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Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine β-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence. [ABSTRACT FROM AUTHOR]

The purpose of this study was to delineate the pattern of sympathetic innervation in the suprasesamoidean region of the deep digital flexor tendon (DDFT) in horses using immunohistochemical staining (IHC) for tyrosine hydroxylase (TH) and alpha-1 adrenergic receptor (α 1 -AR). Fourteen forelimbs were collected from 10 horses. Longitudinal sections of the suprasesamoidean region of healthy DDFTs were harvested. Most of the sympathetic innervation was found to be in the walls of blood vessels. The tendon tissue proper was sparsely innervated, with a lesser degree of innervation within the dorsal fibrocartilage. Increased α 1 -AR immunostaining was also detected in walls of blood vessels and in spindle cells of fibrocartilage. Both α 1 -AR and TH immunostaining were detected in tenocytes. These findings support the presence of autocrine/paracrine catecholaminergic signalling in equine tendon tissue. [ABSTRACT FROM AUTHOR]

Abstract: The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague–Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus. [Copyright &y& Elsevier]

Summary: The endogenous catecholamine norepinephrine (NE) exhibits anti-epileptic properties, however it is not well understood which adrenergic receptor (AR) mediates this effect. The aim of this study was to investigate α1-adrenergic receptor activation in region CA1 of the hippocampus, a subcortical structure often implicated in temporal lobe epilepsies. Using cell-attached and whole-cell recordings in rat hippocampal slices, we confirmed that selective α1-AR activation increases action potential firing in a subpopulation of CA1 interneurons. We found that this response is mediated via the α1A-AR subtype, initiated by sodium influx, and appears independent of second messenger signaling. In CA1 pyramidal cells, α1A-AR activation decreases activity due to increased pre-synaptic GABA and somatostatin release. Examination of post-synaptic receptor involvement revealed that while GABAA receptors mediate the majority of α1A-adrenergic effects on CA1 pyramidal cells, significant contributions are also made by GABAB and somatostatin receptors. Finally, to test whether α1A-AR activation could have potential therapeutic implications, we performed AR agonist challenges using two in vitro epileptiform models. When GABAA receptors were available, α1A-AR activation significantly decreased epileptiform bursting in CA1. Together, our findings directly link stimulation of the α1A-AR subtype to release of GABA and somatostatin at the single cell level and suggest that α1A-AR activation may represent one mechanism by which NE exerts anti-epileptic effects within the hippocampus. [Copyright &y& Elsevier]

Abstract: The biosynthesis of norepinephrine occurs through a multi-enzymatic pathway that includes the enzyme dopamine-β-hydroxylase (DBH). Mice with a homozygous deletion of DBH (Dbh−/−) have a selective and complete absence of norepinephrine. The purpose of this study was to assess the expression of alpha-1, alpha-2 and beta adrenergic receptors (α1-AR, α2-AR and β-AR) in the postnatal absence of norepinephrine by comparing noradrenergic receptors in Dbh−/− mice with those in Dbh heterozygotes (Dbh+/−), which have normal levels of norepinephrine throughout life. The densities of α1-AR, α2-AR and β-AR were assayed with [3H]prazosin, [3H]RX21002 and [125I]-iodo-pindolol autoradiography, respectively. The α2-AR agonist high affinity state was examined with [125I]-para-iodoclonidine autoradiography and α2-AR functionality by α2-AR agonist-stimulated [35S]GTPγS autoradiography. The density of α1-AR in Dbh−/− mice was similar to Dbh+/− mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in α2-AR were found in septum, hippocampus and amygdala, but these were not reflected in α2-AR functionality. The density of β-AR was up-regulated to varying degrees in many brain regions of Dbh−/− mice compared to the heterozygotes. These findings indicate that regulation of noradrenergic receptors by endogenous norepinephrine depends on receptor type and neuroanatomical region. [Copyright &y& Elsevier]

The alpha-1 adrenergic receptors (α1ARs) play important roles in normal physiology and in many disease states, and understanding their signaling pathways and regulatory mechanisms is thus of considerable relevance, in particular for identifying pharmacological targets for therapeutic modulation. The expression, function, localization, trafficking, and stability of these receptors are all subject to complex regulation by diverse molecular mechanisms. This article highlights recent studies from our laboratory and others focused on the localization and trafficking of the alpha-1B adrenergic receptor (α1BAR) subtype and on changes in its stability that are likely to be involved in regulating receptor expression. The role(s) of protein kinase C in α1BAR sequestration, endocytosis, and extracellular signal-regulated kinase (ERK) activation are summarized, and evidence for α1BAR localization in caveolae/rafts is presented. Receptor structural domains involved in the multiple steps and mechanisms of agonist-induced desensitization are described. Finally, aspects of α1BAR structural stability that appear to control its drug-induced up- and down-regulation are discussed. Our understanding of regulation for the α1BAR subtype provides a model for studies of the differential regulation of the other α1AR subtypes and may lead to identification of new molecular targets for therapeutic intervention in a variety of disease states. [Copyright &y& Elsevier]