Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens - PubMed (original) (raw)

Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens

Marcelo T Marin et al. Eur J Neurosci. 2009 Nov.

Abstract

Learned associations are hypothesized to develop between drug effects and contextual stimuli during repeated drug administration to produce context-specific sensitization that is expressed only in the drug-associated environment and not in a non-drug-paired environment. The neuroadaptations that mediate such context-specific behavior are largely unknown. We investigated context-specific modulation of cAMP-response element-binding protein (CREB) phosphorylation and that of four upstream kinases in the nucleus accumbens that phosphorylate CREB, including extracellular signal-regulated kinase (ERK), cAMP-dependent protein kinase, calcium/calmodulin-dependent kinase (CaMK) II and CaMKIV. Rats received seven once-daily injections of cocaine or saline in one of two distinct environments outside their home cages. Seven days later, test injections of cocaine or saline were administered in either the paired or the non-paired environment. CREB and ERK phosphorylation were assessed with immunohistochemistry, and phosphorylation of the remaining kinases, as well as of CREB and ERK, was assessed by western blotting. Repeated cocaine administration produced context-specific sensitized locomotor responses accompanied by context-specific enhancement of the number of cocaine-induced phosphoCREB-immunoreactive and phosphoERK-immunoreactive nuclei in a minority of neurons. In contrast, CREB and CaMKIV phosphorylation in nucleus accumbens homogenates were decreased by cocaine test injections. We have recently shown that a small number of cocaine-activated accumbens neurons mediate the learned association between cocaine effects and the drug administration environment to produce context-specific sensitization. Context-specific phosphorylation of ERK and CREB in the present study suggests that this signal transduction pathway is selectively activated in the same set of cocaine-activated accumbens neurons that mediate this learned association.

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Figures

Figure 1

Figure 1

Locomotor sensitization during repeated treatment and in the test day. Distance travelled of Paired group rats (a) was assessed in the square locomotor boxes (Environment A), while locomotor activity of Non-paired group rats (b) was assessed in the round chamber (Environment B) following each daily injection of saline or 15 mg/kg of cocaine. Activity on test day (c) was evaluated in the square locomotor boxes, seven days after repeated administration of saline or cocaine. Rats were injected at one-hour intervals with saline, then 5, 10 and 20 mg/kg of cocaine. Data represent mean ± SEM (N = 8 rats per group) of locomotor activity during 60 min following each injection for Paired or Non-paired groups of rats. # p < 0.001: locomotor activity on day 7 compared to day 1. * p < 0.01: compared to rats repeated injected with saline and tested with the same drug dose.

Figure 2

Figure 2

Schematic representation of brain regions and immunohistochemistry images. (a) Schematic of coronal section approximately 1.8 mm anterior to Bregma employed in the immunohistochemistry detection. Drawings of coronal sections and coordinates were obtained from the atlas of Paxinos & Watson (1998). The rectangle represents the area used to protein quantification. (b) Example of phosphoCREB-immunoreactive nuclei in nucleus accumbens. (c) Example of phosphoERK-immunoreactive cells in nucleus accumbens. Arrows indicate immunoreactive cells.

Figure 3

Figure 3

Quantification of immunohistochemical results for CREB and ERK phosphorylation in nucleus accumbens. Data represent mean ± SEM (N = 6–8 rats per group) of phosphoCREB (a, b) and phosphoERK (c, d) immunoreactive nuclei from rats injected on test day in a Paired or Non-paired environment. # p < 0.01: compared to rats that received saline test injections following repeated administration of either saline or cocaine. * p < 0.05: compared to rats that received cocaine test injections following repeated saline administration.

Figure 4

Figure 4

Schematic representation of brain regions and fluorescent images of proteins analyzed by Western Blotting. Schematic representation (a) of rostral face (2.0 mm anterior to Bregma) of 1mm slice employed in the assays. The circle represents the area taken for tissue punches. Drawings of coronal sections and coordinates were obtained from the atlas of Paxinos & Watson (1998). (b) Example of fluorescent bands from Western blots of each analyzed protein.

Figure 5

Figure 5

Western blotting analysis of phosphorylation of CREB and upstream kinases in the nucleus accumbens following test injections of saline or 20 mg/kg of cocaine. Data represent mean ± SEM (N = 8 rats per group) phosphorylation levels for CREB (a, b), CaMKIV (c, d), ERK (e, f), CaMKII (g, h) and GluR1 serine-845 (i, j) in rats that received test injections in Paired or Non-paired environments. # p < 0.01: compared to rats that received saline test injections following repeated administration of either saline or cocaine. * p < 0.05: compared to rats that received cocaine test injections following repeated saline administration.

Figure 6

Figure 6

Locomotor activity following test injections of saline or 10 mg/kg of cocaine in the square locomotor boxes, seven days after repeated administration of either saline or cocaine. Data represent mean ± SEM (N = 11–12 rats per group) of locomotor activity during 20 min session for (a) Paired or (b) Non-paired groups of rats. * p < 0.01: compared to rats that received cocaine test injections following repeated saline administration.

Figure 7

Figure 7

Western blotting analysis of phosphorylation of CREB and upstream kinases in the nucleus accumbens following test injections of saline or 10 mg/kg of cocaine. Data represent mean ± SEM (N = 11–12 rats per group) phosphorylation levels of CREB (a, b), CaMKIV (c, d), ERK (e, f), CaMKII (g, h) and GluR1 serine-845 (i, j) from rats that received test injections in Paired or Non-paired environments. # p < 0.05: compared to rats that received saline test injections following repeated administration of either saline or cocaine.

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