Jazmin I. Acosta

Stimulation of 5-HT2C receptors attenuates cue and cocaine-primed reinstatement of cocaine-seeking behavior in rats.

The extinction/reinstatement model has been used in this study to examine the role of 5-HT2C receptors in cocaine-seeking behavior elicited by cocaine-associated cues and cocaine-priming injections. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, intravenously) paired with light and tone cues underwent daily extinction sessions, during which responding had no consequences. After responding diminished, rats were tested for reinstatement of responding by either response-contingent presentations of the cues or a cocaine-priming injection (10 mg/kg, intraperitoneal, i.p.), with and without pretreatment with the 5-HT2C/2B receptor agonist, MK 212 (0.0–1.0 mg/kg, i.p.). MK 212 attenuated cue and cocaine-primed reinstatement, as well as spontaneous and cocaine-induced locomotion at all doses tested. These effects were reversed by coadministration of the 5-HT2C-selective receptor antagonist, SB 242 084 (3.0 mg/kg, i.p.), suggesting they are 5-HT2C receptor-mediated. Although we cannot rule out the possibility that motor impairment might have been involved in the MK 212 effects on cocaine-seeking behavior, some aspects of the data favor the explanation that MK 212 decreases the motivational effects of cocaine and cocaine cues. The latter interpretation is consistent with a growing body of literature suggesting that 5-HT2C receptors play a role in motivated behaviors in general.

Transitional versus surgical menopause in a rodent model: Etiology of ovarian hormone loss impacts memory and the acetylcholine system

Clinical research suggests that type of ovarian hormone loss at menopause influences cognition. Until recently ovariectomy (OVX) has been the primary rodent model to examine effects of ovarian hormone loss on cognition. This model limits evaluations to abrupt and complete ovarian hormone loss, modeling less than 13% of women who receive surgical menopause. The majority of women do not have their ovaries surgically removed and undergo transitional hormone loss via ovarian follicular depletion. 4-Vinylcyclohexene-diepoxide (VCD) produces gradual ovarian follicular depletion in the rodent, with hormone profiles more similar to naturally menopausal women vs. OVX. We directly compared VCD and OVX models to examine whether type of hormone loss (transitional vs. surgical) impacted cognition as assessed on a maze battery as well as the cholinergic system tested via scopolamine mnemonic challenge and brain acetylcholinesterase activity. Middle-aged rats received either sham surgery, OVX surgery, VCD, or VCD then OVX to assess effects of removal of residual ovarian output after transitional menopause and follicular depletion. VCD-induced transitional menopause impaired learning of a spatial recent memory task; surgical removal of residual ovarian hormones by OVX abolished this negative effect of transitional menopause. Furthermore, transitional menopause before OVX was better for memory than an abrupt loss of hormones via OVX only. Surgical ovarian hormone loss, regardless of menopause history, increased hippocampal acetylcholinesterase activity. Circulating gonadotropin and androstenedione levels were related to cognitive competence. Collectively, findings suggest that in the rat, initiation of transitional menopause before surgical ovary removal can benefit mnemonic function and could obviate some negative cognitive consequences of surgical menopause alone.

Premarin improves memory, prevents scopolamine-induced amnesia and increases number of basal forebrain choline acetyltransferase positive cells in middle-aged surgically menopausal rats

Conjugated equine estrogen (CEE) is the most commonly prescribed estrogen therapy, and is the estrogen used in the Womens Health Initiative study. While in-vitro studies suggest that CEE is neuroprotective, no study has evaluated CEEs effects on a cognitive battery and brain immunohistochemistry in an animal model. The current experiment tested whether CEE impacted: I) spatial learning, reference memory, working memory and long-term retention, as well as ability to handle mnemonic delay and interference challenges; and, II) the cholinergic system, via pharmacological challenge during memory testing and ChAT-immunoreactive cell counts in the basal forebrain. Middle-aged ovariectomized (Ovx) rats received chronic cyclic injections of either Oil (vehicle), CEE-Low (10 microg), CEE-Medium (20 microg) or CEE-High (30 microg) treatment. Relative to the Oil group, all three CEE groups showed less overnight forgetting on the spatial reference memory task, and the CEE-High group had enhanced platform localization during the probe trial. All CEE groups exhibited enhanced learning on the spatial working memory task, and CEE dose-dependently protected against scopolamine-induced amnesia with every rat receiving the highest CEE dose maintaining zero errors after scopolamine challenge. CEE also increased number of ChAT-immunoreactive neurons in the vertical diagonal band of the basal forebrain. Neither the ability to remember after a delay nor interference, nor long-term retention, was influenced by the CEE regimen used in this study. These findings are similar to those reported previously for 17 beta-estradiol, and suggest that CEE can provide cognitive benefits on spatial learning, reference and working memory, possibly through cholinergic mechanisms.

Stimulation of 5-HT1B receptors decreases cocaine- and sucrose-seeking behavior

Serotonin systems have been implicated in incentive motivation for cocaine, yet little is known about the role of 5-HT(1B) receptors in these processes. We used the extinction/reinstatement model to examine the effects of the 5-HT(1B/1A) receptor agonist, RU24969, on reinstatement of extinguished cocaine-seeking behavior. Rats trained to self-administer cocaine subsequently underwent extinction. They were then tested twice for cue and cocaine-primed reinstatement of extinguished cocaine-seeking behavior, receiving saline pretreatment 1 day and their assigned dose of RU24969 (0.3, 1.0, 3.0 mg/kg) the other day. Rats were later trained on a schedule of sucrose reinforcement in novel chambers and then tested for effects of RU24969 on cue reinstatement of sucrose-seeking behavior and locomotion. RU24969 decreased cue and cocaine reinstatement of cocaine-seeking behavior and cue reinstatement of sucrose-seeking behavior. Locomotion was increased only at the highest RU24969 dose (3 mg/kg). A subsequent experiment demonstrated that the effects of RU24969 (1 mg/kg) on extinguished cocaine-seeking behavior were reversed by the 5-HT(1B) antagonist GR127935 (3 mg/kg). These findings suggest that the effects of RU24969 on cue and cocaine reinstatement of cocaine-seeking behavior are 5-HT(1B) receptor-mediated. Overall, the results suggest that stimulation of 5-HT(1B) receptors may produce a general decrease in motivation.

Stimulation of 5-HT(1B) receptors enhances cocaine reinforcement yet reduces cocaine-seeking behavior.

Paradoxically, stimulation of 5‐HT1B receptors (5‐HT1BRs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/reinstatement model. We revisited this issue by examining the effects of a 5‐HT1BR agonist, CP94253, on cocaine reinforcement and cocaine‐primed reinstatement, predicting that CP94253 would enhance cocaine‐seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self‐administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine‐seeking behavior (operant responses without cocaine reinforcement). Next, they were pre‐treated with CP94253 (3–10 mg/kg, s.c.) and either tested for cocaine‐primed (10 or 2.5 mg/kg, i.p.) or cue‐elicited reinstatement of extinguished cocaine‐seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self‐administered cocaine doses (0–1.5 mg/kg, i.v.) were examined. Cocaine dose‐dependently reinstated cocaine‐seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue‐elicited reinstatement. In contrast, CP94253 shifted the self‐administration dose‐effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine‐seeking behavior). In subsequent control experiments, CP94253 decreased open‐arm exploration in an elevated plus‐maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5‐HT1BRs produces opposite effects on cocaine reinforcement and cocaine‐seeking behavior, and further suggest that 5‐HT1BRs may be a novel target for developing medications for cocaine dependence.

Neuroscientists as cartographers: mapping the crossroads of gonadal hormones, memory and age using animal models.

Cognitive function is multidimensional and complex, and research in multiple species indicates it is considerably impacted by age and gonadal hormone milieu. One domain of cognitive function particularly susceptible to age-related decrements is spatial memory. Gonadal hormones can alter spatial memory, and they are potent modulators of brain microstructure and function in many of the same brain areas affected by aging. In this paper, we review decades of animal and human literature to support a tertiary model representing interactions between gonadal hormones, spatial cognition and age given that: 1) gonadal hormones change with age, 2) age impacts spatial learning and memory, and 3) gonadal hormones impact spatial learning and memory. While much has been discovered regarding these individual tenets, the compass for future aging research points toward clarifying the interactions that exist between these three points, and understanding mediating variables. Indeed, identifying and aligning the various components of the complex interactions between these tenets, including evaluations using basic science, systems, and clinical perspectives, is the optimal approach to attempt to converge the many findings that may currently appear contradictory. In fact, as discoveries are being made it is becoming clear that the findings across studies that appear contradictory are not contradictory at all. Rather, there are mediating variables that are influencing outcome and affecting the extent, and even the direction, of the effects that gonadal hormones have on cognition during aging. These mediating variables are just starting to be understood. By aligning basic scientific discoveries with clinical interpretations, we can maximize the opportunities for discoveries and subsequent interventions to allow individuals to “optimize their aging” and find their own map to cognitive health as aging ensues.

Effect of schedule of reinforcement on cue-elicited reinstatement of cocaine-seeking behavior.

Cocaine-associated cues can elicit incentive motivational effects that drive cocaine-seeking behavior and contribute to relapse. The extinction/reinstatement model is commonly used to measure these effects in animals. This study examined the influence of training and testing schedules of reinforcement on cue-elicited reinstatement. Lever presses during training resulted in cues and cocaine (0.75 mg/kg/IV) on either continuous or partial reinforcement schedules [fixed ratio (FR) 1 or 11, variable ratio (VR) 5 or 11]. Animals then underwent extinction training, followed by a test for cue-elicited reinstatement of extinguished cocaine-seeking behavior by response-contingent cue presentations on either a continuous (FR 1) or a partial reinforcement schedule (FR 11). Partial reinforcement during training resulted in higher response rates during cue-elicited reinstatement relative to continuous reinforcement. In contrast, delivery of cues on a continuous reinforcement schedule during testing yielded higher response rates relative to delivery on a partial reinforcement schedule. Finally, the shift from a partial to a continuous reinforcement schedule across training and testing phases did not alter response rates. These findings provide important information for choosing parameters for reinstatement of drug-seeking behavior that would allow the most sensitive method to detect changes in response rate after an experimental manipulation.

An update on the cognitive impact of clinically-used hormone therapies in the female rat: Models, mazes, and mechanisms

In women, ovarian hormone loss associated with menopause has been related to cognitive decline. Hormone therapy (HT) may ameliorate some of these changes. Understanding the cognitive impact of female steroids, including estrogens, progestogens, and androgens, is key to discovering treatments that promote brain health in women. The preclinical literature has presented elegant and methodical experiments allowing a better understanding of parameters driving the cognitive consequences of ovarian hormone loss and HT. Animal models have been a valuable tool in this regard, and will be vital to future discoveries. Here, we provide an update on the literature evaluating the impact of female steroid hormones on cognition, and the putative mechanisms mediating these effects. We focus on preclinical work that was done with an eye toward clinical realities. Parameters that govern the cognitive efficacy of HT, from what we know thus far, include but are not limited to: type, dose, duration, and route of HT, age at HT initiation, timing of HT relative to ovarian hormone loss, memory type examined, menopause history, and hormone receptor status. Researchers have identified intricate relationships between some of these factors by studying their individual effects on cognition. As of late, there is increased focus on studying interactions between these variables as well as multiple hormone types when administered concomitantly. This is key to translating preclinical data to the clinic, wherein women typically have concurrent exposure to endogenous ovarian hormones as well as exogenous combination HTs, which include both estrogens and progestins. Gains in understanding the parameters of HT effects on cognition provide exciting novel avenues that can inform clinical treatments, eventually expanding the window of opportunity to optimally enhance cognition and brain health in aging women. This article is part of a Special Issue entitled Hormone Therapy.

A component of Premarin ® enhances multiple cognitive functions and influences nicotinic receptor expression

In women, ovarian hormone loss at menopause has been related to cognitive decline, and some studies suggest that estrogen-containing hormone therapy (HT) can mitigate these effects. Recently, the Womens Health Initiative study found that conjugated equine estrogens, the most commonly prescribed HT, do not benefit cognition. Isolated components of conjugated equine estrogens (tradename Premarin(®)) have been evaluated in vitro, with delta(8,9)-dehydroestrone (∆(8)E1) and equilin showing the strongest neuroprotective profiles. It has not been evaluated whether ∆(8)E1 or equilin impact cognition or the cholinergic system, which is affected by other estrogens and known to modulate cognition. Here, in middle-aged, ovariectomized rats, we evaluated the effects of ∆(8)E1 and equilin treatments on a cognitive battery and cholinergic nicotinic receptors (nAChR). Specifically, we used (125)I-labeled epibatidine binding to assay brain nicotinic receptor containing 4α and 2β subunits (α4β2-nAChR), since this nicotinic receptor subtype has been shown previously to be sensitive to other estrogens. ∆(8)E1 enhanced spatial working, recent and reference memory. ∆(8)E1 also decreased hippocampal and entorhinal cortex α4β2-nAChR expression, which was related to spatial reference memory performance. Equilin treatment did not affect spatial memory or rat α4β2-nAChR expression, and neither estrogen impacted (86)Rb(+) efflux, indicating lack of direct action on human α4β2 nAChR function. Both estrogens influenced vaginal smear profiles, uterine weights, and serum luteinizing hormone levels, analogous to classic estrogens. The findings indicate that specific isolated Premarin(®) components differ in their ability to affect cognition and nAChR expression. Taken with the works of others showing ∆(8)E1-induced benefits on several dimensions of health-related concerns associated with menopause, this body of research identifies ∆(8)E1 as a new avenue to be investigated as a potential component of HT that may benefit brain health and function during aging.

Modeling the effects of fluoxetine on food-reinforced behavior

We propose a novel method to dissociate incentive motivation from memory and motor processes in instrumental performance. Components of a multiple fixed-ratio schedule of food reinforcement were adjusted to envelop the range of response requirements that maintained lever pressing by rats. We sought to manipulate motivation for food rewards with acute administrations of various doses (0–10 mg/kg) of fluoxetine, a 5-HT reuptake inhibitor that reduces food intake. A quantitative model of fixed-ratio performance derived from Killeens (1994) Mathematical Principles of Reinforcement (MPR) provided an adequate account of data from individual rats. Decreases in response rate resulting from fluoxetine were reflected in changes in estimates of activation, indexed by MPR parameter a; estimates of working memory capacity and lever pressing duration were not systematically affected. These results support the use of MPR parameter a to index incentive motivation using multiple fixed-ratio schedules that are adjusted to individual performance.