Addiction Rehab: The Selective Dopamine ?-Hydroxylase Inhibitor Nepicastat Attenuates Multiple Aspects of Cocaine-Seeking Behavior.

The Selective Dopamine ?-Hydroxylase Inhibitor Nepicastat Attenuates Multiple Aspects of Cocaine-Seeking Behavior.

Filed under: Addiction Rehab

Neuropsychopharmacology. 2013 Jan 3;
Schroeder JP, Alisha Epps S, Grice TW, Weinshenker D

Although norepinephrine (NE) does not typically modulate cocaine self-administration under traditional schedules of reinforcement, it is required for different inducers of the reinstatement of cocaine-seeking behavior via activation of multiple adrenergic receptor subtypes. We predicted that blockade of NE synthesis would attenuate all known modalities of reinstatement, and showed previously that the selective dopamine ?-hydroxylase (DBH) inhibitor, nepicastat, had no effect on either maintenance of operant cocaine self-administration maintained on a fixed-ratio 1 schedule or reinstatement of food seeking, but did abolish cocaine-primed reinstatement (Schroeder et al., 2010). In the present series of studies, we first evaluated the dose-dependent effect of nepicastat (5, 50, or 100?mg/kg) on novelty-induced locomotor activity, and found that it blunted exploration only at the highest dose. Next, we assessed the ability of nepicastat (50?mg/kg) to reduce breakpoint responding for cocaine on a progressive ratio schedule and reinstatement induced by drug-associated cues and stress. We found that nepicastat significantly lowered the breakpoint for cocaine, but not for regular chow or sucrose, and attenuated cue-, footshock-, and yohimbine-induced reinstatement. Combined, these results indicate that nepicastat can reduce the reinforcing properties of cocaine under a stringent schedule and can attenuate relapse-like behavior produced by cocaine, formerly cocaine-paired cues, and physiological and pharmacological stressors. Thus, nepicastat is one of those rare compounds that can reduce reinforced cocaine seeking as well as all three reinstatement modalities, while sparing exploratory behavior and natural reward seeking, making it a promising pharmacotherapy for cocaine addiction.Neuropsychopharmacology accepted article preview online, 3 January 2013; doi:10.1038/npp.2012.267.
HubMed – addiction


The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement.

Filed under: Addiction Rehab

Neuropsychopharmacology. 2012 Dec 18;
Barbier E, Vendruscolo LF, Schlosburg JE, Edwards S, Juergens N, Park PE, Misra KK, Cheng K, Rice KC, Schank J, Schulteis G, Koob GF, Heilig M

Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1?h: ShA) or long (12?h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared to heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with short and long access to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from long access self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid dependent subjects.Neuropsychopharmacology accepted article preview online, 18 December 2012; doi:10.1038/npp.2012.261.
HubMed – addiction


NeuroD Modulates Opioid Agonist-Selective Regulation of Adult Neurogenesis and Contextual Memory Extinction.

Filed under: Addiction Rehab

Neuropsychopharmacology. 2012 Nov 29;
Zheng H, Zhang Y, Li W, Loh HH, Law PY

Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of NeuroD activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate or magnitude. Fentanyl-induced CPP required much longer time for extinction than morphine-induced CPP. We observed a parallel decrease in NeuroD activities and neurogenesis after morphine-induced CPP but not after fentanyl-induced CPP. Increasing NeuroD activities with NeuroD-lentivirus (nd-vir) injection at the dentate gyrus (DG) prior to CPP training reversed morphine-induced decreases in NeuroD activities and neurogenesis, and prolonged the time required for extinction of morphine-induced CPP. On the other hand, decreasing NeuroD activities via injection of miRNA-190 virus (190-vir) reversed the fentanyl effect on NeuroD and neurogenesis and shortened the time required for extinction of fentanyl-induced CPP. Another contextual memory task, the Morris Water Maze (MWM), was affected similarly by alteration of NeuroD activities. The reduction in NeuroD activities either by morphine treatment or 190-vir injection decreased MWM task retention, while the increase in NeuroD activities by nd-vir prolonged MWM task retention. Thus, by controlling NeuroD activities, opioid agonists differentially regulate adult neurogenesis and subsequent contextual memory retention. Such drug-related memory regulation could have implications in eventual context-associated relapse.Neuropsychopharmacology accepted article preview online, 29 November 2012; doi:10.1038/npp.2012.242.
HubMed – addiction



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