During the early postpartum period or following estrogen/progesterone administration, pups elicit maternal behavior accompanied by a robust dopamine (DA) response in the nucleus accumbens (NAC) of female rats (Afonso et al., 2009). To determine whether DA responds to ostensibly "salient" stimuli in the absence of consummatory behaviors, we examined NAC shell DA responses during restricted (stimuli placed in a perforated box), and unrestricted access to pup and food stimuli. Microdialysis samples were collected from female rats that were either cycling and postpartum (Experiment 1), or after ovariectomy and treated with empty and hormone-filled capsules (Experiment 2). Relative to nonprimed controls, hormonally primed females had suppressed basal DA concentrations and facilitated pup-evoked DA responses, regardless of stimulus access condition. In contrast, food-evoked DA responses were unchanged by hormonal priming and were greater when females consumed food compared with distal (restricted) exposure to food. During pup and food restriction conditions, the lack of any "appetitive" behavioral differences, even in pup experienced postpartum females, was surprising. In Experiment 3, we confirmed that postpartum dams allocated time equivalently to restricted pup and food stimuli, even after pup deprivation. This was in sharp contrast to the effects of deprivation during the unrestricted access phase. Together, our data demonstrated that, in hormonally primed females, distal pup cues could evoke DA responses without prior stimulus experience, ongoing maternal (behavioral) responses, or clear evidence of robust pup saliency. The results suggest that NAC DA response reflects a state of responsiveness related to basal DA suppression in the hormonally primed female rat.
Estrogen has been shown to enhance the effects of antipsychotics in humans. To investigate the mechanisms of how this may occur, the current study examined estradiol's effects on dopaminergic transmission and behavior in amphetamine-sensitized and non-sensitized female rats. Sixty-four ovariectomized female Sprague-Dawley rats were used for this study. Half of the rats were sensitized to four once-daily injections of 1 mg/kg amphetamine and the other half served as controls. Rats received chronic administration of either low-dose haloperidol (0.25 mg/kg/day) or saline vehicle via osmotic minipumps implanted subcutaneously. The groups were further subdivided with respect to estradiol treatment: low chronic estrogen (subcutaneous estradiol implant, 0.36 mg/pellet: 90-day release, plus an additional oil vehicle injection every second day) and high pulsatile estrogen (subcutaneous estradiol implant plus an additional 10 μg/kg estradiol injection every second day). Motor activity was assessed at day 2 and day 12 during haloperidol treatment, while nucleus accumbens dopamine availability was assessed via microdialysis 10 days into antipsychotic treatment. Haloperidol treatment along with high, but not low, estradiol replacement was effective in reducing amphetamine-induced locomotor activity in sensitized rats. High estradiol treatment also augmented the effects of chronic haloperidol in reducing dopaminergic release in sensitized rats. These data suggest that estradiol levels affect both the behavioral and the dopamine responses to chronic antipsychotic treatment.
Studies in both rodents and humans have made much progress in shedding light on how fluctuations in ovarian hormones can affect memory in women across the lifespan. Specifically, advances in neuroscience have identified multiple memory systems that are each mediated by different brain areas. Two memory systems used to navigate an environment are 'place' and 'response' memory. They are defined as either using an allocentric strategy: using a spatial or cognitive map of the surroundings, or an egocentric strategy: using habitual-turns/ movements, respectively. Studies in neuroendocrinology have shown that estrogen levels can bias a female to use one memory system over another to solve a task, such that high estrogen levels are associated with using place memory and low levels with using response memory. Furthermore, recent advances in identifying and localizing estrogen receptors in the rodent brain are uncovering which brain regions are affected by estrogen and providing insight into how hormonal fluctuations during the menstrual cycle, pregnancy, and menopause might affect which memory system is facilitated or impaired in women at different life stages. These studies can help point the way to improving cognitive health in women. Estrogen and cognitionModern Western society is not only marked by longer life expectancies, but young women are also waiting longer to have children and having fewer of them, therefore having more menstrual cycles in their lifetimes than ever before. Progesterone (P) and 17β-estradiol (E2; the most potent of the estrogens during reproductive years) vary across the menstrual cycle in a consistent and fluctuating manner.During the first half of the cycle, or follicular phase, E2 and P levels are low; E2 levels then start to increase steadily at the end of menstruation, reaching a peak in the middle of the menstrual cycle, right before ovulation occurs. This is followed by the luteal phase, when E2 levels plateau while P levels increase and peak until menstruation begins again (Figure 1). Thus, E2 and P work hand in hand across a woman's cycle to orchestrate menstruation, ovulation, and conception.However, these hormones appear to be exerting other effects on the female brain, which could be subject to subtle changes as hormone levels fluctuate over time. human menstrual cycle (top panel) and the ~4 day rat estrous cycle (bottom panel). Human menstrual cycle begins with a follicular (mentrual and preovulatory) phase, followed by ovulation, and ends with a luteal phase (spanning end of ovulation to pre-menstrual phase).
The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90-100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapid-sampling microdialysis (1 sample/min) and high-performance liquid chromatography-tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non-dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5-s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5-s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive.
Studies using in vivo microdialysis have shown that 17β-estradiol (E2) increases dopamine (DA) transmission in the dorsal striatum. Both systemic administration of E2 and local infusion into the dorsal striatum rapidly enhance amphetamine-induced DA release. However, it is not known to what degree these effects reflect tonic and/or phasic DA release. It was hypothesized that E2 acts directly within the DS to rapidly increase phasic DA transmission. In urethane-anesthetized (1.5mL/kg) female rats, we used fast-scan cyclic voltammetry to study the effects of E2 on phasic, electrically-evoked release of DA in the dorsal striatum. Rats were ovariectomized and implanted with a silastic tube containing 5% E2 in cholesterol, previously shown to mimic low physiological serum concentrations of∼20-25pg/mL. DA release was evoked every 1min by delivering biphasic electrical stimulation in the substantia nigra. Local infusions of E2 (244.8pg/μl) into the dorsal striatum increased the amplitude of the electrically evoked DA transients. Behaviorally significant stimuli and events trigger phasic release of DA. The present findings predict that E2 would boost such signaling in behaving subjects.
The priming effect of rewards is a boost in the vigor of reward seeking resulting from the previous receipt of a reward. Extensive work has been carried out on the priming effect of electrical brain stimulation, but much less research exists on the priming effect of natural rewards, such as food. While both reinforcement and motivation are linked with dopamine transmission in the brain, the priming effect of rewards does not appear to be dopamine‐dependent. In the present study, an operant method was developed to measure the priming effect of food and then applied to investigate whether it is affected by dopamine receptor antagonism. Long‐Evans rats were administered saline or one of the three doses (0.01, 0.05, 0.075 mg/kg) of the dopamine D1 receptor family antagonist, SCH23390, or the dopamine D2 receptor family antagonist, eticlopride. Although dopamine receptor antagonism affected pursuit of food, it did not eliminate the priming effect. These data suggest that despite the involvement of dopamine transmission in reinforcement and motivation, the priming effect of food does not depend on dopamine transmission.
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