Region and context-specific intracellular responses associated with cocaine-induced conditioned place preference expression

Abstract

The development and maintenance of cocaine addiction depend heavily on learned reward-environment associations that can induce drug-seeking behavior and relapse. Understanding the mechanisms underlying these cue-induced conditioned responses is important for relapse prevention. To test whether intracellular responses measured after cocaine conditioned place preference (CPP) expression are context-dependent, we re-exposed cocaine-treated rats (drug-free) to an environment previously paired with cocaine or saline, 24 h after the CPP test. After 8 days of cocaine CPP training with one of two cocaine doses (5 mg/kg or 20 mg/kg, i.p.), CPP was expressed only after conditioning with the higher cocaine dose. In CPP expressing rats, locomotor responses after re-exposure to the cocaine-chamber were greater than in rats re-exposed to the saline-paired chamber. Nucleus Accumbens (NAc) phosphorylated ERK (pERK) levels were increased after re-exposure to the cocaine-paired, but not the saline-paired chamber, regardless of whether or not CPP behavior was expressed. Caudate Putamen (CPu) pERK and FosB protein levels increased after re-exposure to the cocaine chamber only after conditioning with the higher cocaine dose. Conversely, the higher cocaine dose, independent of environment, resulted in increased NAc FosB, ΔFosB and phosphorylated CREB (pCREB) protein levels compared to those conditioned with 5 mg/kg cocaine (non-CPP-expressing). Our results suggest that NAc ERK phosphorylation may be involved with retrieving the contextual information of a cocaine-association, without necessarily motivating the expression of CPP behavior. Additionally, we show distinct patterns of intracellular responses in the NAc and CPu indicating a region-specific role for pERK/pCREB/FosB intracellular signaling in the retrieval of cocaine-context associations.

NMDAR dependent intracellular responses associated with cocaine conditioned place preference behavior

“…However, NAc pERK levels, but not pCREB levels, during the post-test were positively correlated with CPP scores. These data are consistent with previous studies showing that NAc ERK phosphorylation is associated with cocaine CPP [5] [7] [9] [11] [12] [40]. Here, we extend these results and show that during CPP expression, different patterns of intracellular signaling responses in the NAc and CPu emerge based on whether or not cocaine-CPP behavior has been acquired/expressed.…”

“…The place preference apparatus (purchased from Med Associates, Georgia, VT) previously described [7] [9] [36] consisted of a rectangular cage with three chambers: 2 square conditioning chambers (28cm in length) separated by a neutral rectangular chamber (12cm long and 4cm wide). The two conditioning chambers were differentiated by tactile and visual cues; in one, the floor was a stainless steel mesh and the walls were white, and in the other, the floor was made up of a grid of stainless steel rods and the walls were black.…”

“…The dorsal and ventral striatum, the caudate-putamen (CPu 1 ) and nucleus accumbens (NAc) respectively, have been implicated in the regulation of habitual and reward-associated responses associated with addiction [4]. These brain regions undergo cocaine-induced neuroplastic changes in intracellular signaling similar to those underlying long-term memory processes [5] [6] [7]. For example, ERK, CREB and Fos proteins are signaling molecules that have been implicated in memory processes [5] [7] [8] [9] [10] [11] [12].…”

Chronic stress‐induced mechanical hyperalgesia is controlled by capsaicin‐sensitive neurones in the mouse

“…However, the InsC and DMH may exert their effects by modulating the activity of other pain‐regulating structures, but through different signalling mechanisms. For example, CRS induces ERK activation in the RVM (Imbe et al., ), in which we did not find FosB expression changes, probably due to the distinct regulation of these activity‐induced factors (Nygard et al., ).…”

Blockade of patch-based μ opioid receptors in the striatum attenuates methamphetamine-induced conditioned place preference and reduces activation of the patch compartment

“…Twenty-four h later, the rats were returned to the chambers for 20 min with the partition removed, and the time on each side recorded to determine each animal’s initial bias. Conditioning began the next day, and consisted of 8 days of alternating saline or METH injections, with rats confined to the preferred side, as determined by the preconditioning bias test, on saline exposure days (days 1, 3, 5 and 7 of conditioning,), and the initially non-preferred side on drug exposure days (days 2, 4, 6, and 8 of conditioning; (Nygard et al, 2015). Rats were randomly assigned to one of four groups: vehicle/saline, vehicle/METH, CTAP/saline, or CTAP/METH.…”