Female mice lacking membrane estrogen receptor alpha display impairments in spatial memory.

Estrogens exert effects on cognition by acting on estrogen receptors (ER) including ERα. Activation of nuclear ERα results in classical genomic signaling leading to transcriptional changes that occur over hours to days. In contrast, activation of ERα localized to the membrane results in rapid signaling with effects occurring in seconds to minutes. The goal of the current study was to determine the role of membrane ERα in spatial memory. Female wildtype (WT) and transgenic mice that lack membrane ERα and express nuclear only ERα (NOER) were trained on an eight-arm radial-maze task. Following training, mice were tested on delay trials, in which delays ranging from 30 min to 5 h were inserted between the 4th and 5th arm choices. Performance was measured by number of proactive and retroactive errors. Proactive errors are short-term working memory errors defined by reentries into arms previously visited during the post-delay period or errors made during the pre-delay period. Retroactive errors are delay-dependent memory errors, defined as reentries into arms during the post-delay that were previously visited during the pre-delay. Consistent with a role for membrane ERα in rapid signaling, NOER mice made more proactive errors than WTs across all delays. NOER mice made more retroactive errors than WTs only after the 5-h delay. WT and NOER mice performed similarly on elevated plus maze and open field tests indicating no effects of membrane ERα on anxiety-related behavior or locomotor activity. Results reveal that membrane ERα plays important roles in both short-term and longer-term delay-dependent memory either directly or potentially indirectly through a role in the regulation of estradiol levels via the hypothalamic-pituitary-gonadal axis.

Effects of ∆9-THC on memory in ovariectomized and intact female rats.

The effects of marijuana's major psychoactive cannabinoid, ∆9-tetrahydrocannibinol (∆9-THC), were examined on memory in female rats by training subjects to respond under a repeated acquisition and delayed-performance procedure. During this task, subjects acquired a different 4-response sequence each session, which was then recalled after a delay. Sequence retention was tested following various delays, and quantified by a percent savings measure. Response rate and percent errors were also recorded. Subsequent to training, subjects underwent an ovariectomy (OVX) or sham surgery (intact). The OVX group then underwent implantation of subcutaneous 17ß-estradiol capsules while the intact group received chronic administration of 1 mg/kg of the estrogen receptor modifier, tamoxifen. Increasing delays from 1 min to 24 h produced delay-dependent decreases in percent savings in both OVX and intact rats. Acute administration of ∆9-THC (0.32-3.2 mg/kg) dose-dependently decreased retention, increased percent errors, and decreased response rate in both groups when the delay was 1 h. However, intact rats showed a significantly lower percent savings than OVX rats at the 0.56-mg/kg dose. Delays of 3 h enhanced the disruptive effects of ∆9-THC more in intact than OVX rats; furthermore, implantation of 17ß-estradiol attenuated ∆9-THC-induced disruptions in OVX rats and significantly increased estradiol levels and uterine weight as compared to intact rats. Although chronic tamoxifen administration did not alter ∆9-THC's effects on memory in intact rats, it did significantly decrease response rate. These results demonstrate the capacity of chronic 17ß-estradiol for attenuating ∆9-THC's acute memory-disrupting effects in OVX female rats.

Effects of noncontingent ethanol, DHEA, and pregnanolone administration on ethanol self-administration in outbred female rats.

Previous research from this laboratory demonstrated that male outbred rats (Long-Evans) can be trained to prefer ethanol (10% v/v) over water during 30-min home-cage sessions and that higher ethanol concentrations (18-32% v/v) can serve as a reinforcer under various operant schedules. Further, we have shown that two neurosteroids, dehydroepiandrosterone (DHEA) and pregnanolone, can readily decrease ethanol self-administration in males. The present study used the same procedures in an attempt to systematically replicate the previous findings in female outbred rats. Rats were first trained to self-administer ethanol in the home cage using a saccharin-fading procedure. Subsequently, a two-bottle preference test was initiated by substituting different ethanol concentrations after subjects reliably consumed 10% ethanol alone. Water was always available during this phase. Next, subjects were transitioned to a fixed-ratio 10 (FR-10) schedule of reinforcement with 0.1 mL of ethanol (18% v/v) serving as the reinforcer so that a concentration-effect curve could be established. Upon completion, subjects were transitioned to an FR-10 FR-20 multiple schedule of ethanol (32% v/v) and food reinforcement to determine whether noncontingent ethanol, DHEA, and pregnanolone could selectively decrease ethanol intake. Not surprisingly, female subjects preferentially consumed ethanol over water at concentrations of 3.2-18% (v/v) during the home-cage procedure, and significantly increased the mean dose of ethanol consumed and blood ethanol concentration (BEC). Similarly, increasing concentrations under an FR-10 schedule significantly increased the dose of ethanol presented and BEC compared to control (water). Finally, under the multiple schedule, noncontingent injections of ethanol (0.32-1.8 g/kg), DHEA (10-100 mg/kg), and pregnanolone (1.8-32 mg/kg) dose-dependently decreased food- and ethanol-maintained responding and the dose of ethanol presented. BEC was significantly decreased by the neurosteroids, but increased by ethanol due to its noncontingent administration. Together, these data replicate only a subset of the data previously obtained in males, suggesting there are sex differences particularly with respect to the effects of DHEA and pregnanolone.

Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone.

Mephedrone (4-methylmethcathinone), a constituent of the recreational substances known as "bath salts", is a synthetic cathinone that can produce auditory and visual hallucinations, as well as problematic cardiovascular effects. This study compared the discriminative stimulus effects of mephedrone (0.32-10 mg/kg) with other prototypical drugs of abuse: cocaine (0.56-32 mg/kg), d-amphetamine (0.18-3.2 mg/kg), ketamine (1.8-18 mg/kg), phencyclidine (PCP, 1-5.6 mg/kg), heroin (1-10 mg/kg), 2,5-dimethoxy-4-iodoamphetamine (R-DOI, 0.1-1 mg/kg), Δ9-tetrahydrocannabinol (Δ9-THC 0.56-5.6 mg/kg), 3,4-methylenedioxyamphetamine (MDA, 0.32-5.6 mg/kg), methylphenidate (1-10 mg/kg), and 3,4-methylenedioxypyrovalerone (MDPV, 0.56-5.6 mg/kg). The discriminative stimulus effects of mephedrone were also assessed after administration of the sigma receptor antagonist rimcazole (0.32-10 mg/kg), the relatively selective norepinephrine transporter (NET) inhibitor desipramine (1.8-18 mg/kg), and the selective serotonin transporter (SERT) inhibitor fluoxetine (1-18 mg/kg). Initially, rats were trained to discriminate an intraperitoneal injection of mephedrone (3.2 mg/kg) from saline under a fixed-ratio 20 schedule of food presentation. Following training, cumulative doses of mephedrone and the other drugs were administered to test for substitution (80% drug-lever responding). Of the drugs tested, including those that were tested in combination with mephedrone (i.e., rimcazole, desipramine, and fluoxetine), only cocaine fully substituted for mephedrone without substantially decreasing response rate. In addition, the three drugs administered in combination with mephedrone shifted the cumulative dose-effect curves leftward (percent drug-lever responding) and down (response rate), although fluoxetine did so in a dose-dependent manner ranging from antagonism to potentiation. In summary, the discriminative stimulus effects of mephedrone were most similar to those for the central nervous system (CNS) stimulant, cocaine, and SERT and DAT activity were necessary for these effects.