Analysis of alternative pathways for reducing nitrogen oxide emissions.

UNLABELLED: Strategies for reducing tropospheric ozone (O3) typically include modifying combustion processes to reduce the formation of nitrogen oxides (NOx) and applying control devices that remove NOx from the exhaust gases of power plants, industrial sources and vehicles. For portions of the U.S., these traditional controls may not be sufficient to achieve the National Ambient Air Quality Standard for ozone. We apply the MARKet ALlocation (MARKAL) energy system model in a sensitivity analysis to explore whether additional NOx reductions can be achieved through extensive electrification of passenger vehicles, adoption of energy efficiency and conservation measures within buildings, and deployment of wind and solar power in the electric sector. Nationally and for each region of the country, we estimate the NOx implications of these measures. Energy efficiency and renewable electricity are shown to reduce NOx beyond traditional controls. Wide-spread light duty vehicle electrification produces varied results, with NOx increasing in some regions and decreasing in others. However, combining vehicle electrification with renewable electricity reduces NOx in all regions. IMPLICATIONS: State governments are charged with developing plans that demonstrate how air quality standards will be met and maintained. The results presented here provide an indication of the national and regional NOx reductions available beyond traditional controls via extensive adoption of energy efficiency, renewable electricity, and vehicle electrification.

Local changes in neurosteroid levels in the substantia nigra reticulata and the ventral tegmental area alter chronic ethanol withdrawal severity in male withdrawal seizure-prone mice.

BACKGROUND: Allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA receptors (GABAA Rs) that affects ethanol (EtOH) withdrawal. Finasteride (FIN), a 5α-reductase inhibitor that blocks the formation of ALLO and other GABAergic neurosteroids, alters EtOH sensitivity. Recently, we found that Withdrawal Seizure-Prone mice from the first genetic replicate (WSP-1) exhibited behavioral tolerance to the anticonvulsant effect of intrahippocampal ALLO during EtOH withdrawal and that intrahippocampal FIN significantly increased EtOH withdrawal severity. The purpose of this study was to determine whether neurosteroid manipulations in the substantia nigra reticulata (SNR) and ventral tegmental area (VTA) produced effects during EtOH withdrawal comparable to those seen with intrahippocampal ALLO and FIN. METHODS: Male WSP-1 mice were surgically implanted with bilateral guide cannulae aimed at the SNR or VTA at 2 weeks prior to EtOH vapor or air exposure for 72 hours. Initial studies examined the anticonvulsant effect of a single ALLO infusion (0, 100, or 400 ng/side) at a time corresponding to peak withdrawal in the air- and EtOH-exposed mice. Separate studies examined the effect of 4 FIN infusions (0 or 10 µg/side/d) during the development of physical dependence on the expression of EtOH withdrawal. RESULTS: ALLO infusion exerted a potent anticonvulsant effect in EtOH-naïve mice, but a diminished anticonvulsant effect during EtOH withdrawal. Administration of FIN into the SNR exerted a delayed proconvulsant effect in EtOH-naïve mice, whereas infusion into the VTA increased EtOH withdrawal duration. CONCLUSIONS: Activation of local GABAA Rs in the SNR and VTA via ALLO infusion is sufficient to exert an anticonvulsant effect in naïve mice and to produce behavioral tolerance to the anticonvulsant effect of ALLO infusion during EtOH withdrawal. Thus, EtOH withdrawal reduced sensitivity of GABAA Rs to GABAergic neurosteroids in 2 neuroanatomical substrates within the basal ganglia in WSP-1 male mice.

The development of male-oriented behavior in rams.

The sheep offers a unique mammalian model in which to study paradoxical same-sex sexual partner preferences. Variations in sexual partner preferences occur spontaneously with as many as 8% of rams in a population exhibiting a sexual preference for other rams (male-oriented). The current review presents an overview and update of the male-oriented ram model and discusses several theories that have been invoked to explain same-sex preferences in this species. Although our understanding of the biological determinants and underlying neural substrates of sexual attraction and mate selection are far from complete, compelling evidence is discussed that supports the idea that neural substrates regulating sexual partner preferences are organized during prenatal development. The challenge for future research will be to construct an integrated picture of how hormones, genes, and experience shape sexual partner preference.

Manipulation of GABAergic steroids: Sex differences in the effects on alcohol drinking- and withdrawal-related behaviors.

Alcoholism is a complex disorder that represents an important contributor to health problems worldwide and that is difficult to encompass with a single preclinical model. Additionally, alcohol (ethanol) influences the function of many neurotransmitter systems, with the interaction at gamma-aminobutyric acid(A) (GABA(A)) receptors being integral for ethanol's reinforcing and several withdrawal-related effects. Given that some steroid derivatives exert rapid membrane actions as potent positive modulators of GABA(A) receptors and exhibit a similar pharmacological profile to that of ethanol, studies in the laboratory manipulated GABAergic steroid levels and determined the impact on ethanol's rewarding- and withdrawal-related effects. Manipulations focused on the progesterone metabolite allopregnanolone (ALLO), since it is the most potent endogenous GABAergic steroid identified. The underlying hypothesis is that fluctuations in GABAergic steroid levels (and the resultant change in GABAergic inhibitory tone) alter sensitivity to ethanol, leading to changes in the positive motivational or withdrawal-related effects of ethanol. This review describes results that emphasize sex differences in the effects of ALLO and the manipulation of its biosynthesis on alcohol reward-versus withdrawal-related behaviors, with females being less sensitive to the modulatory effects of ALLO on ethanol-drinking behaviors but more sensitive to some steroid manipulations on withdrawal-related behaviors. These findings imply the existence of sex differences in the sensitivity of GABA(A) receptors to GABAergic steroids within circuits relevant to alcohol reward versus withdrawal. Thus, sex differences in the modulation of GABAergic neurosteroids may be an important consideration in understanding and developing therapeutic interventions in alcoholics.

Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice.

RATIONALE: Recent work in our laboratory documented that the "sipper" method of operant ethanol self-administration produced high ethanol intake and blood ethanol concentrations as well as the typical extinction "burst" in responding under nonreinforced conditions in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined in mice with this model. OBJECTIVES: Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of ethanol self-administration, the present study determined the effect of ALLO on the reinstatement of extinguished ethanol-seeking behavior and compared this effect to the reinstatement of responding for sucrose reward. MATERIALS AND METHODS: Separate groups of male C57BL/6 mice were trained to lever press for access to a 10% ethanol (10E) or a 5% sucrose (5S) solution. A single response requirement of 16 presses (RR16) on an active lever resulted in 30 min of continuous access to the 10E or 5S solution. After the animals responded on the RR16 schedule for 14 weeks, mice were exposed to 30 min extinction sessions where responding had no scheduled consequence. Once responding stabilized below the preextinction baseline, mice received an intraperitoneal injection of ALLO (0, 3.2, 5.6, 10, or 17 mg/kg) 15 min prior to the extinction session in a within-subjects design. RESULTS: ALLO produced a dose-dependent increase in responding under nonreinforced conditions in both the 10E and 5S groups. Additional work documented the ability of a conditioned cue light or a compound cue (light+lever retraction) to reinstate nonreinforced responding on the previously active lever. CONCLUSIONS: These findings definitively show that conditioned cues and priming with ALLO are potent stimuli for reinstating both ethanol- and sucrose-seeking behavior in C57BL/6 mice.

Marginal abatement cost curve for nitrogen oxides incorporating controls, renewable electricity, energy efficiency, and fuel switching.

A marginal abatement cost curve (MACC) traces out the relationship between the quantity of pollution abated and the marginal cost of abating each additional unit. In the context of air quality management, MACCs are typically developed by sorting control technologies by their relative cost-effectiveness. Other potentially important abatement measures such as renewable electricity, energy efficiency, and fuel switching (RE/EE/FS) are often not incorporated into MACCs, as it is difficult to quantify their costs and abatement potential. In this paper, a U.S. energy system model is used to develop a MACC for nitrogen oxides (NOx) that incorporates both traditional controls and these additional measures. The MACC is decomposed by sector, and the relative cost-effectiveness of RE/EE/FS and traditional controls are compared. RE/EE/FS are shown to have the potential to increase emission reductions beyond what is possible when applying traditional controls alone. Furthermore, a portion of RE/EE/FS appear to be cost-competitive with traditional controls. IMPLICATIONS: Renewable electricity, energy efficiency, and fuel switching can be cost-competitive with traditional air pollutant controls for abating air pollutant emissions. The application of renewable electricity, energy efficiency, and fuel switching is also shown to have the potential to increase emission reductions beyond what is possible when applying traditional controls alone.

Rapid effects of 17ß-estradiol on male copulatory behaviors are not elicited by the novel membrane active estrogenic compound STX.

Estrogens have been shown to rapidly promote male copulatory behaviors with a time-course that suggests rapid signaling events are involved. The present study tested the hypothesis that estrogen acts through a novel Gq protein-coupled membrane estrogen receptor (ER). Thus, either estradiol (E2), STX (a diphenylacrylamide compound that selectively activates a membrane ER pathway), or vehicle were administered acutely to castrated male rats that bore subcutaneous (sc) dihydrotestosterone implants to maintain genital sensitivity. Appetitive (level changes, genital investigation) and consummatory (mounts, intromissions, ejaculations) components of male sexual behavior were measured in a bilevel testing apparatus. Testing showed that E2 treatment promoted olfactory and mounting behaviors, but had no effect on motivation as measured by anticipatory level changes. STX treatment showed no effect on either component of male sexual behavior. These results support previous results that showed that E2 can rapidly affect male sexual behaviors but fail to support a role for the specific membrane-initiated pathway activated by STX.

Localization of brain 5α-reductase messenger RNA in mice selectively bred for high chronic alcohol withdrawal severity.

Several lines of evidence suggest that fluctuations in endogenous levels of the γ-aminobutyric acid (GABA)ergic neurosteroid allopregnanolone (ALLO) represent one mechanism for regulation of GABAergic inhibitory tone in the brain, with an ultimate impact on behavior. Consistent with this idea, there was an inverse relationship between ALLO levels and symptoms of anxiety and depression in humans and convulsive activity in rodents during alcohol withdrawal. Our recent studies examined the activity and expression of 5α-reductase (Srd5a1), the rate-limiting enzyme in the biosynthesis of ALLO, during alcohol withdrawal in mice selectively bred for high chronic alcohol withdrawal (Withdrawal Seizure-Prone [WSP]) and found that Srd5a1 was downregulated in the cortex and hippocampus over the time course of dependence and withdrawal. The purpose of the present studies was to extend these findings and more discretely map the regions of Srd5a1 expression in mouse brain using radioactive in situ hybridization in WSP mice that were ethanol naïve, following exposure to 72h ethanol vapor (dependent) or during peak withdrawal. In naïve animals, expression of Srd5a1 was widely distributed throughout the mouse brain, with highest expression in specific regions of the cerebral cortex, hippocampus, thalamus, hypothalamus, and amygdala. In dependent animals and during withdrawal, there was no change in Srd5a1 expression in cortex or hippocampus, which differed from our recent findings in dissected tissues. These results suggest that local Srd5a1 mRNA expression in WSP brain may not change in parallel with local ALLO content or withdrawal severity.

Sex differences in acute ethanol withdrawal severity after adrenalectomy and gonadectomy in Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mice.

Recent findings suggest that the ability of ethanol (EtOH) to increase the levels of neurosteroids with potent gamma-aminobutyric acid (GABA)ergic properties can influence measures of EtOH sensitivity. Earlier studies determined that removal of the adrenals and gonads diminished the steroidogenic effect of EtOH and significantly increased acute EtOH withdrawal severity in two inbred mouse strains that differed in withdrawal severity, suggesting the contribution of anticonvulsant GABAergic steroids to acute withdrawal in intact animals. Thus, the goal of the present study was to investigate the consequence of steroid removal on acute EtOH withdrawal through excision of the adrenals and gonads, in another genetic animal model of EtOH withdrawal differences, the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines. Male and female WSP and WSR mice underwent surgical removal of the adrenals and gonads or no organ removal (SHAM). One to 2 weeks later, baseline handling-induced convulsions (HICs) were assessed, mice were given a 4 g/kg dose of EtOH, and HICs were measured hourly for 12 h and then at 24 h. The combination surgery significantly increased EtOH withdrawal in WSP and WSR female mice, as measured by area under the curve (AUC) and peak HIC scores. The AUC was significantly positively correlated with plasma corticosterone levels and significantly negatively correlated with progesterone levels. In contrast, surgical status did not alter withdrawal severity in male WSP and WSR mice. Overall, the increase in acute EtOH withdrawal severity in female WSP and WSR mice after adrenalectomy and gonadectomy corroborate our recent evidence that withdrawal from a high dose of EtOH can be modulated by anticonvulsant steroids produced in the periphery.

The neurosteroid environment in the hippocampus exerts bi-directional effects on seizure susceptibility in mice.

The progesterone derivative allopregnanolone (ALLO) rapidly potentiates gamma-aminobutyric acid(A) (GABA(A)) receptor mediated inhibition. The present studies determined whether specific manipulation of neurosteroid levels in the hippocampus would alter seizure susceptibility in an animal model genetically susceptible to severe ethanol (EtOH) withdrawal, Withdrawal Seizure-Prone (WSP) mice. Male WSP mice were surgically implanted with bilateral guide cannulae aimed at the CA1 region of the hippocampus one week prior to measuring seizure susceptibility to the convulsant pentylenetetrazol (PTZ), given via timed tail vein infusion. Bilateral intra-hippocampal infusion of ALLO (0.1 microg/side) was anticonvulsant, increasing the threshold dose of PTZ for onset to myoclonic twitch and face and forelimb clonus by 2- to 3-fold. In contrast, infusion of the 5 alpha-reductase inhibitor finasteride (FIN; 2 microg/side), which decreases endogenous ALLO levels, exhibited a proconvulsant effect. During withdrawal from chronic EtOH exposure, WSP mice were tolerant to the anticonvulsant effect of intra-hippocampal ALLO infusion, consistent with published results following systemic injection. Finally, administration of intra-hippocampal FIN given only during the development of physical dependence significantly increased EtOH withdrawal severity, measured by handling-induced convulsions. These findings are the first demonstration that bi-directional manipulation of hippocampal ALLO levels produces opposite behavioral consequences that are consistent with alterations in GABAergic inhibitory tone in drug-naive mice. Importantly, EtOH withdrawal rendered WSP mice less sensitive to ALLO's anticonvulsant effect and more sensitive to FIN's proconvulsant effect, suggesting an alteration in the sensitivity of hippocampal GABA(A) receptors in response to fluctuations in GABAergic neurosteroids during ethanol withdrawal.