Maria Hadjimarkou | University Of Nicosia Cyprus (original) (raw)

Papers by Maria Hadjimarkou

Journal of Pharmacology and Experimental Therapeutics, 2002

Ventricular administration of the opioid dynorphin A 1-17 induces feeding in rats. Because its ph... more Ventricular administration of the opioid dynorphin A 1-17 induces feeding in rats. Because its pharmacological characterization has not been fully identified, the present study examined whether a dose-response range of general and selective opioid antagonists as well as antisense oligodeoxynucleotide (AS ODN) opioid probes altered daytime feeding over a 4-h time course elicited by dynorphin. Dynorphin-induced feeding was significantly reduced by a wide range of doses (5-80 nmol i.c.v.) of the selective 1 -opioid antagonist nor-binaltorphamine. Correspondingly, AS ODN probes directed against either exons 1 and 2, but not 3 of the -opioid receptor clone (KOR-1) reduced dynorphin-induced feeding, whereas a missense oligodeoxynucleotide control probe was ineffective. Furthermore, AS ODN probes directed against either exons 1 or 2, but not 3 of the 3 -like opioid receptor clone (KOR-3/ORL-1) also attenuated dynorphin-induced feeding. Although the selective -antagonist ␤-funaltrexamine (20 -80 nmol) reduced dynorphininduced feeding, an AS ODN probe directed only against exon 1 of the -opioid receptor clone was transiently effective. Neither general (naltrexone, 80 nmol) nor ␦ (naltrindole, 80 nmol)selective opioid antagonists were particularly effective in reducing dynorphin-induced feeding, and an AS ODN probe targeting the individual exons of the ␦-opioid receptor clone failed to significantly reduce dynorphin-induced feeding. These converging antagonist and AS ODN data firmly implicate the 1 -opioid receptor and the KOR-1 and KOR-3/ORL-1 opioid receptor genes in the mediation of dynorphin-induced feeding.

The Journal of pharmacology and experimental therapeutics, 2001

Ventricular administration of the opioid beta END induces feeding in rats. Since its pharmacologi... more Ventricular administration of the opioid beta END induces feeding in rats. Since its pharmacological characterization has not been fully identified, the present study examined whether equimolar doses of general and selective opioid antagonists as well as AS ODN opioid probes altered spontaneous daytime feeding over a 4-h time course elicited by beta END. beta END-induced feeding was significantly reduced by moderate (20--40-nmol, i.c.v.) doses of general (naltrexone) opioid antagonists, and lower (0.5--40-nmol) doses of selective mu (beta-funaltrexamine)-antagonists. Correspondingly, AS ODN probes directed against either exons 1, 3, or 4, but not exon 2, of the mu-opioid receptor clone reduced beta END-induced feeding; a missense ODN control probe was ineffective. The delta-antagonist Nti (20-40 nmol) reduced beta END-induced feeding to a lesser degree, and AS ODN probes targeting exon 1, but not 2 or 3, of the delta-opioid receptor clone significantly reduced beta END-induced feedi...

Peptides, 2002

This paper is the twenty-fourth installment of the annual review of research concerning the opiat... more This paper is the twenty-fourth installment of the annual review of research concerning the opiate system. It summarizes papers published during 2001 that studied the behavioral effects of the opiate peptides and antagonists. The particular topics covered this year include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology(Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

Peptides, 2002

This paper is the twenty-fourth installment of the annual review of research concerning the opiat... more This paper is the twenty-fourth installment of the annual review of research concerning the opiate system. It summarizes papers published during 2001 that studied the behavioral effects of the opiate peptides and antagonists. The particular topics covered this year include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology(Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

Peptides, 2003

This paper is the twenty-fifth consecutive installment of the annual review of research concernin... more This paper is the twenty-fifth consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2002 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

Journal of Pharmacology and Experimental Therapeutics, 2004

Central administration of general and selective opioid receptor subtype antagonists in the rat ha... more Central administration of general and selective opioid receptor subtype antagonists in the rat has revealed a substantial role for mu, a moderate role for kappa, and a minimal role for delta receptors in the mediation of deprivation-induced feeding. Antisense probes directed against the kappa opioid receptor (KOP), nociceptin opioid receptor (NOP), and delta opioid receptor (DOP) genes in rats result in reductions similar to kappa and delta antagonists, whereas antisense probes directed against the mu opioid receptor (MOP) gene produced modest reductions relative to mu antagonists, suggesting that isoforms of the MOP gene may mediate deprivation-induced feeding. Since these isoforms were initially identified in mice, the present study compared the effects of general and selective opioid receptor antagonists on deprivation-induced feeding in rats and mice and antisense probes directed against exons of the MOP, DOP, KOP, and NOP genes on deprivation-induced feeding in the mouse. Food-deprived (12 and 24 h) rats and mice displayed similar profiles of reductions in deprivation-induced feeding following general, mu, and kappa opioid antagonists. In contrast, mice, but not rats, displayed reductions in deprivation-induced intake following delta antagonism as well as DOP antisense probes, suggesting a species-specific role for the delta receptor. Antisense probes directed against the KOP and NOP genes also reduced deprivation-induced intake in mice in a manner similar to kappa antagonism. However, the significant reductions in deprivation-induced feeding following antisense probes directed against either exons 2, 4, 7, 8, or 13 of the MOP gene were modest compared with mu antagonism, suggesting a role for multiple mu-mediated mechanisms.

Endocrine, 2005

25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression m... more 25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression may play a role in the behavioral alterations resulting from congenital hypothyroidism.

Endocrine, 2005

25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression m... more 25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression may play a role in the behavioral alterations resulting from congenital hypothyroidism.

Synapse, 2009

Opioid agonists and antagonists respectively increase and decrease food intake. That selective mu... more Opioid agonists and antagonists respectively increase and decrease food intake. That selective mu opioid antagonists are more effective than antisense probes directed against the mu opioid receptor (MOR-1) gene in reducing deprivationinduced feeding suggests a role for isoforms. Both food restriction and deprivation alter protein and mRNA levels of opioid peptides and receptors. Antisera directed against Exon 4 of the MOR-1-like immunoreactivity (LI) (Exon 4) clone or directed against mouse Exons 7/8 (mE7/8-LI) revealed high levels of immunoreactivity in brain nuclei related to feeding behavior. Therefore, the present study assessed MOR-1LI and mE7/8-LI in hypothalamic and extrahypothalamic sites in rats exposed to ad libitum feeding, food restriction (2, 7, 14 days), or food deprivation (24, 48 h). MOR-1-LI displayed robust reactivity, but was insensitive to food restriction or deprivation. mE7/8-LI, both in terms of cell counts and relative optical density, was significantly and selectively increased in the dorsal and ventral parvocellular subdivisions of the hypothalamic paraventricular nucleus in food-restricted (14 days) rats, but all other restriction or deprivation regimens were ineffective in other hypothalamic nuclei. In contrast, significant and site-specific decreases in relative optical density in the rostral part of the nucleus tractus solitarius (NTS) were observed in food-restricted (2, 7 days) or food-deprived (24, 48 h) animals, but these regimens were ineffective in the other extrahypothalamic sites. This study indicates the sensitivity of this mE7/8-LI probe in the hypothalamic parvocellular paraventricular nucleus and rostral NTS to food restriction and deprivation in rats. Synapse 63:585-597, 2009. V V C 2009 Wiley-Liss, Inc. M.M.H. and C.A. contributed equally to this work.

Psychoneuroendocrinology, 2010

Methamphetamine (MA) abuse has reached epidemic proportions in the United States. Users of MA rep... more Methamphetamine (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

Nutritional Neuroscience, 2003

Male rats display significantly greater analgesic responses following morphine than female rats, ... more Male rats display significantly greater analgesic responses following morphine than female rats, with neonatal gonadal manipulations reversing the sex-dependent pattern. The present study assessed whether dose-dependent (0.0005-5 microg, icv) effects of morphine-induced feeding were sensitive to sex-dependent and neonatal gonadectomy manipulations. Sex differences in morphine-induced feeding varied as a function of morphine dose with males showing greater increases at low (0.0005 microg) doses, and females showing greater increases at high (5 microg) doses. Neonatal castration, respectively, enhanced and reduced morphine-induced feeding at very low (0.0005 microg) and low (0.005 microg) doses. In contrast, neonatal testosterone administered to females enhanced morphine-induced feeding at higher (0.5-5 microg) doses. These data indicate that sex and neonatal gonadectomy differences in morphine-induced feeding are dependent upon the dose of morphine employed.

Neurotoxicity Research, 2013

In utero exposure to cigarette smoke has severe consequences for the developing fetus, including ... more In utero exposure to cigarette smoke has severe consequences for the developing fetus, including increased risk of birth complications and behavioral and learning disabilities later in life. Evidence from animal models suggests that the cognitive deficits may be a consequence of in utero nicotine exposure in the brain during critical developmental periods. However, maternal smoking exposes the fetus to not only nicotine but also a hypoxic intrauterine environment. Thus, both nicotine and hypoxia are capable of initiating cellular cascades, leading to long-term changes in synaptic patterning that have the potential to affect cognitive functions. This study investigates the combined effect of in utero exposure to nicotine and hypoxia on neuronal and glial elements in the hippocampal CA1 field. Fetal guinea pigs were exposed in utero to normoxic or hypoxic conditions in the presence or absence of nicotine. Hypoxia increased the protein levels of matrix metalloproteinase-9 (MMP-9) and synaptophysin and decreased the neural density as measured by NeuN immunoreactivity (ir). Nicotine exposure had no effect on these neuronal parameters but dramatically increased the density of astrocytes immunopositive for glial fibrillary acidic protein (GFAP). Further investigation into the effects of in utero nicotine exposure revealed that both GFAP-ir and NeuN-ir in the CA1 field were significantly reduced in adulthood. Taken together, our data suggest that prenatal exposure to nicotine and hypoxia not only alters synaptic patterning acutely during fetal development, but that nicotine also has long-term consequences that are observed well into adulthood. Moreover, these effects most likely take place through distinct mechanisms.

Journal of Pharmacology and Experimental Therapeutics, 2004

Central administration of general and selective opioid receptor subtype antagonists in the rat ha... more Central administration of general and selective opioid receptor subtype antagonists in the rat has revealed a substantial role for mu, a moderate role for kappa, and a minimal role for delta receptors in the mediation of deprivation-induced feeding. Antisense probes directed against the kappa opioid receptor (KOP), nociceptin opioid receptor (NOP), and delta opioid receptor (DOP) genes in rats result in reductions similar to kappa and delta antagonists, whereas antisense probes directed against the mu opioid receptor (MOP) gene produced modest reductions relative to mu antagonists, suggesting that isoforms of the MOP gene may mediate deprivation-induced feeding. Since these isoforms were initially identified in mice, the present study compared the effects of general and selective opioid receptor antagonists on deprivation-induced feeding in rats and mice and antisense probes directed against exons of the MOP, DOP, KOP, and NOP genes on deprivation-induced feeding in the mouse. Food-deprived (12 and 24 h) rats and mice displayed similar profiles of reductions in deprivation-induced feeding following general, mu, and kappa opioid antagonists. In contrast, mice, but not rats, displayed reductions in deprivation-induced intake following delta antagonism as well as DOP antisense probes, suggesting a species-specific role for the delta receptor. Antisense probes directed against the KOP and NOP genes also reduced deprivation-induced intake in mice in a manner similar to kappa antagonism. However, the significant reductions in deprivation-induced feeding following antisense probes directed against either exons 2, 4, 7, 8, or 13 of the MOP gene were modest compared with mu antagonism, suggesting a role for multiple mu-mediated mechanisms.

Experimental Neurology, 2010

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopa... more Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.

European Journal of Neuroscience, 2008

Studies from multiple species, including humans, suggest that gonadal hormones, and ovarian hormo... more 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.

Endocrinology, 2014

The paucity of clinical and preclinical studies investigating sex differences in sleep has result... more The paucity of clinical and preclinical studies investigating sex differences in sleep has resulted in mixed findings as to the exact nature of these differences. Although gonadal steroids are known to modulate sleep in females, less is known about males. Moreover, little evidence exists concerning the origin of these sex differences in sleep behavior. Thus, the goal of this study was to directly compare the sensitivity of sleep behavior in male and female Sprague Dawley rats to changes in the gonadal steroid milieu and to test whether the sex differences in sleep are the result of brain sexual differentiation or differences in circulating gonadal steroids. Here we report the magnitude of change in sleep behavior induced by either estradiol (E2) or testosterone (T) was greater in females compared with males, suggesting that sleep behavior in females is more sensitive to the suppressive effects of gonadal steroids. Furthermore, we demonstrated that the organizational effects of early gonadal steroid exposure result in male-like responsivity to gonadal steroids and directly alter the activity of the ventrolateral preoptic area (VLPO), an established sleep-promoting nucleus, in adult masculinized females. Moreover, the nonaromatizable androgen dihydrotestosterone did not suppress sleep in either males or females, suggesting that the T-mediated effect in females was due to the aromatization of T into E2. Together our data suggest that, like sex behavior, sex differences in sleep follow the classical organizational/activational effects of gonadal steroids.

Brain Research, 2003

The present study examined the interrelationships between feeding responses produced by A opioid ... more The present study examined the interrelationships between feeding responses produced by A opioid receptor agonists and melanocortin-3 or 4 (MC-3/4) receptor antagonists. Feeding induced by the A-sensitive opioid peptide, h-endorphin (hEND, 10 Ag, icv) was significantly and dose-dependently reduced by pretreatment with the MC-3/4 receptor agonist, melanotan-II (MTII: 0.01 -10 nmol, icv). Moreover, the selective A opioid antagonist, h-funaltrexamine (hFNA: 2 -20 Ag, icv), significantly and dose-dependently reduced feeding and weight gain elicited by the potent MC-3/4 receptor antagonist, SHU-9119 (0.5 nmol, icv), especially at those intake periods (24 -48 h) when SHU-9119 produced maximal ingestive effects. These data extend previous findings demonstrating interactions between opioid and melanocortin receptors in the mediation of food intake. D

Journal of Pharmacology and Experimental Therapeutics, 2002

Ventricular administration of the opioid dynorphin A 1-17 induces feeding in rats. Because its ph... more Ventricular administration of the opioid dynorphin A 1-17 induces feeding in rats. Because its pharmacological characterization has not been fully identified, the present study examined whether a dose-response range of general and selective opioid antagonists as well as antisense oligodeoxynucleotide (AS ODN) opioid probes altered daytime feeding over a 4-h time course elicited by dynorphin. Dynorphin-induced feeding was significantly reduced by a wide range of doses (5-80 nmol i.c.v.) of the selective 1 -opioid antagonist nor-binaltorphamine. Correspondingly, AS ODN probes directed against either exons 1 and 2, but not 3 of the -opioid receptor clone (KOR-1) reduced dynorphin-induced feeding, whereas a missense oligodeoxynucleotide control probe was ineffective. Furthermore, AS ODN probes directed against either exons 1 or 2, but not 3 of the 3 -like opioid receptor clone (KOR-3/ORL-1) also attenuated dynorphin-induced feeding. Although the selective -antagonist ␤-funaltrexamine (20 -80 nmol) reduced dynorphininduced feeding, an AS ODN probe directed only against exon 1 of the -opioid receptor clone was transiently effective. Neither general (naltrexone, 80 nmol) nor ␦ (naltrindole, 80 nmol)selective opioid antagonists were particularly effective in reducing dynorphin-induced feeding, and an AS ODN probe targeting the individual exons of the ␦-opioid receptor clone failed to significantly reduce dynorphin-induced feeding. These converging antagonist and AS ODN data firmly implicate the 1 -opioid receptor and the KOR-1 and KOR-3/ORL-1 opioid receptor genes in the mediation of dynorphin-induced feeding.

The Journal of pharmacology and experimental therapeutics, 2001

Ventricular administration of the opioid beta END induces feeding in rats. Since its pharmacologi... more Ventricular administration of the opioid beta END induces feeding in rats. Since its pharmacological characterization has not been fully identified, the present study examined whether equimolar doses of general and selective opioid antagonists as well as AS ODN opioid probes altered spontaneous daytime feeding over a 4-h time course elicited by beta END. beta END-induced feeding was significantly reduced by moderate (20--40-nmol, i.c.v.) doses of general (naltrexone) opioid antagonists, and lower (0.5--40-nmol) doses of selective mu (beta-funaltrexamine)-antagonists. Correspondingly, AS ODN probes directed against either exons 1, 3, or 4, but not exon 2, of the mu-opioid receptor clone reduced beta END-induced feeding; a missense ODN control probe was ineffective. The delta-antagonist Nti (20-40 nmol) reduced beta END-induced feeding to a lesser degree, and AS ODN probes targeting exon 1, but not 2 or 3, of the delta-opioid receptor clone significantly reduced beta END-induced feedi...

Peptides, 2002

This paper is the twenty-fourth installment of the annual review of research concerning the opiat... more This paper is the twenty-fourth installment of the annual review of research concerning the opiate system. It summarizes papers published during 2001 that studied the behavioral effects of the opiate peptides and antagonists. The particular topics covered this year include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology(Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

Peptides, 2002

This paper is the twenty-fourth installment of the annual review of research concerning the opiat... more This paper is the twenty-fourth installment of the annual review of research concerning the opiate system. It summarizes papers published during 2001 that studied the behavioral effects of the opiate peptides and antagonists. The particular topics covered this year include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology(Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

Peptides, 2003

This paper is the twenty-fifth consecutive installment of the annual review of research concernin... more This paper is the twenty-fifth consecutive installment of the annual review of research concerning the endogenous opioid system, now spanning over a quarter-century of research. It summarizes papers published during 2002 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

Journal of Pharmacology and Experimental Therapeutics, 2004

Central administration of general and selective opioid receptor subtype antagonists in the rat ha... more Central administration of general and selective opioid receptor subtype antagonists in the rat has revealed a substantial role for mu, a moderate role for kappa, and a minimal role for delta receptors in the mediation of deprivation-induced feeding. Antisense probes directed against the kappa opioid receptor (KOP), nociceptin opioid receptor (NOP), and delta opioid receptor (DOP) genes in rats result in reductions similar to kappa and delta antagonists, whereas antisense probes directed against the mu opioid receptor (MOP) gene produced modest reductions relative to mu antagonists, suggesting that isoforms of the MOP gene may mediate deprivation-induced feeding. Since these isoforms were initially identified in mice, the present study compared the effects of general and selective opioid receptor antagonists on deprivation-induced feeding in rats and mice and antisense probes directed against exons of the MOP, DOP, KOP, and NOP genes on deprivation-induced feeding in the mouse. Food-deprived (12 and 24 h) rats and mice displayed similar profiles of reductions in deprivation-induced feeding following general, mu, and kappa opioid antagonists. In contrast, mice, but not rats, displayed reductions in deprivation-induced intake following delta antagonism as well as DOP antisense probes, suggesting a species-specific role for the delta receptor. Antisense probes directed against the KOP and NOP genes also reduced deprivation-induced intake in mice in a manner similar to kappa antagonism. However, the significant reductions in deprivation-induced feeding following antisense probes directed against either exons 2, 4, 7, 8, or 13 of the MOP gene were modest compared with mu antagonism, suggesting a role for multiple mu-mediated mechanisms.

Endocrine, 2005

25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression m... more 25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression may play a role in the behavioral alterations resulting from congenital hypothyroidism.

Endocrine, 2005

25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression m... more 25 a a mRNA in dKO as compared to dWT animals. Such differences in RORa a a a a mRNA expression may play a role in the behavioral alterations resulting from congenital hypothyroidism.

Synapse, 2009

Opioid agonists and antagonists respectively increase and decrease food intake. That selective mu... more Opioid agonists and antagonists respectively increase and decrease food intake. That selective mu opioid antagonists are more effective than antisense probes directed against the mu opioid receptor (MOR-1) gene in reducing deprivationinduced feeding suggests a role for isoforms. Both food restriction and deprivation alter protein and mRNA levels of opioid peptides and receptors. Antisera directed against Exon 4 of the MOR-1-like immunoreactivity (LI) (Exon 4) clone or directed against mouse Exons 7/8 (mE7/8-LI) revealed high levels of immunoreactivity in brain nuclei related to feeding behavior. Therefore, the present study assessed MOR-1LI and mE7/8-LI in hypothalamic and extrahypothalamic sites in rats exposed to ad libitum feeding, food restriction (2, 7, 14 days), or food deprivation (24, 48 h). MOR-1-LI displayed robust reactivity, but was insensitive to food restriction or deprivation. mE7/8-LI, both in terms of cell counts and relative optical density, was significantly and selectively increased in the dorsal and ventral parvocellular subdivisions of the hypothalamic paraventricular nucleus in food-restricted (14 days) rats, but all other restriction or deprivation regimens were ineffective in other hypothalamic nuclei. In contrast, significant and site-specific decreases in relative optical density in the rostral part of the nucleus tractus solitarius (NTS) were observed in food-restricted (2, 7 days) or food-deprived (24, 48 h) animals, but these regimens were ineffective in the other extrahypothalamic sites. This study indicates the sensitivity of this mE7/8-LI probe in the hypothalamic parvocellular paraventricular nucleus and rostral NTS to food restriction and deprivation in rats. Synapse 63:585-597, 2009. V V C 2009 Wiley-Liss, Inc. M.M.H. and C.A. contributed equally to this work.

Psychoneuroendocrinology, 2010

Methamphetamine (MA) abuse has reached epidemic proportions in the United States. Users of MA rep... more Methamphetamine (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

Nutritional Neuroscience, 2003

Male rats display significantly greater analgesic responses following morphine than female rats, ... more Male rats display significantly greater analgesic responses following morphine than female rats, with neonatal gonadal manipulations reversing the sex-dependent pattern. The present study assessed whether dose-dependent (0.0005-5 microg, icv) effects of morphine-induced feeding were sensitive to sex-dependent and neonatal gonadectomy manipulations. Sex differences in morphine-induced feeding varied as a function of morphine dose with males showing greater increases at low (0.0005 microg) doses, and females showing greater increases at high (5 microg) doses. Neonatal castration, respectively, enhanced and reduced morphine-induced feeding at very low (0.0005 microg) and low (0.005 microg) doses. In contrast, neonatal testosterone administered to females enhanced morphine-induced feeding at higher (0.5-5 microg) doses. These data indicate that sex and neonatal gonadectomy differences in morphine-induced feeding are dependent upon the dose of morphine employed.

Neurotoxicity Research, 2013

In utero exposure to cigarette smoke has severe consequences for the developing fetus, including ... more In utero exposure to cigarette smoke has severe consequences for the developing fetus, including increased risk of birth complications and behavioral and learning disabilities later in life. Evidence from animal models suggests that the cognitive deficits may be a consequence of in utero nicotine exposure in the brain during critical developmental periods. However, maternal smoking exposes the fetus to not only nicotine but also a hypoxic intrauterine environment. Thus, both nicotine and hypoxia are capable of initiating cellular cascades, leading to long-term changes in synaptic patterning that have the potential to affect cognitive functions. This study investigates the combined effect of in utero exposure to nicotine and hypoxia on neuronal and glial elements in the hippocampal CA1 field. Fetal guinea pigs were exposed in utero to normoxic or hypoxic conditions in the presence or absence of nicotine. Hypoxia increased the protein levels of matrix metalloproteinase-9 (MMP-9) and synaptophysin and decreased the neural density as measured by NeuN immunoreactivity (ir). Nicotine exposure had no effect on these neuronal parameters but dramatically increased the density of astrocytes immunopositive for glial fibrillary acidic protein (GFAP). Further investigation into the effects of in utero nicotine exposure revealed that both GFAP-ir and NeuN-ir in the CA1 field were significantly reduced in adulthood. Taken together, our data suggest that prenatal exposure to nicotine and hypoxia not only alters synaptic patterning acutely during fetal development, but that nicotine also has long-term consequences that are observed well into adulthood. Moreover, these effects most likely take place through distinct mechanisms.

Journal of Pharmacology and Experimental Therapeutics, 2004

Central administration of general and selective opioid receptor subtype antagonists in the rat ha... more Central administration of general and selective opioid receptor subtype antagonists in the rat has revealed a substantial role for mu, a moderate role for kappa, and a minimal role for delta receptors in the mediation of deprivation-induced feeding. Antisense probes directed against the kappa opioid receptor (KOP), nociceptin opioid receptor (NOP), and delta opioid receptor (DOP) genes in rats result in reductions similar to kappa and delta antagonists, whereas antisense probes directed against the mu opioid receptor (MOP) gene produced modest reductions relative to mu antagonists, suggesting that isoforms of the MOP gene may mediate deprivation-induced feeding. Since these isoforms were initially identified in mice, the present study compared the effects of general and selective opioid receptor antagonists on deprivation-induced feeding in rats and mice and antisense probes directed against exons of the MOP, DOP, KOP, and NOP genes on deprivation-induced feeding in the mouse. Food-deprived (12 and 24 h) rats and mice displayed similar profiles of reductions in deprivation-induced feeding following general, mu, and kappa opioid antagonists. In contrast, mice, but not rats, displayed reductions in deprivation-induced intake following delta antagonism as well as DOP antisense probes, suggesting a species-specific role for the delta receptor. Antisense probes directed against the KOP and NOP genes also reduced deprivation-induced intake in mice in a manner similar to kappa antagonism. However, the significant reductions in deprivation-induced feeding following antisense probes directed against either exons 2, 4, 7, 8, or 13 of the MOP gene were modest compared with mu antagonism, suggesting a role for multiple mu-mediated mechanisms.

Experimental Neurology, 2010

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopa... more Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.

European Journal of Neuroscience, 2008

Studies from multiple species, including humans, suggest that gonadal hormones, and ovarian hormo... more 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.

Endocrinology, 2014

The paucity of clinical and preclinical studies investigating sex differences in sleep has result... more The paucity of clinical and preclinical studies investigating sex differences in sleep has resulted in mixed findings as to the exact nature of these differences. Although gonadal steroids are known to modulate sleep in females, less is known about males. Moreover, little evidence exists concerning the origin of these sex differences in sleep behavior. Thus, the goal of this study was to directly compare the sensitivity of sleep behavior in male and female Sprague Dawley rats to changes in the gonadal steroid milieu and to test whether the sex differences in sleep are the result of brain sexual differentiation or differences in circulating gonadal steroids. Here we report the magnitude of change in sleep behavior induced by either estradiol (E2) or testosterone (T) was greater in females compared with males, suggesting that sleep behavior in females is more sensitive to the suppressive effects of gonadal steroids. Furthermore, we demonstrated that the organizational effects of early gonadal steroid exposure result in male-like responsivity to gonadal steroids and directly alter the activity of the ventrolateral preoptic area (VLPO), an established sleep-promoting nucleus, in adult masculinized females. Moreover, the nonaromatizable androgen dihydrotestosterone did not suppress sleep in either males or females, suggesting that the T-mediated effect in females was due to the aromatization of T into E2. Together our data suggest that, like sex behavior, sex differences in sleep follow the classical organizational/activational effects of gonadal steroids.

Brain Research, 2003

The present study examined the interrelationships between feeding responses produced by A opioid ... more The present study examined the interrelationships between feeding responses produced by A opioid receptor agonists and melanocortin-3 or 4 (MC-3/4) receptor antagonists. Feeding induced by the A-sensitive opioid peptide, h-endorphin (hEND, 10 Ag, icv) was significantly and dose-dependently reduced by pretreatment with the MC-3/4 receptor agonist, melanotan-II (MTII: 0.01 -10 nmol, icv). Moreover, the selective A opioid antagonist, h-funaltrexamine (hFNA: 2 -20 Ag, icv), significantly and dose-dependently reduced feeding and weight gain elicited by the potent MC-3/4 receptor antagonist, SHU-9119 (0.5 nmol, icv), especially at those intake periods (24 -48 h) when SHU-9119 produced maximal ingestive effects. These data extend previous findings demonstrating interactions between opioid and melanocortin receptors in the mediation of food intake. D