS) accumulation. The adrenergic stress agonists adrenaline, noradrenaline, and isoprenaline caused DNA damage and apoptosis of embryonic stem (ES) cells and embryonal carcinoma stem cells. The effects were mimicked by β2 receptor-coupled signalling molecules and abrogated by selective blockade of β2 receptors and inhibition of the receptor signalling pathway. RNA interference targeting β2 receptors of ES cells conferred the cells the ability to resist the DNA damage and apoptosis. In addition, adrenergic stimulation caused a consistent accumulation of ROS in the cells and the effect was abrogated by β2 receptor blockade; quenching of ROS reversed the induced DNA damage. This finding will improve the understanding of the stem cell regulatory physiology/pathophysiology in an adrenergic receptor subtype signalling mechanism.

Heart disease: recruitment of MEF2 activity by β-blockers wards off cardiomyocyte death.

Heart disease: recruitment of MEF2 activity by β-blockers wards off cardiomyocyte death.

Adrenergic regulation of innate immunity: a review.

The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential.

Analgesic Effect of Electroacupuncture on Paclitaxel-induced Neuropathic Pain via Spinal Opioidergic and Adrenergic Mechanisms in Mice

Analgesic Effect of Electroacupuncture on Paclitaxel-induced Neuropathic Pain via Spinal Opioidergic and Adrenergic Mechanisms in Mice

Adrenergic Control of the Cutaneous Circulation during Cryotherapy

Cryotherapy application is a widely clinically used therapeutic technique using ice or cold water applied to the skin surface to reduce local blood flow. While beneficial, cryotherapy treatment does have the potential to induce some detrimental physiological side effects. For example, cryotherapy treatment induces pronounced tissue ischemia that is sustained for hours even during a post-treatment rewarming period. PURPOSE: To investigate the role of adrenergic receptor activation on cutaneous blood flow during 30 min of cryotherapy as well as during the subsequent 1 hr of passive rewarming. We hypothesized that adrenergic-mediated vasoconstriction is involved in pronounced and sustained cutaneous vasoconstriction that occurs during cooling and passive rewarming. METHODS: To date 4 complete data sets have been collected with 2 partial, incomplete datasets. A commercially available cryotherapy unit with a water perfused bladder was used. The bladder was placed on the lateral portion of the calf. Four microdialysis membranes were threaded through the dermis of the skin directly underneath the water bladder. One site was perfused with lactated ringers solution (CON), one with bretylium tosylate (BRE), one with propranolol+yohimbine+BIBP (PBY), and one with propranolol+BIBP (PB). Skin temperature (SkT) and skin vascular conductance (SkVC) was measured at each site. Subjects had 0 °C water perfused through the cryotherapy bladder for 30 min, followed by passive rewarming (i.e. water shut off) for 1 hr, followed by direct heating with 46 °C for 10 min. RESULTS: SkT fell from 33°C to 17.7°C during 30 min of cold water application across all sites. SkVC at CON was reduced ∼80% after 30 min of cooling and was not significantly different than PB (p>0.05). Vasoconstriction was attenuated at the BRE and PBY sites during cooling compared the control (SkVC: BRE = 58% reduction, PBY = 37% reduction, CON 80% reduction (p<0.05 for each comparison). Following 10 min of active warming the BRE site was not different than CON (SkBF: 46% reduction vs. 28% reduction (P>0.05). CONCLUSION: Our preliminary finding was that adrenergic function mediates the vasoconstriction that occurs with cryotherapy application. This is in line with previous literature investigating the adrenergic mechanisms of vasoconstriction with skin cooling.

Altered urinary sodium excretion response after central cholinergic and adrenergic stimulation of adult spontaneously hypertensive rats.

In this study, we hypothesized that blunting of the natriuresis response to intracerebroventricularly (i.c.v.) microinjected cholinergic and adrenergic agonists is involved in the development of hypertension in spontaneously hypertensive rats (SHR). We evaluated the effect of i.c.v. injection of cholinergic and noradrenergic agonists, at increasing concentrations, and of muscarinic cholinergic and α1 and α2-adrenoceptor antagonists on blood pressure and urinary sodium handling in SHR, compared with age-matched Wistar Kyoto rats (WR). We confirmed that CCh and NE microinjected into the lateral ventricle (LV) of conscious rats leads to enhanced natriuresis. This response was associated with increased proximal and post-proximal sodium excretion accompanied by an unchanged rate of glomerular filtration. We showed that cholinergic-induced natriuresis in WR and SHR was attenuated by previous i.c.v. administration of atropine and was significantly lower in the hypertensive strain than in WR. In both groups the natriuretic effect of injection of noradrenaline into the LV was abolished by previous local injection of an α1-adrenoceptor antagonist (prazosin). Conversely, LV α2-adrenoceptor antagonist (yohimbine) administration potentiated the action of noradrenaline. The LV yohimbine pretreatment normalized urinary sodium excretion in SHR compared with age-matched WR. In conclusion, these are, as far as we are aware, the first results showing the importance of interaction of central cholinergic and/or noradrenergic receptors in the pathogenesis of spontaneous hypertension. These experiments also provide good evidence of the existence of a central adrenergic mechanism consisting of α1 and α2-adrenoceptors which works antagonistically on regulation of renal sodium excretion.

Adrenergic mechanisms of myocardium contractility regulation in genetic model of Alzheimer’s disease

Aim. Study is aimed to investigate contractility impairments and receptor mechanisms of adrenergic regulation of myocardium inotropic function in Alzheimer’s disease model on transgenic mice.Methods. Experiments were performed on isolated preparations of atria and ventricles myocardium of mice. Transgenic mice of B6C3-Tg(APP695)85Dbo Tg(PSENI)85Dbo genotype were used as animal model of Alzheimer’s disease. Contractile responses of myocardium were registered by conventional myographic technique in isometric conditions. To evaluate the expression of adrenergic receptors, immunofluorescence staining of myocardium with specific antibodies was performed.Results. Transgenic mice showed not only a decreased effect of norepinephrine on myocardium inotropic function but also the inversion of the effect of norepinephrine - the use of 10-5-10-4 M of norepinephrine decreased myocardium inotropic function. Immunofluorescent staining showed decrease of expression of β1- and especially β2-adrenergic receptors ventricular myocardium of transgenic mice comparing to wild type mice. Adrenergic deregulation was registered in ventricles, but not in atria. The features of adrenergic regulatory mechanisms of myocardial contractility in transgenic APP/PS1 mice aged 8-10 months are specific, although somewhat similar to wild type mice aged 8-10 months, and are evidently due to Alzheimer’s disease. The inversion of norepinephrine inotropic effect (from positive to negative) may be explained by switching the intracellular cascade pathway of β2-adrenergic receptors effects to another type of G-protein.Conclusion. The results indicate that peripheral adrenergic mechanisms of myocardial contractility regulation are impaired in studied transgenic mice model of Alzheimer’s disease. Obtained data widen our understanding of Alzheimer’s disease pathogenesis, as well as our conception of relations between cardiovascular diseases and neurodegeneration.

Norepinephrine Protects against Amyloid-β Toxicity via TrkB.

The locus coeruleus (LC), the brainstem noradrenergic nucleus that is the sole source of norepinephrine (NE) in the forebrain, is one of the first structures affected in Alzheimer's disease (AD). Experimental ablation of the LC exacerbates, while increasing NE abates, AD-like neuropathology and cognitive deficits in animal models of the disease. Some neuroprotective effects of NE appear to be mediated by tropomyosin-related kinase B (TrkB), the canonical receptor for brain-derived neurotrophic factor (BDNF). Here, we report that NE dose-dependently protected primary cortical and LC neurons from amyloid-β (Aβ) toxicity. The neuroprotective effects of NE were fully prevented by the Trk receptor antagonist K252a but only partially attenuated by adrenergic receptor antagonists and not mimicked by adrenergic agonists. Activation of TrkB by NE in cortical and LC neurons was confirmed by immunoblot and immunocytochemistry for phospho-TrkB. These results indicate that NE can activate TrkB and protect against Aβ toxicity, at least in part, via adrenergic receptor-independent mechanisms, and have implications for the consequences of LC degeneration in AD and potential therapies for the disease.

Analgesic effect of electroacupuncture on paclitaxel-induced neuropathic pain via spinal opioidergic and adrenergic mechanisms in mice.

This study was designed to determine the antinociceptive effect and related neuronal mechanism of electroacupuncture (EA) on paclitaxel (PTX)-induced neuropathic pain in mice. PTX (4 mg/kg, i.p.) was administered once a day for 5 consecutive days to induce neuropathic pain. EA stimulation (2 mA, 2 Hz, 30 min) was applied at the ST36 acupoint bilaterally once in every 2 days. Repeated EA stimulation significantly attenuated PTX-induced mechanical allodynia and thermal hyperalgesia. In a separate set of experiment, the antinociceptive effect of a single EA stimulation 8 days after PTX treatment was reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or propranolol (beta-adrenoceptor antagonist), but not prazosin (alpha1-adrenoceptor antagonist). Moreover, EA remarkably suppressed the PTX-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn, and intrathecal pretreatment of naloxone, idazoxan (IDA) or propranolol blocked the effect of EA. In conclusion, EA stimulation at the ST36 acupoint significantly diminished PTX-induced neuropathic pain in mice via the mediation of spinal opioid receptor, alpha2- and beta-adrenoceptors.

Bronchodilatory and B-adrenergic effects of methanolic and aqueous extracts of Althaea root on isolated tracheobronchial smooth rat muscle.

Background:The smooth muscle contractions of the tracheobronchial airways are mediated through the balance of adrenergic, cholinergic and peptidergic nervous mechanisms. This research was designed to determine the bronchodilatory and B-adrenergic effects of methanolic and aqueous extracts of root Althaea on the isolated tracheobronchial smooth muscle of the rat.Materials and Methods:In this experimental study, 116 tracheobronchial sections (5 mm) from 58 healthy male Sprague-Dawley rats were dissected and divided into 23 groups. The effect of methanolic and aqueous extracts of the root Althaea was assayed at different concentrations (0.2, 0.6, 2.6, 6.6, 14.6 μg/ml) and epinephrine (5 μm) in the presence and absence of propranolol (1 μM) under one g tension based on the isometric method. This assay was recorded in an organ bath containing Krebs-Henseleit solution for tracheobronchial smooth muscle contractions using potassium chloride (KCl) (60 mM) induction.Results:Epinephrine (5 μm) alone and root methanolic and aqueous extract concentrations (0.6-14.6 μg/ml) reduced tracheobronchial smooth muscle contractions induced using KCl (60 mM) in a dose dependent manner. Propranolol inhibited the antispasmodic effect of epinephrine on tracheobronchial smooth muscle contractions, but could not reduce the antispasmodic effect of the root extract concentrations.Conclusion:The methanolic and aqueous extracts of Althaea root inhibited the tracheobronchial smooth muscle contractions of rats in a dose dependent manner, but B-adrenergic receptors do not appear to engage in this process. Understanding the mechanism of this process can be useful in the treatment of pulmonary obstructive diseases like asthma.

Adrenergic and imidazoline mechanisms of arterial baroreceptor reflex in the short and long-term regulation of blood pressure

Objective. The purpose of this work was to study how selective activation of сentral adrenergic and imidazoline receptors influence functional state of the blood baroreceptor reflex (BR) in the short and long-term regulation of blood pressure (BP) at rest and under emotional stress. Design and methods. Experiments were conducted on awake Wistar rats. Clonidine (1 and 10 mg/kg) was used for adrenergic receptors activation, moxonidine (10 and 100 mg/kg) was used for imidazoline receptor activation. Emotional stress was caused by sound signal (a ring). Results. Studies demonstrated that the activation of central imidazoline receptors does not change BP level, while alpha 2‑adrenergic systems play a major role in the central regulation of vascular tone and cardiac function. Both imidazoline and alpha 2‑adrenergic systems participate in functioning of baroreceptor reflex. Conclusions. Emotional stress-associated imidazoline receptor activation restores initial BR and reduces BP elevation in rats. Alpha 2‑adrenergic systems do not have a significant impact on cardiovascular manifestations of emotional tension.

Chemistry, Physiology, and Pharmacology of &amp;#946;.-Adrenergic Mechanisms in the Heart. Why are .&amp;#946;-Blocker Antiarrhythmics Superior?

Stimulation of β-adrenergic receptors in the heart is the most effective endogenous way to increase the mechanical performance of cardiac tissues to meet the requirements of a fight-or-flight situation or stress. On the other hand, sustained activation of cardiac β-receptors initiates maladaptive remodeling of the myocardium leading to cardiomyopathies and heart failure. Since both acute and chronic stimulation of β-adrenoceptors are arrhythmogenic, the application of β-receptor blockers exerts effective antiarrhytmic actions at both short and long time scale. Compared to other classes of antiarrhythmic agents, β-blockers are the class of antiarrhythmics that was shown to decrease mortality in postinfarct patients. Chemical, physiological, and pharmacological properties of the β-adrenoceptor related signaling, the role of β-1, β-2, and β-3 receptor subtypes, consequences of acute and long term β-adrenergic stimulation and the underlying proarrhythmic mechanisms, including the changes in cardiac ion currents and Ca(2+) handling, are reviewed in this paper together with the clinical relevance of cardioprotective β-blocking therapy.

Cocaine increases dopaminergic neuron and motor activity via midbrain α1 adrenergic signaling.

Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an α1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of α1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine.