Incubation of nicotine seeking is associated with enhanced protein kinase A-regulated signaling of dopamine- and cAMP-regulated phosphoprotein of 32 kDa in the insular cortex - PubMed (original) (raw)

Incubation of nicotine seeking is associated with enhanced protein kinase A-regulated signaling of dopamine- and cAMP-regulated phosphoprotein of 32 kDa in the insular cortex

Amir Abdolahi et al. Eur J Neurosci. 2010 Feb.

Abstract

A recent clinical study demonstrated that damage to the insular cortex can disrupt tobacco addiction. The neurobiological mechanisms for this effect are not yet understood. In this study we used an animal model of nicotine addiction to examine the possibility that changes in insular cortex levels of dopamine (DA)- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a phosphoprotein enriched in DA neurons containing DA D1 receptors, may be associated with changes in vulnerability to nicotine addiction. Once rats acquired self-administration, they were given unlimited access to nicotine (0.01 mg/kg/infusion) for 23 h/day for a total of 10 days. Each infusion was paired with a visual cue (stimulus light) and auditory cue (sound of pump). Nicotine seeking, as assessed under a cue-induced reinstatement paradigm, and markers of DARPP-32 signaling, as assessed using western blot analysis, were examined in separate groups of rats at two different abstinent intervals: 1 and 7 days. Consistent with findings with other drugs of abuse, rats in the 7-day abstinence group took longer to extinguish and responded at higher levels during reinstatement testing as compared with rats in the 1-day reinstatement group. Relative to saline controls, rats in the 7-day but not the 1-day abstinence group had higher levels of DARPP-32 phosphorylated at the protein kinase A site in the insular cortex. These results demonstrate incubation of drug seeking following extended access to nicotine self-administration and suggest that enhanced protein kinase A signaling in the insular cortex via phosphorylation of DARPP-32 at Thr34 is associated with this effect.

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Figures

Fig. 1

Fig. 1

Schematic of the time-line of experimental events for the behavioral and molecular groups. The behavioral groups included nicotine self-administering rats that were tested at either 1 or 7 days of abstinence and the molecular groups included nicotine and saline self-administering rats from which tissue was obtained at either 1 or 7 days following the last self-administration session.

Fig. 2

Fig. 2

Schematic illustration of brain regions used for molecular studies. The insular cortex and nucleus accumbens core and shell were identified and dissected from 2-mm-thick coronal brain slices as shown. mPFC, medial prefrontal cortex; NAc, nucleus accumbens.

Fig. 3

Fig. 3

Extended access nicotine self-administration. (Left panel) Mean (±SEM) number of infusions self-administered as a function of day during the extended access self-administration period averaged across the four nicotine self-administration groups and the saline control group. *Significant difference between nicotine and saline (P < 0.05). (Right panel) Mean (±SEM) nicotine intake (g/kg) averaged over the 10-day extended access period for each of the four nicotine self-administration groups.

Fig. 4

Fig. 4

Incubation of nicotine-seeking behavior. (Left panel) Extinction. Mean (±SEM) number of responses on the lever formerly associated with nicotine for each of the five 1-h extinction sessions for rats in the 1- and 7-day abstinence groups. *Significant difference between the 1- and 7-day abstinence groups (P < 0.05). (Right panel) Reinstatement. Mean (±SEM) number of responses made during the 1-h reinstatement session as compared with the last extinction session for rats in the 1- and 7-day abstinence groups. *Significant difference between the number of responses made during the reinstatement session as compared with the number made during the last extinction session (P < 0.05). +Significant difference between the 1- and 7-day abstinence groups (P < 0.05).

Fig. 5

Fig. 5

Effect of abstinence length on total and phosphorylated levels of DARPP-32 in the insular cortex. Total DARPP-32 (left panel) and phosphorylated levels of DARPP-32 at Thr34 (middle panel) and Thr75 (right panel) were quantified by densitometry, and the data were normalized to tubulin. Immunoblots for the detection of total DARPP-32 and phospho-Thr34 and phospho-Thr75 are shown above each respective panel. *Significant difference as compared with saline (P < 0.05). Data represent means ± SEM. A.U., arbitrary unit.

Fig. 6

Fig. 6

Effect of abstinence length on total and phosphorylated levels of DARPP-32 in the nucleus accumbens core. Total DARPP-32 (left panel) and phosphorylated levels of DARPP-32 at Thr34 (middle panel) and Thr75 (right panel) were quantified by densitometry, and the data were normalized to tubulin. Immunoblots for the detection of total DARPP-32 and phospho-Thr34 and phospho-Thr75 are shown above each respective panel. *Significant difference as compared with saline and the 1-day abstinence group (P < 0.05). Data represent means ± SEM. A.U., arbitrary unit.

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