17ß-Estradiol infusions into the dorsal striatum rapidly increase dorsal striatal dopamine release in vivo.

Systemic injections of 17ß-estradiol (E2) in ovariectomized (OVX) female rats rapidly enhance dorsal striatal dopamine (DA) release in response to amphetamine (AMPH). Additionally, a single injection of E2 rapidly (within 30min) enhances amphetamine-induced DA release. In situ studies show that this rapid effect of E2 occurs specifically within the dorsal striatum (DS). The present study investigated the in vivo effects of E2 infused into the DS, medial prefrontal cortex (mPFC) or the substantia nigra (SN) on dorsal striatal DA release. Rats were OVX and implanted with a silastic tube containing 5% E2 in cholesterol, previously shown to mimic low physiological serum concentrations of 18-32pg/ml. Single-probe microdialysis was used to measure extracellular DA levels in the DS. In addition, DA release was measured subsequent to systemic injections of the indirect DA agonist, AMPH (0.5mg/kg SC), administered simultaneously with E2 (0.544µg/100µl) or its vehicle, cyclodextrin (VEH) (0.520µg/100µl). Local infusions of E2 into the DS resulted in a greater amphetamine-induced dorsal striatal DA release in comparison to vehicle. Local infusions of E2 into the mPFC or the SN did not result in an enhancement of amphetamine-induced DA levels in the DS. These studies suggest that increases in dorsal striatal DA release in response to systemic E2 are a consequence of E2 actions within the DS itself.

Estradiol and striatal dopamine receptor antagonism influence memory system bias in the female rat.

Estradiol (E2) has been shown to influence learning and memory systems used by female rats to find a reward. Rats with high levels of E2 tend to use allocentric, or place, memory while rats with low levels of E2 use egocentric, or response, memory. It has been shown that systemic dopamine receptor antagonism interacts with E2 to affect which memory system is used. Here, dopamine antagonists were administered directly into either the dorsal striatum or nucleus accumbens to determine where in the brain this interaction takes place. Seventy-four young adult, female, Sprague-Dawley rats were trained and tested in a modified plus-maze. All rats were ovariectomized, received a subcutaneous low E2 implant, and were implanted with bilateral cannulae into either the dorsal striatum or the nucleus accumbens. Additionally, high E2 rats received daily injections of E2 in a sesame oil solution while low E2 rats received daily injections of vehicle. After reaching criterion levels of performance in a plus-maze task, rats were administered microinjections of either a dopamine D1 receptor (SCH 23390; 0.1 µg/ml and 0.01 µg/ml) or D2 receptor (raclopride; 2 µg/ml and 0.5 µg/ml) antagonist or a vehicle control (saline) in a counterbalanced manner. High E2 rats exhibited a trend towards a place memory bias while low E2 rats showed a response memory bias. Dorsal striatal administration of a D1, but not D2, dopamine receptor antagonist caused a switch in the memory system used by both high and low E rats. There was no significant effect of dopamine receptor antagonism in the nucleus accumbens group. Thus, E2 determined which memory system controlled behavior in a plus-maze task. Moreover, this effect was modulated by dopamine D1R antagonism in the dorsal but not ventral striatum suggesting that memory systems are, in part, mediated by E2 and dopamine in this region.

Latent inhibition is affected by phase of estrous cycle in female rats.

Estrogen has been shown to have a strong modulatory influence on several types of cognition in both women and female rodents. Latent inhibition is a task in which pre-exposure to a neutral stimulus, such as a tone, later impedes the association of that stimulus with a particular consequence, such as a shock. Previous work from our lab demonstrates that high levels of estradiol (E2) administered to ovariectomized (OVX) female rats abolishes latent inhibition when compared to female rats with low levels of E2 or male rats. To determine if this E2-induced impairment also occurs with the natural variations of ovarian hormones during the estrous cycle, this behavior was investigated in cycling female rats. In addition, pre-pubertal male and female rats were also tested in this paradigm to determine if the previously described sex differences are activational or organizational in nature. In a latent inhibition paradigm using a tone and a shock, adult rats were conditioned during different points of the estrous cycle. Rats conditioned during proestrus, a period of high E2 levels, exhibited attenuated latent inhibition when compared to rats conditioned during estrus or metestrus, periods associated with low levels of E2. Moreover, this effect is not seen until puberty indicating it is dependent on the surge of hormones at puberty. This study confirms recent findings that high E2 interferes with latent inhibition and is the first to show this is based in the activational actions of hormones.

Use of cognitive strategies in rats: the role of estradiol and its interaction with dopamine.

Accumulating evidence suggests a role for estrogen in the use of a particular cognitive strategy when solving a maze task. In order to confirm the role of estrogen in this phenomenon, ovariectomized (OVX) female rats receiving either high ( approximately 90 pg/ml) or low ( approximately 32 pg/ml) circulating levels of 17beta-estradiol benzoate (E2) performed a plus maze task for a reward. Consistent with previous research, OVX rats receiving low levels of E2 utilized a striatum-mediated response strategy while OVX rats administered high levels of E2 employed a hippocampus-mediated place strategy. Furthermore, following a systemic injection of a moderate dose of either a dopamine D1 (SKF 83566, 0.1 mg/kg IP) or D2 (raclopride, 0.5 mg/kg IP) receptor antagonist, low E2 rats were seen to use the opposite strategy and exercise a hippocampus-mediated place strategy in order to obtain the reward. At the same doses, high E2 rats did not change from using a place strategy. At a lower dose, these drugs shifted high E2 rats such that they showed an equal propensity for either strategy; this was not observed in low E2 rats. These results corroborate previous findings that E2 plays a significant role in the use of either a response or place strategy when solving a maze for a reward. In addition, the shift in strategy after dopamine receptor blockade implies the importance of central dopamine function in selecting a cognitive strategy to solve such tasks. It is suggested that estrogen alters cognitive strategy not only by improving hippocampal function, but also by altering dopamine-regulated striatal function.

Blockade of substantia nigra dopamine D1 receptors reduces intravenous cocaine reward in rats.

RATIONALE: We have recently found that blockade of dopamine D1-type receptors in the ventral tegmental area reduces the rewarding effects of intravenous cocaine; here, we explored the possibility that blockade of D1 receptors in the adjacent substantia nigra (SN)--not usually considered part of reward circuitry--might have similar effects. OBJECTIVE: To test the hypothesis that blockade of dopamine D1 receptors in the SN reduces the rewarding effects of cocaine. METHODS: Twenty one rats were prepared with intravenous catheters and with bilateral guide cannulae implanted such that injections could be made directly into the SN or just dorsal to the SN. The rats were trained to self-administer intravenous cocaine (1.0 mg/kg per injection) on a fixed-ratio 1 (FR1) schedule of reinforcement. After stable responding developed, 13 of the animals were tested following pretreatment with bilateral microinjections of SCH 23390 at doses of 0, 1, 2 or 4 microg/0.5 microl into the SN and 8 were tested with injections of 0 microg or 4 microg/0.5 microl into a site 2 mm dorsal to the SN site. RESULTS: Microinjections of SCH 23390 in the SN significantly increased rates of cocaine self-administration, while injections dorsal to SN had no significant effect on responding. CONCLUSIONS: These data suggest that blockade of dendritically released DA in the SN reduces the rewarding effects of cocaine. These findings complement accumulating evidence that the rewarding effects of cocaine are not restricted to the drug's ability to elevate dopamine levels in the nucleus accumbens.