Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Establishment creation and destruction across business density cycles: US evidence

This paper investigates how business establishment entry and exit are affected by cycles in business density. We assess how entry/exit behave when markets over and under shoot a dynamic equilibrium number of businesses and whether these effects differ between manufacturing and service industries. Overall, we find persistent cycles where the actual number of business establishments is typically not equal to the dynamic equilibrium number even though it gravitates towards it. We uncover a systematic pattern which indicates that in disequilibrium entry is dis-equilibrating while closure is equilibrating. For example, the entry rate plays a dis-equilibrating role by accelerating in an overshoot, however as exits accelerate even faster in an overshoot they help move the industry towards an equilibrium. Overall, the results indicate that entrepreneurs and corporations operate with a herd instinct thereby increasing establishments in a cyclical business density over shoot and decreasing them in an under shoot. In terms of economic policy, the results question whether government policy aimed at promoting business creation and expansion ought to have a counter business density cyclical dimension. In other words, should business start-up and growth be promoted more strongly in business density under shoots than over shoots

Seasonality of bivalve larvae within a high Arctic fjord

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Spirituality: everyone has it, but what is it?

Spirituality has been the subject of discussion over many years, yet understanding its nature, and usefulness during illness, can be elusive. Nurses and other health-care practitioners can often be in the position to help patients discuss spiritual matters because of their direct contact on a frequent basis, but might not feel confident to do so because the subject can appear to be overly complex. This paper summarizes some of the essential elements of spirituality as synthesized from literature that refers to it. The literature draws attention to spirit as the core of a person's being, and the notion that spirituality comprises multiple dimensions that exist internally or become externally manifest through behaviours. The presence and use of spirituality can lead to such outcomes as peace of mind, self-fulfilment and alleviation of suffering. Underpinning all spirituality is the concept of transcendence where a person can be ‘lifted up’ above the challenges of illness

AMPA-receptor GluR1 subunits are involved in the control over behavior by cocaine-paired cues

The learning processes underlying the formation of drug-cue associations involve changes in synaptic transmission mediated by AMPA receptors. Here, we examine the consequences of targeted deletion of the gene encoding GluR1 subunits of AMPA receptors (gria1 knockouts (KO)) on cocaine self-administration and on the ability of cocaine-paired cues to affect cocaine-seeking in mice. Cocaine self-administration was unaffected by gria1 deletion, as was the ability of a cocaine-paired cue to reinstate responding following extinction, following either a 3 or a 66 day delay. However, gria1 KOs over-responded during extinction. The KOs were unable initially to learn a new response to access a cue previously conditioned to cocaine (conditioned reinforcement (CR)), although a second test 2 months later revealed that this was a transient deficit. These studies indicate that GluR1-containing AMPA-receptors are not involved in cocaine self-administration, cue-induced reinstatement of cocaine seeking, or incubation of the cocaine seeking response. In order to understand the specificity of the deficits in CR responding, a parallel study was performed with food reward. As with cocaine, there were no effects of gria1 deletion on food self-administration or cue-induced reinstatement, and KOs over-responded during extinction. However, even immediately after instrumental training for food, KO mice demonstrated responding for CR, suggesting that the CR deficit observed with a cocaine cue is specific to drug reward. These data indicate that GluR1-containing AMPA receptors are important in stimulus reward learning, though the method of cue-reward association formation, the reward class, and the behavioral end point are critical variables in determining their involvement