Sexually dimorphic intracellular responses after cocaine-induced conditioned place preference expression

Abstract

Sex differences in cocaine’s mechanisms of action and behavioral effects have been widely reported. However, little is known about how sex influences intracellular signaling cascades involved with drug-environment associations. We investigated whether ERK/CREB intracellular responses in the mesocorticolimbic circuitry underlying cocaine environmental associations are sexually dimorphic. We used a standard 4 day conditioned place preference (CPP) paradigm using 20mg/kg cocaine—a dose that induced CPP in male and female Fischer rats. In the nucleus accumbens (NAc) following CPP expression, cocaine treated animals showed increased phosphorylated ERK (pERK), phosphorylated CREB (pCREB) and ΔFosB protein levels. In the hippocampus (HIP) and caudate putamen (CPu), pERK and FosB/ΔFosB levels were also increased, respectively. Cocaine females had a larger change in HIP pERK and CPu ΔFosB levels than cocaine males; partly due to lower protein levels in saline female rats when compared to saline males. Prefrontal cortex (PfC) pCREB levels increased in cocaine males, but not females, whereas PfC pERK levels were increased in cocaine females, but not males. CPP scores were positively correlated to NAc pERK, HIP pERK and CPu FosB protein levels, suggesting that similar to males, the ERK/CREB intracellular pathway in mesocorticolimbic regions undergoes cocaine induced neuroplasticity in female rats. However, there seem to be intrinsic (basal) sexual dimorphisms in this pathway that may contribute to responses expressed after cocaine-CPP. Taken together, our results suggest that cellular responses associated with the expression of learned drug-environment associations may play an important role in sex differences in cocaine addiction and relapse.

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.…”

“…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]. …”

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

“…The aim of the present study was to determine the extent to which increases in phosphorylated protein levels previously observed after cocaine-CPP expression (Nygard et al, 2013), are context-induced. Consistent with our hypothesis, drug-free re-exposure to the environment paired with cocaine during CPP training context dependently increased NAc pERK levels when compared to animals re-exposed to the control environment.…”

“…A three chamber place preference apparatus (Med Associates, Georgia, VT, USA), was used as previously described (Russo et al, 2003; Nygard et al, 2013). Briefly, a rectangular neutral chamber with gray walls and a smooth PVC floor separated two square conditioning chambers with distinct visual and tactile cues.…”