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Cocaine craving during protracted withdrawal requires PKC? priming within vmPFC.

ABSTRACT: In individuals with a history of drug taking, the capacity of drug-associated cues to elicit indices of drug craving intensifies or incubates with the passage of time during drug abstinence. This incubation of cocaine craving, as well as difficulties with learning to suppress drug-seeking behavior during protracted withdrawal, are associated with a time-dependent deregulation of ventromedial prefrontal cortex (vmPFC) function. As the molecular bases for cocaine-related vmPFC deregulation remain elusive, the present study assayed the consequences of extended access to intravenous cocaine (6?hours/day; 0.25?mg/infusion for 10?day) on the activational state of protein kinase C epsilon (PKC?), an enzyme highly implicated in drug-induced neuroplasticity. The opportunity to engage in cocaine seeking during cocaine abstinence time-dependently altered PKC? phosphorylation within vmPFC, with reduced and increased p-PKC? expression observed in early (3?days) and protracted (30?days) withdrawal, respectively. This effect was more robust within the ventromedial versus dorsomedial PFC, was not observed in comparable cocaine-experienced rats not tested for drug-seeking behavior and was distinct from the rise in phosphorylated extracellular signal-regulated kinase observed in cocaine-seeking rats. Further, the impact of inhibiting PKC? translocation within the vmPFC using TAT infusion proteins upon cue-elicited responding was determined and inhibition coinciding with the period of testing attenuated cocaine-seeking behavior, with an effect also apparent the next day. In contrast, inhibitor pretreatment prior to testing during early withdrawal was without effect. Thus, a history of excessive cocaine taking influences the cue reactivity of important intracellular signaling molecules within the vmPFC, with PKC? playing a critical role in the manifestation of cue-elicited cocaine seeking during protracted drug withdrawal.

SUBMITTER: Miller BW

PROVIDER: S-EPMC4945488 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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Cocaine craving during protracted withdrawal requires PKCε priming within vmPFC.

Miller Bailey W BW Wroten Melissa G MG Sacramento Arianne D AD Silva Hannah E HE Shin Christina B CB Vieira Philip A PA Ben-Shahar Osnat O Kippin Tod E TE Szumlinski Karen K KK

Addiction biology 20160114 3

In individuals with a history of drug taking, the capacity of drug-associated cues to elicit indices of drug craving intensifies or incubates with the passage of time during drug abstinence. This incubation of cocaine craving, as well as difficulties with learning to suppress drug-seeking behavior during protracted withdrawal, are associated with a time-dependent deregulation of ventromedial prefrontal cortex (vmPFC) function. As the molecular bases for cocaine-related vmPFC deregulation remain ...[more]

PMID: 26769453

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Project description:Arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of hypothalamus has important roles in regulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress-related behaviors during chronic stress. It is unknown, however, whether AVP in the PVN is involved in the modulation of HPA activity after chronic cocaine exposure. Here, we examined the gene expression alterations of AVP in the hypothalamus, and V1b receptor and pro-opiomelanocortin (POMC) in the anterior pituitary, as well as HPA hormonal changes, in Fischer rats after chronic cocaine and withdrawal, using two different chronic (14-day) 'binge' pattern administration regimens: steady-dose cocaine (SDC, 45 mg/kg/day) and escalating-dose cocaine (EDC, 45 up to 90 mg/kg/day). There was a significant (7-fold) plasma adrenocorticotropic hormone (ACTH) elevation after chronic EDC (but not SDC), coupled with increased V1b and POMC mRNA levels in the anterior pituitary. From acute (1-day) to protracted (14-day) withdrawal from chronic EDC (but not from SDC), we found persistent elevations of both plasma ACTH and corticosterone levels and AVP mRNA levels in the PVN. Selective V1b antagonist SSR149415 (5 mg/kg) attenuated acute withdrawal-induced HPA activation after EDC. To study potential roles of endogenous opioids in modulating the AVP gene, we administered naloxone (1 mg/kg); we found that opioid receptor antagonism increased AVP mRNA levels in cocaine-naive rats, but not in cocaine-withdrawn rats, suggesting less tonic opioid inhibition of PVN AVP neurons after chronic EDC. To assess the effects of cocaine withdrawal on sub-populations of PVN AVP neurons, we utilized AVP-enhanced green fluorescent protein (EGFP) promoter transgenic mice and found that acute withdrawal following chronic EDC increased the number of AVP-EGFP neurons in the parvocellular PVN (pPVN). These results suggest that during protracted withdrawal, enhanced pPVN AVP gene expression is associated with persistent elevations of basal HPA activity; a hyposensitivity of PVN AVP gene expression to naloxone is indicative of reduced opioidergic tone. Our studies indicate that the AVP and its V1b receptor system may be a potential therapeutic target for treating anxiety and depressive symptoms associated with cocaine addiction.

Dataset Information

Cocaine craving during protracted withdrawal requires PKC? priming within vmPFC.

Publications

Cocaine craving during protracted withdrawal requires PKCε priming within vmPFC.

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