Gene transcripts selectively down‐regulated in the shell of the nucleus accumbens long after heroin self‐administration are up‐regulated in the core independent of response contingency

Jacobs, Edwin H.; Vries, T.J. De; Smit, August B.; Schoffelmeer, Anton N. M.

doi:10.1096/fj.03-0317fje

Cited by 30 publications

(28 citation statements)

References 33 publications

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“…These results are in line with previous studies demonstrating differential neuroadaptations in rats receiving heroin in a response-contingent vs -non-contingent manner (Kuntz et al, 2008;Jacobs et al, 2004;Jacobs et al, 2005), and these data may have particular importance for addiction and pain management fields, respectively. Interestingly, we also found that increases in NAc TacR1 mRNA following repeated (moderate dose) heroin was reduced following non-contingent, escalated-dose heroin exposure, possibly reflecting tolerance-associated changes in the NK1 receptor system.…”

Section: Discussionsupporting

confidence: 91%

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

Barbier

Vendruscolo

Schlosburg

et al. 2012

Neuropsychopharmacol

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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 selfadministration. 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 anxietylike 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 with 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. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA 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.

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Section: Discussionsupporting

confidence: 91%

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

Barbier

Vendruscolo

Schlosburg

et al. 2012

Neuropsychopharmacol

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“…Inactivation of the NAc core, but not the shell, inhibits heroin self-administration (26) and heroin-induced reinstatement of drug-seeking behavior (K.M., unpublished data). Further, self-administration of heroin is associated with upregulation of gene transcripts involved in neuronal function within the NAc core but down-regulation of these same tran- scripts within the NAc shell (29). Notably, inactivation of the NAc core (but not shell) (19,30) or interference with prefrontal glutamatergic projections to the NAc core (20) also prevents cocaine-induced reinstatement of drug-seeking behavior (14).…”

Section: Discussionmentioning

confidence: 99%

Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior

Yao

McFarland

Fan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

103

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The nucleus accumbens (NAc) is central to heroin addiction. Activation of opiate receptors in the NAc dissociates Gi/o into ␣ and ␤␥ subunits. G␣i inhibits cAMP production, but ␤␥ regulates several molecular pathways, including protein kinase A (PKA). We show in NAc͞striatal neurons that opiates paradoxically activate PKA signaling by means of ␤␥ dimers. Activation requires G␣i3 and an activator of G protein signaling 3 (AGS3). AGS3 competes with ␤␥ for binding to G␣i3-GDP and enhances the action of unbound ␤␥. AGS3 and G␣i3 knockdown prevents opiate activation of PKA signaling. In rats self-administering heroin, AGS3 antisense in the NAc core, but not shell, eliminates reinstatement of heroin-seeking behavior, a model of human relapse. Thus, G␣i3͞␤␥͞AGS3 appears to mediate opiate receptor activation of PKA signaling as well as heroin-seeking behavior.opiate receptor ͉ nucleus accumbens core ͉ addiction ͉ ␤␥ subunits ͉ G␣i3 H eroin addiction, a worldwide socioeconomic and public health problem, is difficult for physicians to treat, often because addicts frequently relapse when they try to stop using heroin during abstinence. Heroin activates opiate receptors (1). However, we do not understand the postsynaptic cellular mechanisms produced by opiate receptor (MOR) activation that contribute to craving for and relapse to heroin. Sharma et al. (2) provided pioneering evidence in NG108-15 cells that ␦ opiate receptor (DOR) activation initially decreases cAMP levels, followed by restoration of cAMP to normal levels during continued exposure to morphine; cAMP increases further in response to opiate receptor blockade. Many investigators have confirmed an opiate-induced increase of cAMP͞protein kinase A (PKA) signaling that is exaggerated upon opiate withdrawal (3, 4). In vivo, increased cAMP͞PKA activity may be associated with opiate-induced tolerance and dependence and is thought to contribute to the reinforcing properties of opiates (5).Postsynaptic G i/o -coupled opiate receptors are expressed on GABAergic medium spiny neurons in the nucleus accumbens (NAc), a brain region thought to account, in part, for craving, reward, and reinforcement of addicting drugs (6, 7). MOR and DOR activation dissociates heterotrimeric G i/o proteins into free ␣ and ␤␥ subunits. G␣ i released from G i/o ␤␥ inhibits several isoforms of adenylyl cyclase (AC) (8) and appears to account for opiate inhibition of cAMP production. By contrast, ␤␥ dimers, which are simultaneously released during receptor activation, can stimulate AC2 and AC4 (9-13). However, the precise molecular mechanisms that facilitate this paradoxical G i/ocoupled opiate receptor-induced stimulation of cAMP͞PKA signaling are not clearly understood.Recent evidence suggests that an activator of G protein signaling 3 (AGS3) regulates G protein signaling in the NAc (14). By competing with ␤␥ for binding to G␣ i3 , AGS3 appears to stabilize a specific G␣ i3 -GDP complex formed before the reassociation of free G␣ i3 and ␤␥ subunits (15). The bound form of G␣ i3 does not inhibit...

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“…Animals that self-administer vs receive opioids passively show differential electrophysiological activity of cells in the ventral tegmental area (Kiyatkin and Rebec, 2001) and prefrontal cortex (Lee et al, 1999), as well as differences in nucleus accumbens dopamine release (Hemby et al, 1995) and neurotransmitter turnover rates (Smith et al, 1980(Smith et al, , 1982(Smith et al, , 1984a. Chronic morphine SA relative to PA alters acetylcholine and benzodiazepine receptor density (Smith et al, 1984b), and the expression of various proteins (Self et al, 1995) and gene transcripts in the nucleus accumbens shell (Jacobs et al, 2002) but not nucleus accumbens core (Jacobs et al, 2004) relative to chronic PA.…”

Section: Introductionmentioning

confidence: 99%

Mu-opioid Self-Administration vs Passive Administration in Heroin Abusers Produces Differential EEG Activation

Greenwald

Roehrs

2004

Neuropsychopharmacol

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Psychoactive drug self-administration (SA) produces different neurobiological effects than passive administration (PA) in non-human animals; however, such consequences have never been examined in human drug abusers. The present study compared electroencephalographic (EEG) activation produced by intravenous PA and SA of the mu-opioid fentanyl in eight heroin-dependent, methadone-stabilized male participants. In phase 1, participants received cumulative PA of fentanyl (up to 1.5 mg/70 kg; session 1), then bolus PA of placebo and fentanyl 1.5 mg/70 kg (session 2). High-dose fentanyl significantly increased the amplitude of slow-frequency (delta-and theta-band) EEG activity. In phase 2, bolus fentanyl 1.5 mg/70 kg was available for SA, requiring the participant to complete 1500 responses, in each of two sessions after saline or naloxone pretreatment. Delta EEG peak amplitude increases were greater following fentanyl SA than fentanyl PA, primarily over the central midline region, and were attenuated by naloxone pretreatment. The EEG increase and its attenuation by naloxone agree with preclinical evidence and suggest that SA-related EEG responses were mediated by opioid receptors.

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Gene transcripts selectively down‐regulated in the shell of the nucleus accumbens long after heroin self‐administration are up‐regulated in the core independent of response contingency

Cited by 30 publications

References 33 publications

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior

Mu-opioid Self-Administration vs Passive Administration in Heroin Abusers Produces Differential EEG Activation

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