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

Endocannabinoid Regulation of Acute and Protracted Nicotine Withdrawal: Effect of FAAH Inhibition

Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use

Campo della Fiera

La ricerca \ue8 stata avviata (nel 2000) per verificare l' esistenza, ormai pressoch\ue8 accertata, del santuario federale degli Etruschi, il fanum Voltumnae delle fonti letterarie. Lo scavo, i cui risultati sono stati accolti con ampio consenso dalla comunit\ue0 scientifica, copre finora una superficie di oltre 3 ha

Campo della Fiera

La ricerca \ue8 stata avviata (nel 2000) per verificare l' esistenza, ormai pressoch\ue8 accertata, del santuario federale degli Etruschi, il fanum Voltumnae delle fonti letterarie. Lo scavo, i cui risultati sono stati accolti con ampio consenso dalla comunit\ue0 scientifica, copre finora una superficie di oltre 3 ha

Campo della Fiera, Orvieto

Scavo, analisi delle strutture e dei reperti (Ia.C.-XIV d.C.

Campo della Fiera, Orvieto

Scavo dell'area della chiesa medievale di san Pietro in vetere. Analisi delle strutture murarie e dei reperti (I a.C.-XIV d.C.

Campo della Fiera (Orvieto)

Scavo, analisi delle strutture e dei reperti (Ia.C.-XIV d.C.

Activation of PPARgamma receptors by pioglitazone leads to reduction of alcohol drinking and relapse to alcohol seeking: An effect that is potentiated by concomitant administration of naltrexone

The PPARgamma receptor is a ligand-activated transcription factor of the nuclear hormone receptor superfamily activated by selective agonists belong to the class of thiazolidinediones (TZDs).In the brain PPARgamma receptors are widely expressed in glia cells as well as in neurones. Recently, we investigated the role of this receptors in alcohol addictive related behaviors in genetically selected alcohol preferring Marchigian Sardinian (msP) rats. For this purpose we tested the effect of pioglitazone (Actos®), a prototypical TZD approved for the treatment of insulin resistance in Type II diabetes, on alcohol drinking and relapse behavior in msP rats We also investigated to whether pioglitazone potentiates the effect of naltrexone (drug approved for the treatment of alcoholim) on alcohol drinking and relapse. Results showed that activation of PPARgamma by pioglitazone (0-30 mg/kg) lowers alcohol intake and relapse to alcohol seeking elicited administration of yohimbine (a pharmacological stressor) but not by cues predictive of alcohol availability. On the other hand, naltrexone (0-1 mg/kg) lowered ethanol consumption and cue- but not yohimbine-induced relapse We have, then, investigated the effect of concomitant administration of the two drugs. Results showed that drug combination elicits a more pronounced inhibition of ethanol intake. Moreover, simultaneous administration results in a pronounced inhibition of both cue and yohimbine stress-induced alcohol seeking. These findings opens new vistas in the use pioglitazone in combination with naltrexone for the treatment of alcoholism