The γ-aminobutyric acid (GABA) type A receptor (GABA A R) is the major inhibitory neurotransmitter receptor in the brain. Its multiple subunits show regional, developmental, and disease-related plasticity of expression; however, the regulatory networks controlling GABA A R subunit expression remain poorly understood. We report that the seizure-induced decrease in GABA A R α1 subunit expression associated with epilepsy is mediated by the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway regulated by brain-derived neurotrophic factor (BDNF). BDNF-and seizure-dependent phosphorylation of STAT3 cause the adenosine 3′,5′-monophosphate (cAMP) response element-binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. JAK/STAT pathway inhibition prevents the seizure-induced decrease in GABA A R α1 abundance in vivo and, given that BDNF is known to increase the abundance of GABA A R α4 in a JAK/STATindependent manner, indicates that BDNF acts through at least two distinct pathways to influence GABA A R-dependent synaptic inhibition.

In the past 20 years we have learned a great deal about GABA receptor (GABAR) subtypes, and which behaviors are regulated or which drug effects are mediated by each subtype. However, the question of where GABARs involved in specific drug effects and behaviors are located in the brain remains largely unanswered. We review here recent studies taking a circuit pharmacology approach to investigate the functions of GABAR subtypes in specific brain circuits controlling fear, anxiety, learning, memory, reward, addiction, and stress-related behaviors. The findings of these studies highlight the complexity of brain inhibitory systems and the importance of taking a subtype-, circuit-, and neuronal population-specific approach to develop future therapeutic strategies using cell type-specific drug delivery.

Studies from multiple species, including humans, suggest that gonadal hormones, and ovarian hormones in particular, influence the physiology of sleep, but the mechanisms by which these hormones influence sleep behaviors are unknown. Previously, we demonstrated a 50% reduction in lipocalin-prostaglandin D synthase (L-PGDS) transcript levels, following estradiol treatment, at the level of the ventrolateral preoptic area (VLPO), a putative sleep-active nucleus. Catalytic activity of L-PGDS produces prostaglandin D(2) (PGD(2)), an endogenous somnogen. Based on our previous studies, we hypothesized that estradiol is acting via PGD(2) to suppress neuronal activity in the VLPO of females. To begin to test whether this is true, we quantified the number of Fos-immunopositive cells in hormonally manipulated male and female rats. We found that in females during the light phase, estradiol suppressed Fos expression in VLPO neurons. Interestingly, protein expression of L-PGDS followed the same pattern. Surprisingly, changes in the hormonal milieu of males had no effect. Using telemetry to record electroencephalograms from gonadally intact females, we found, in the light phase of proestrus when estradiol levels are high, a marked reduction in rapid eye movement (REM) sleep compared with the other days of the estrous cycle. However, during the dark phase of proestrus when estrogen and progesterone levels are elevated, significantly less time was spent in both non-REM and REM sleep. Thus, it seems that hormones in females play a major role in the regulation of sleep and arousal via activation of neurons in key sleep and arousal centers.

SummaryMethamphetamine (MA) abuse has reached epidemic proportions in the United States. Users of MA report dramatic increases in sexual drive that have been associated with increased engagement in risky sexual behavior leading to higher rates of sexually transmitted diseases and unplanned pregnancies. The ability of MA to enhance sexual drive in females is enigmatic since related psychostimulants like amphetamine and cocaine appear not to affect sexual drive in women, and in rodents models, amphetamine has been reported to be inhibitory to female sexual behavior. Examination of MA's effects on female sexual behavior in an animal model is lacking. Here, using a rodent model, we have demonstrated that MA enhanced female sexual behavior. MA (5mg/kg) or saline vehicle was administered once daily for three days to adult ovariectomized rats primed with ovarian steroids. MA treatment significantly increased the number of proceptive events and the lordosis response compared to hormonally-primed, saline controls. The effect of MA on the neural circuitry underlying the motivation for sexual behavior was examined using Fos immunoreactivity. In the medial amygdala and the ventromedial nucleus of the hypothalamus, nuclei implicated in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of InterestThe authors declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NIH Public Access Author ManuscriptPsychoneuroendocrinology. Author manuscript; available in PMC 2011 February 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript motivated behaviors, ovarian hormones and MA independently enhance the neuronal activation, but more striking was the significantly greater activation induced by their combined administration. Increases in dopamine neurotransmission may underlie the MA/hormone mediated increase in neuronal activation. In support of this possibility, ovarian hormones significantly increased tyrosine hyroxylase (the rate limiting enzyme in dopamine synthesis) immunoreactivity in the medial amygdala. Thus our present data suggest that the interactions of MA and ovarian hormones leads to changes in the neural substrate of key nuclei involved in mediating female sexual behaviors, and these changes may underlie MA's ability to enhance these behaviors.