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Reacquisition of Cocaine Conditioned Place Preference and Its Inhibition by Previous Social Interaction Preferentially Affect D1-medium Spiny Neurons in the Accumbens Corridor

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Reacquisition of Cocaine Conditioned Place Preference and Its Inhibition by Previous Social Interaction Preferentially Affect D1-medium Spiny Neurons in the Accumbens Corridor

Janine M Prast et al. Front Behav Neurosci.

Abstract

We investigated if counterconditioning with dyadic (i.e., one-to-one) social interaction, a strong inhibitor of the subsequent reacquisition of cocaine conditioned place preference (CPP), differentially modulates the activity of the diverse brain regions oriented along a mediolateral corridor reaching from the interhemispheric sulcus to the anterior commissure, i.e., the nucleus of the vertical limb of the diagonal band, the medial septal nucleus, the major island of Calleja, the intermediate part of the lateral septal nucleus, and the medial accumbens shell and core. We also investigated the involvement of the lateral accumbens core and the dorsal caudate putamen. The anterior cingulate 1 (Cg1) region served as a negative control. Contrary to our expectations, we found that all regions of the accumbens corridor showed increased expression of the early growth response protein 1 (EGR1, Zif268) in rats 2 h after reacquisition of CPP for cocaine after a history of cocaine CPP acquisition and extinction. Previous counterconditioning with dyadic social interaction inhibited both the reacquisition of cocaine CPP and the activation of the whole accumbens corridor. EGR1 activation was predominantly found in dynorphin-labeled cells, i.e., presumably D1 receptor-expressing medium spiny neurons (D1-MSNs), with D2-MSNs (immunolabeled with an anti-DRD2 antibody) being less affected. Cholinergic interneurons or GABAergic interneurons positive for parvalbumin, neuropeptide Y or calretinin were not involved in these CPP-related EGR1 changes. Glial cells did not show any EGR1 expression either. The present findings could be of relevance for the therapy of impaired social interaction in substance use disorders, depression, psychosis, and autism spectrum disorders.

Keywords: D1 medium spiny neurons; accumbens; cocaine; conditioned place preference; diagonal band; island of Calleja; septum; social interaction.

Figures

Figure 1
Figure 1
Experimental timeline. Experimental groups and group sizes are listed on the left. See Materials and Methods Section for more details.
Figure 2
Figure 2
Social interaction during extinction prevents reacquisition of cocaine CPP. Shown are times spent in the different compartments of the CPP box, i.e., the cocaine- (coc), neutral (neu), or saline- (sal) associated compartment, or the saline compartment where social interaction counterconditioning took place (int). Time in the compartment is presented in seconds as the group mean ± s.e.m. Total session duration was 900 s. Significant differences between the time spent in the coc compartment and the time spent in the sal or int compartment are shown as an asterisk: *p < 0.05; **p < 0.01; ***p < 0.001 (One-Way ANOVA). Data are shown for the Sprague–Dawley rats of the COCAINE and SOCIAL groups for the initial cocaine CPP test (CPP, top row), for the test at the end of the fourth extinction/counterconditioning cycle (test 4, middle row), i.e., at the end of either a cocaine CPP extinction treatment with saline (COCAINE group) or a social interaction counterconditioning procedure (SOCIAL group), and during the final cocaine CPP reacquisition test (performed 24 h after a final cocaine reexposure, i.e., in a cocaine-free state).
Figure 3
Figure 3
Colocalization of neuronal markers with EGR1 expression 2 h after cocaine CPP reacquisition. Brains were harvested and fixed for double fluorescence immunohistochemistry 2 h after the start of a 15-min cocaine CPP reacquisition test session. EGR1 immunoreactivity (green) remained restricted to nuclei. All other neuronal markers are shown in red. Colocalization of immunoreactivity was found only in medium spiny neurons (MSNs) positive for dynorphin (A) or the dopamine D2 receptor (D). No colocalization with EGR1 was observed in cholinergic interneurons (marker: choline acetyltransferase; (B) or GABAergic interneurons positive for calretinin (C), neuropeptide Y (E), or parvalbumin (F). Images were taken with a confocal laser scanning microscope with a magnification of 100× (bar size, 10 μm).
Figure 4
Figure 4
Colocalization of EGR1 with the neuronal marker NeuN but not with glial markers. EGR1 immunoreactivity is shown in green, all other markers are shown in red. Colocalization of immunoreactivity was found only in cells positive for the neuronal nuclear protein NeuN (A). No colocalization with EGR1 was observed in glial cells. The employed glial markers were glial fibrillary acidic protein for astrocytes (B), myelin basic protein for oligodendrocytes (C), and tomato lectin for microglia (D). Images were taken with a laser scanning confocal microscope with a magnification of 100× (bar size, 10 μm).
Figure 5
Figure 5
Activation of the accumbens corridor by cocaine CPP and its inhibition by previous social interaction counterconditioning. Shown are the merged images of EGR1- and DYN-labeled neurons, presumably D1-MSNs, or EGR1- and DRD2-labeled neurons in animals that were conditioned for cocaine and extinguished with saline (COCAINE, left panel) or animals that were conditioned for cocaine followed by social interaction counterconditioning (SOCIAL, right panel). Bar size, 50 μm.
Figure 6
Figure 6
Social interaction reverses cocaine CPP reacquisition-induced EGR1 expression in the whole accumbens corridor. Panel (A) shows a diagram taken from the brain atlas of Paxinos and Watson (2007) on the left side. The numbers refer to the following regions: 1, accumbens corridor; 2, AcbCl; 3, CPu; and 4, Cg1. On the right side of (A), the individual 250 μm counting bins of the different accumbens corridor regions are overlaid on a calbindin staining at an AP location of ±0.992 mm from Bregma (modified from Paxinos et al., 2009). Abbreviations (see Materials and Methods) follow the nomenclature of the atlas of Paxinos and Watson (2007). Panels (B–D) show group mean ± s.e.m. of EGR1-positive nuclei per mm2 (B) or the number of EGR1-positive D1-MSNs (DYN-positive, C) or EGR1-positive D2-MSNs (DRD2-positive, D) in the respective brain areas. For reasons of clarity, significant differences between treatment group are only given for the comparison of NONCONT vs. COCAINE (#p < 0.05; ##p < 0.01; ###p < 0.001) and COCAINE vs. SOCIAL (*p < 0.05; **p < 0.01; ***p < 0.001). For the complete statistical analysis, see Table 1.
Figure 7
Figure 7
Cocaine CPP-induced EGR1 expression is reversed by social interaction preferentially in D1-MSNs. Shown are means ± s.e.m.'s of EGR1-immunoreactive nuclei expressed as percent of dynorphin-labeled cells, presumably D1-MSNs (open bars) vs. D2-MSNs labeled with the dopamine D2 receptor (grid-pattern bars) for the accumbens corridor regions, the AcbCl, and the CPu. Panel (A) (red bars) shows the percent of activated D1-MSNs and D2-MSNs for the COCAINE group, whereas panel (B) (green) those for the SOCIAL group. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 8
Figure 8
EGR1 expression in the whole accumbens corridor 2 h after cocaine CPP reacquisition correlates with time spent in the cocaine compartment. The correlation of EGR1 expression per mm2 vs. the time spent in the cocaine compartment during the cocaine CPP reacquisition test is given for animals that had undergone cocaine conditioning and extinction with saline (COCAINE, red triangles, filled) and for animals that were counterconditioned with social interaction after an initial cocaine conditioning (SOCIAL, green circles, filled) and is shown as a continuous line. There was no statistically significant correlation (shown as a dashed line) between the EGR1 expression per mm2 and the time spent in the cocaine compartment for animals injected noncontingently with cocaine (NONCONT; red triangles, unfilled).

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References

    1. Acquas E., Pisanu A., Spiga S., Plumitallo A., Zernig G., Di Chiara G. (2007). Differential effects of intravenous R,S-(+-)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(-)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core. J. Neurochem. 102, 121–132 10.1111/j.1471-4159.2007.04451.x - DOI - PubMed
    1. Acquas E., Wilson C., Fibinger H. C. (1996). Nonstriatal dopamine D1 receptors regulate striatal acetylcholine release in vivo1. J. Pharmacol. Exp. Ther. 281, 360–368 - PubMed
    1. American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th Edn. Washington, DC: American Psychiatric Association
    1. Berlanga M. L., Olsen C. M., Chen V., Ikegami A., Herring B. E., Duvauchelle C. L., et al. (2003). Cholinergic interneurons of the nucleus accumbens and dorsal striatum are activated by the self-administration of cocaine. Neuroscience 120, 1149–1156 10.1016/S0306-4522(03)00378-6 - DOI - PubMed
    1. Bertran-Gonzalez J., Bosch C., Maroteaux M., Matamales M., Herve D., Valjent E., et al. (2008). Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to Cocaine and haloperidol. J. Neurosci. 28, 5671–5685 10.1523/JNEUROSCI.1039-08.2008 - DOI - PMC - PubMed
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