Sex differences in the effects of estradiol in the nucleus accumbens and striatum on the response to cocaine: neurochemistry and behavior

Abstract

Background: Females exhibit more rapid escalation of cocaine use and enhanced cocaine-taking behavior as compared to males. While ovarian hormones likely play a role in this increased vulnerability, research has yet to examine the role of estradiol in affecting the behavioral and neurological response to cocaine in a brain region- and sex-specific way.

Methods: First, we examined stereotypy and locomotor sensitization after repeated cocaine administration (10 mg/kg i.p.) in intact (SHAM) and castrated (CAST) males, and ovariectomized (OVX) females treated with 5 μg estradiol benzoate (EB) or vehicle (OIL). Next, we used in vivo microdialysis to examine the effects of acute EB treatment on cocaine-induced DA in the regions mediating the display of these behaviors (i.e., the dorsolateral striatum, DLS; and the nucleus accumbens, NAc; respectively).

Results: We find that EB enhances sensitization of cocaine-induced stereotypy in OVX females after 12 days of cocaine treatment, and after a 10-day withdrawal. Similarly, the OVX/EB females show enhanced locomotor sensitization compared to the other three groups on the same days. Using in vivo microdialysis to assess the neurochemical response, we find that EB rapidly enhances cocaine-induced DA in DLS dialysate of OVX females but not CAST males, and has no effect in NAc of either sex.

Conclusions: With these experiments, we show that there are sex differences in the effects of estradiol to preferentially enhance the response to cocaine in the DLS over the NAc in females, which may contribute to the preferential sensitization of stereotypy in females.

Keywords: Behavioral sensitization; Dopamine; Drug abuse; Microdialysis; Sex differences.

Figure 1. The effect of hormones on and sex differences in the number of stereotyped forelimb movements plus headbobs after 10 mg/kg cocaine

A) The mean number of stereotyped behaviors (+/−SEM) exhibited in the 60 min following cocaine administration, after 1 (left) and 12 (right) days of cocaine exposure. (The dashed lines within each bar represent the means for control groups receiving saline only.) On Day 1, there are no differences in the number of stereotyped behaviors exhibited by the cocaine or saline treated groups. Sensitization (stereotyped behaviors on Day 12 minus Day 1) was seen in all cocaine-treated groups and the OVX/EB females exhibited enhanced stereotypy compared to the other three cocaine-treated groups (* p < 0.05). B) Challenge Day. The number of stereotyped behaviors exhibited after a challenge dose of cocaine by animals receiving 12 days of cocaine (left side; solid bars) or saline (right side; notched bars). The cocaine-treated animals exhibited significantly more stereotyped behaviors than did their saline-treated counterparts and in comparison to their behavior on Day 12 (a; p < 0.05). Among the animals previously treated with cocaine, OVX/EB females showed the greatest increase in stereotypy compared to the other cocaine-treated groups (^ p < 0.05). When comparing the display of stereotyped behaviors within the saline-treated animals that received cocaine for the first time on Challenge Day, OVX/EB animals showed more stereotyped behaviors than SHAM/OIL and OVX/OIL (# p < 0.05).

Figure 2. The effect of hormones on and sex differences in locomotor behavior (quadrant crossings) after 10 mg/kg cocaine

A) The mean number of quadrants crossed (+/−SEM) in 60 min on Day 1 and Day 12 of treatment. (The dashed lines within the bars represent the means for the saline-treated groups.) On Day 1, OVX/OIL females exhibited higher locomotor activity compared to CAST/OIL and SHAM/OIL males ($ p < 0.05). Sensitization (stereotyped behaviors on Day 12 minus Day 1) was seen in all cocaine-treated groups. The OVX/EB females show a greater increase in locomotor behavior than the other three groups (* p < 0.05). B) The number of quadrants crossed after a challenge dose of cocaine by animals receiving cocaine (left side; solid bars) or saline treatment (right side; notched bars) for the first 12 days. On Challenge Day only the SHAM/OIL males previously treated with cocaine exhibited sensitization relative to saline-treated counterparts (a, p < 0.05). Within the animals previously treated with cocaine, OVX/EB females showed the greatest increase in locomotion compared to the CAST group (^ p < 0.05). There were no differences in Challenge Day locomotion among the saline-treated groups.

Figure 3. Cocaine-induced increase in DA dialysate from (A) female DLS, (B) male DLS, (C) female NAc, and (D) male NAc

Data are presented as mean (+ SEM) DA increase from baseline during each 10-min sample collection (pg/10 min). Collections taken at 10, 20, and 30 min are after a subcutaneous injection of EB or OIL (5μg in 0.1ml oil, or oil alone); collections from 40 through 120 min are following cocaine administration (10 mg/kg, i.p.; indicated by the arrow). ‘a’ indicates that DA in DLS of EB females is significantly greater than NAc EB females (p<0.05); ‘#’ indicates that DA is higher in DLS in EB females compared to OIL females (p<0.05); * indicates a significant main effect of sex in NAc, with DA being higher in males than in females, regardless of treatment (p < 0.05). There was no effect of EB in the males in either brain regions.