A Psychological Dimension of Stress Selectively Alters Serotonin-1A Receptor Function in the Dorsal Raphe Nucleus

Acute, traumatic, stress is an experiential factor that can predispose an individual to the development of psychiatric disorders such as depression and post-traumatic stress disorder. However, not all individuals react similarly to traumatic events. This variability has led to the study of the components that can mitigate the unwanted consequences of stress. One component that potently modulates the consequences of stress is stressor controllability. Indeed, uncontrollable, but not controllable, stress produces a variety of behaviors that have been termed anxiety- or depression-like. The studies herein elucidate a mechanism that could explain the behavioral differences following uncontrollable and controllable stress. We found that uncontrollable stress functionally impairs serotonin-1A receptors in the dorsal raphe nucleus, while controllable stress does not. Furthermore, this protective effect of control was mediated by the medial prefrontal cortex. Finally, an initial experience with controllable stress prevented subsequent uncontrollable stress-induced impairments of serotonin-1A receptor function. These results indicate that activation of the medial prefrontal cortex produces both short- and long-term resistance to some of the consequences of stress

Chronic Activation of Corticotropin-Releasing Factor Type 2 Receptors Reveals a Key Role for 5-HT1A Receptor Responsiveness in Mediating Behavioral and Serotonergic Responses to Stressful Challenge

BackgroundThe corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation.MethodsTransgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions.ResultsMice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei.ConclusionsChronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders

Opioid activation of toll-like receptor 4 contributes to drug reinforcement

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4−/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.M. R. Hutchinson... J. Thomas, K. van Steeg... A. A. Somogyi... et al

The effects of a single exposure to uncontrollable stress on the subsequent conditioned place preference responses to oxycodone, cocaine, and ethanol in rats

The original publication can be found at www.springerlink.comRationale Acute stress has been shown to facilitate the rewarding effects of a number of commonly abused drugs, although the stressor typically must be administered either immediately before or during drug administration and often in the same environment. We have previously reported that a single session of an uncontrollable (inescapable tailshock, IS), but not controllable (escapable tailshock, ES), stressor can enhance the conditioned place preference (CPP) response to morphine, even when stressor and drug administration are separated temporally and spatially. However, this persistent, trans-situational enhancement did not occur to amphetamine CPP. Objectives The following experiments were conducted to determine whether the long-term effects of IS on drug reward are specific to opioids. Materials and methods Adult, male Sprague–Dawley rats were exposed to a single session of IS or remained in their home cages (HC). Twenty-four hours later, using an unbiased procedure, CPP conditioning was conducted with either oxycodone (0, 2, or 5 mg/kg, sc), cocaine (0, 1, 5, or 10 mg/kg, ip), or ethanol (0.3, 1, or 2 g/kg, ip). Another group of rats were exposed to IS, ES, or HC treatment and conditioned with oxycodone (5 mg/kg, sc) 24 h later. Results IS enhanced the subsequent CPP response to oxycodone, but not cocaine or ethanol. This enhancement was dependent on the controllability of the stressor, as ES did not affect oxycodone CPP. Conclusions These results indicate that the long-term, trans-situational enhancing effect of uncontrollable stress on drug reward is specific to opioids

Synthesis of Acridines through Alkyne Addition to Diarylamines

A new synthesis of substituted acridines is achieved by palladium-catalyzed addition of terminal acetylenes between the aryl rings of bis(2-bromophenyl)amine. By including a diamine base and elevating the temperature, the reaction pathway favors the formation of acridine over a double Sonogashira reaction to form bis(tolan)amine. This method is demonstrated with several aryl-alkynes and alkyl-alkynes