Sleep-wake and diurnal modulation of nitric oxide in the perifornical-lateral hypothalamic area: real-time detection in freely behaving rats.

Nitric oxide (NO) has been implicated in the regulation of sleep. The perifornical-lateral hypothalamic area (PF-LHA) is a key wake-promoting region and contains neurons that are active during behavioral or cortical activation. Recently, we found higher levels of NO metabolites (NOx), an indirect measure of NO levels, in the PF-LHA during prolonged waking (SD). However, NO is highly reactive and diffuses rapidly and the NOx assay is not sensitive enough to detect rapid-changes in NO levels across spontaneous sleep-waking states. We used a novel Nafion®-modified Platinum (NF-PT) electrode for real-time detection of NO levels in the PF-LHA across sleep-wake cycles, dark-light phases, and during SD. Sprague-Dawley male rats were surgically prepared for chronic sleep-wake recording and implantation of NF-PT electrode into the PF-LHA. Electroencephalogram (EEG), electromyogram (EMG), and electrochemical current generated by NF-PT electrode were continuously acquired for 5-7days including one day with 3h of SD. In the PF-LHA, NO levels exhibited a waking>rapid eye movement (REM)>non-rapid eye movement (nonREM) sleep pattern (0.56±0.03µM>0.47±0.02µM>0.42±0.02µM; p<0.01). NO levels were also higher during the dark- as compared to the light-phase (0.53±0.03µM vs. 0.44±0.02µM; p<0.01). NO levels increased during 3h of SD as compared to undisturbed control (0.58±0.04µM vs. 0.47±0.01µM; p<0.05). The findings indicate that in the PF-LHA, NO is produced during behavioral or cortical activation. Since elevated levels of NO inhibits most of the PF-LHA neurons that are active during cortical activation, these findings support a hypothesis that NO produced in conjunction with the activation of PF-LHA neurons during waking/SD, inhibits the same neuronal population to promote sleep.

Mechanisms mediating effects of nitric oxide on perifornical lateral hypothalamic neurons.

The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of sleep. Recently we found that NO levels in the PF-LHA are higher during sustained waking and that NO exerts predominantly inhibitory effects, especially on PF-LHA neurons excited by tactile stimulation. The mechanisms underlying this NO-evoked inhibitory action on the PF-LHA neurons were assessed in the present study. We investigated the contributions of adenosinergic, GABAergic, and sGC-cGMP signaling mechanisms in mediating nitrergic influences on the PF-LHA neurons. The extracellular discharge activity of PF-LHA neurons was recorded in combination with microdialytic delivery of pharmacological agents adjacent to the recorded neurons in urethane-anesthetized rats. First, we quantified changes in the discharge activity of the PF-LHA neurons during the blockade of the adenosine A(1) receptor, GABA(A) receptor, and sGC-cGMP pathway. Then, we determined the efficacy of blocking adenosine A(1) receptor, GABA(A) receptor, and sGC signaling mechanisms in attenuating the inhibitory influences of 3,3-bis(aminoethyl)-1-hydroxy-1-oxo-1-triazene (a NO donor) (NOC-18), a NO donor, on the discharge activity of the PF-LHA neurons. We found that NOC-18-induced suppression in the discharge activity of PF-LHA neurons was significantly attenuated during the blockade of adenosine A(1) receptor-, GABA(A) receptor-, and sGC-cGMP-mediated signaling. These findings suggest that NO-evoked inhibition of PF-LHA neurons involves a complex mechanism including, but may not be limited to, adenosinergic, GABAergic and sGC-cGMP signaling pathways. The findings are consistent with a generalized sleep-promoting role of NO within the PF-LHA and, given the sleep-promoting roles of adenosinergic and GABAergic systems in this area, further suggest that this effect may be mediated through nitrergic interactions with other neurotransmitters and neuromodulators.

Fragrance material review on 3-phenyl-3-buten-1-yl acetate.

A toxicologic and dermatologic review of 3-phenyl-3-buten-1-yl acetate when used as a fragrance ingredient is presented. 3-Phenyl-3-buten-1-yl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 3-phenyl-3-buten-1-yl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on 2-methyl-4-phenyl-2-butyl acetate.

A toxicologic and dermatologic review of 2-methyl-4-phenyl-2-butyl acetate when used as a fragrance ingredient is presented. 2-Methyl-4-phenyl-2-butyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-methyl-4-phenyl-2-butyl acetate were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, skin sensitization, and elicitation data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on ethyl phenyl carbinyl acetate.

A toxicologic and dermatologic review of ethyl phenyl carbinyl acetate when used as a fragrance ingredient is presented. Ethyl phenyl carbinyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for ethyl phenyl carbinyl acetate were evaluated, then summarized, and includes: physical properties; acute toxicity; skin irritation; and skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Salubrinal, an endoplasmic reticulum stress blocker, modulates sleep homeostasis and activation of sleep- and wake-regulatory neurons.

Endoplasmic reticulum (ER) stress has been associated with the regulation of sleep and wake. We have previously shown that i.c.v. administration of a specific ER stress modulator, Salubrinal (SALUB), which inhibits global protein translation by blocking the dephosphorylation of eukaryotic initiation factor 2α (p-eIF2α), increased non-rapid eye movement (NREM) sleep. Here we report on the relationship between ER stress response and sleep homeostasis by measuring the amount and intensity of homeostatic recovery sleep in response to the i.c.v. administration of SALUB in adult freely behaving rats. We have also tested the hypothesis that SALUB induces sleep by activating sleep-promoting neurons and inhibiting wake-promoting neurons in the basal forebrain (BF) and hypothalamus by quantifying the effects of SALUB treatment on c-Fos expression in those neuronal groups. The present study found that i.c.v. administration of SALUB significantly modified the homeostatic sleep response. SALUB administered during sleep deprivation increased sleep intensity, indicated by slow-wave activity (SWA), during recovery sleep, whereas its administration during recovery sleep increased the amount of recovery sleep. We also found that SALUB induced c-Fos activation of GABAergic neurons in the sleep-promoting rostral median preoptic nucleus while simultaneously reducing c-Fos activation of wake-promoting lateral hypothalamic orexin-expressing neurons and magnocellular BF cholinergic neurons. The current findings suggest that ER stress pathway plays a role in the homeostatic control of NREM sleep in response to sleep deprivation and provides a mechanistic explanation for the sleep modulation by molecules signaling the need for brain protein synthesis.

Fragrance material review on benzyl acetate.

A toxicologic and dermatologic review of benzyl acetate when used as a fragrance ingredient is presented. Benzyl acetate is a member of the fragrance structural group aryl alkyl alcohol simple acid esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for benzyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, toxicokinetics, repeated dose, reproductive toxicity, genotoxicity, or carcinogenicity data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Refer Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on piperonyl acetate.

A toxicologic and dermatologic review of piperonyl acetate when used as a fragrance ingredient is presented. Piperonyl acetate is a member of the fragrance structural group aryl alkyl alcohol simple acid esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for piperonyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, toxicokinetics, and genotoxicity data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on 1,1-dimethyl-2-phenylethyl acetate.

A toxicologic and dermatologic review of 1,1-dimethyl-2-phenylethyl acetate when used as a fragrance ingredient is presented. 1,1-Dimethyl-2-phenylethyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an Aryl Alkyl Alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to 1,1-dimethyl-2-phenylethyl acetate and is not intended as a stand-alone document. Available data were evaluated, then summarized, and includes: physical properties; acute toxicity; skin irritation; mucous membrane (eye) irritation; skin sensitization; elicitation; and toxicokinetics data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on p-anisyl acetate.

A toxicologic and dermatologic review of p-anisyl acetate when used as a fragrance ingredient is presented. p-Anisyl acetate is a member of the fragrance structural group aryl alkyl alcohol simple acid esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for p-anisyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, and genotoxicity data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on 2-phenylpropyl acetate.

A toxicologic and dermatologic review of 2-phenylpropyl acetate when used as a fragrance ingredient is presented. 2-Phenylpropyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-phenylpropyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on benzyl isobutyrate.

A toxicologic and dermatologic review of benzyl isobutyrate when used as a fragrance ingredient is presented. Benzyl isobutyrate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for benzyl isobutyrate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, or skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on 1,1-dimethyl-2-phenylethyl propionate.

A toxicologic and dermatologic review of 1,1-dimethyl-2-phenylethyl propionate when used as a fragrance ingredient is presented. 1,1-Dimethyl-2-phenylethyl propionate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1,1-dimethyl-2-phenylethyl propionate were evaluated, then summarized, and includes: physical properties; acute toxicity; skin irritation; and skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (submitted for publication) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on p-isopropylbenzyl acetate.

A toxicologic and dermatologic review of p-isopropylbenzyl acetate when used as a fragrance ingredient is presented. p-Isopropylbenzyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1 to 4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for p-isopropylbenzyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, and skin sensitization data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on benzyl 2-hydroxypropionate.

A toxicologic and dermatologic review of benzyl 2-hydroxypropionate when used as a fragrance ingredient is presented. Benzyl 2-hydroxypropionate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for benzyl 2-hydroxypropionate were evaluated, then summarized, and includes: physical properties and acute toxicity data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on 1,3-dimethyl-3-phenylbutyl acetate.

A toxicologic and dermatologic review of 1,3-dimethyl-3-phenylbutyl acetate when used as a fragrance ingredient is presented. 1,3-Dimethyl-3-phenylbutyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1 to 4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1,3-dimethyl-3-phenylbutyl acetate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, and photoallergy data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on phenethyl isobutyrate.

A toxicologic and dermatologic review of phenethyl isobutyrate when used as a fragrance ingredient is presented. Phenethyl isobutyrate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate, and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for phenethyl isobutyrate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, and genotoxicity data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on (4-methoxyphenyl)methyl isobutyrate.

A toxicologic and dermatologic review of (4-methoxyphenyl)methyl isobutyrate when used as a fragrance ingredient is presented. (4-Methoxyphenyl)methyl isobutyrate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to (4-methoxyphenyl)methyl isobutyrate and is not intended as a stand-alone document. Available data were evaluated, then summarized, and includes physical properties data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on phenethyl propionate.

A toxicologic and dermatologic review of phenethyl propionate when used as a fragrance ingredient is presented. Phenethyl propionate is a member of the fragrance structural group aryl alkyl alcohol simple acid esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for phenethyl propionate were evaluated, then summarized, and includes: physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, and elicitation data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

Fragrance material review on 1,1-dimethyl-2-phenylethyl isobutyrate.

A toxicologic and dermatologic review of 1,1-dimethyl-2-phenylethyl isobutyrate when used as a fragrance ingredient is presented. 1,1-Dimethyl-2-phenylethyl isobutyrate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1,1-dimethyl-2-phenylethyl isobutyrate were evaluated, then summarized, and includes physical properties data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al., 2012 for an overall assessment of the safe use of this material and all AAASAE in fragrances.