Undivided trauma in a divided Cyprus: Modified emotional Stroop study.

OBJECTIVE: The purpose of the study was to examine the subliminal existence of war-related trauma in the Greek-Cypriot and Turkish-Cypriot communities in Cyprus. Previous research has demonstrated that Cypriots, regardless of their ethnicity have been affected by many psychological burdens, including anxiety and trauma related symptoms due to the wars in Cyprus (1963, 1974). The emotional Stroop task has been widely used to determine the presence of PTSD and its impact on executive functions. Hence, it was hypothesized that traumatic stress specific to the wars in Cyprus would be evident through interference of information processing of war-related words in a modified version of the Emotional Stroop Task specific to the conflicts in Cyprus. METHOD: Two versions of the modified emotional Stroop task for Cyprus (MEST-CY) were developed in the two languages (Greek and Turkish) spoken by the 2 communities, with neutral and war-related words relevant for each community. A sample of 111 Cypriots from both ethnic backgrounds (56 Turkish Cypriots, 55 Greek Cypriots) took part. RESULTS: Participants from both ethnicities showed significantly greater latency scores (interference) for war-related words compared to neutral words. CONCLUSIONS: This is the first study to show emotional trauma and changes in cognitive functioning related specifically to the wars in Cyprus, in both communities. Due to its specificity in detecting attentional bias to war-related words which are specific to Cyprus, MEST-CY can serve as a useful assessment tool for the presence of war-related PTSD and as a pre- and posttask for PTSD intervention studies. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

GPER1/GPR30 in the brain: Crosstalk with classical estrogen receptors and implications for behavior.

The GPER1/GPR30 is a membrane estrogen receptor (mER) that binds 17ß-estradiol (17ß-E) with high affinity and is thought to play a role in cancer progression and cardiovascular health. Though widespread in the central nervous system, less is known about this receptor's function in the brain. GPER1 has been shown to activate kinase cascades and calcium flux within cells rapidly, thus fitting in with the idea of being a mER that mediates non-genomic signaling by estrogens. Signaling from GPER1 has been shown to improve spatial memory, possibly via release of neurotransmitters and generation of new spines on neurons in the hippocampus. In addition, GPER1 activation contributes to behaviors that denote anxiety and to social behaviors such as social memory and lordosis behavior in mice. In the male hippocampus, GPER1 activation has also been shown to phosphorylate the classical intracellular estrogen receptor (ER)α, suggesting that crosstalk with ERα is important in the display of these behaviors, many of which are absent in ERα-null mice. In this review, we present a number of categories of such crosstalk, using examples from literature. The function of GPER1 as an ERα collaborator or as a mER in different tissues is relevant to understanding both normal physiology and abnormal pathology, mediated by estrogen signaling.

Gonadal steroid modulation of sleep and wakefulness in male and female rats is sexually differentiated and neonatally organized by steroid exposure.

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.

Differential responses of hippocampal neurons and astrocytes to nicotine and hypoxia in the fetal guinea pig.

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.

Sleep alterations in an environmental neurotoxin-induced model of parkinsonism.

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.

Methamphetamine facilitates female sexual behavior and enhances neuronal activation in the medial amygdala and ventromedial nucleus of the hypothalamus.

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 3 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 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 hydroxylase (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.

Changes in mouse mu opioid receptor Exon 7/8-like immunoreactivity following food restriction and food deprivation in rats.

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 deprivation-induced 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.

Estradiol suppresses rapid eye movement sleep and activation of sleep-active neurons in the ventrolateral preoptic area.

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.

Opioid receptor subtype antagonists differentially alter GABA agonist-induced feeding elicited from either the nucleus accumbens shell or ventral tegmental area regions in rats.

Food intake is significantly increased by administration of either GABAA (e.g., muscimol) or GABAB (e.g., baclofen) agonists into either the shell region of the nucleus accumbens (NAC) or the ventral tegmental area (VTA); these responses are selectively blocked by pretreatment with corresponding GABAA and GABAB antagonists. Previous studies found that a single dose (5 microg) of the general opioid antagonist, naltrexone reduced feeding elicited by muscimol, but not baclofen in the NAC shell, and reduced feeding elicited by baclofen, but not muscimol in the VTA. The present study compared feeding responses elicited by either muscimol or baclofen in either the VTA and NAC shell following pretreatment with equimolar doses of selective mu (0.4, 4 microg), delta (0.4, 4 microg), or kappa (0.6, 6 microg) opioid receptor subtype antagonists. Muscimol (25 ng) and baclofen (200 microg) each significantly and equi-effectively increased food intake over 4 h following VTA or NAC shell microinjections. Muscimol-induced feeding elicited from the VTA was significantly enhanced by mu or delta antagonists, and was significantly reduced by kappa antagonists. Baclofen-induced feeding elicited from the VTA was significantly reduced by mu or kappa, but not delta antagonists. Muscimol-induced feeding elicited from the NAC was significantly reduced by either mu, kappa or delta antagonists. Baclofen-induced feeding elicited from the NAC was significantly reduced by kappa or delta, but not mu antagonists. These data indicate differential opioid receptor subtype antagonist-induced mediation of GABA receptor subtype agonist-induced feeding elicited from the VTA and NAC shell. This is consistent with previously demonstrated differential GABA receptor subtype antagonist-induced mediation of opioid-induced feeding elicited from these same sites. Thus, functional relationships exist for the elaborate anatomical and physiological interactions between these two neurochemical systems in the VTA and NAC shell.

Endogenous opiates and behavior: 2002.

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).

Interrelationships between mu opioid and melanocortin receptors in mediating food intake in rats.

The present study examined the interrelationships between feeding responses produced by mu opioid receptor agonists and melanocortin-3 or 4 (MC-3/4) receptor antagonists. Feeding induced by the mu-sensitive opioid peptide, beta-endorphin (betaEND, 10 microg, i.c.v.) was significantly and dose-dependently reduced by pretreatment with the MC-3/4 receptor agonist, melanotan-II (MTII: 0.01-10 nmol, i.c.v.). Moreover, the selective mu opioid antagonist, beta-funaltrexamine (betaFNA: 2-20 mug, i.c.v.), significantly and dose-dependently reduced feeding and weight gain elicited by the potent MC-3/4 receptor antagonist, SHU-9119 (0.5 nmol, i.c.v.), 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.

Differential dose-dependent effects of central morphine treatment upon food intake in male and female rats receiving neonatal hormone manipulations.

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.

Feeding induced by food deprivation is differentially reduced by G-protein alpha-subunit antisense probes in rats.

Antisense oligodeoxynucleotide (AS ODN) probes directed against the alpha-subunit of different G-proteins have been used to differentiate feeding responses in rats elicited by different opioid agonists, including morphine, beta-endorphin and dynorphin. Furthermore, antisense probes directed against G(o)alpha, but not G(s)alpha, G(q)alpha or G(i)alpha, significantly reduced nocturnal feeding in rats. The present study examined whether food intake and weight changes elicited by 24 h of food deprivation were significantly altered by ventricular administration of antisense probes directed against either G(i)alpha(1), G(i)alpha(2), G(i)alpha(3), G(s)alpha, G(o)alpha, G(q)alpha or G(x/z)alpha as well as a control nonsense probe in rats. Deprivation-induced weight loss was significantly enhanced by antisense probes directed against G(s)alpha and G(x/z)alpha, whereas weight recovery 24 h following reintroduction of food was significantly reduced by antisense probes directed against G(i)alpha(2), G(q)alpha and G(o)alpha. Selective antisense probe effects were noted for deprivation-induced intake with G(s)alpha and G(q)alpha probes exerting the greatest reductions, G(x/z)alpha, G(i)alpha(2), and G(i)alpha(3) probes exerting lesser effects, and G(i)alpha(1) and G(o)alpha probes failing to affect deprivation-induced intake. Importantly, the nonsense control probe failed to alter deprivation-induced intake or weight. The reductions in deprivation-induced intake by AS ODN probes directed against G(s)alpha or G(q)alpha were not accompanied by any evidence of a conditioned taste aversion. These data indicate important distinctions between G-protein mediation of different effector signaling pathways mediating feeding responses elicited under natural (e.g. nocturnal feeding) and regulatory challenge (e.g. food deprivation) conditions.

Dynorphin A(1-17)-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats.

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 kappa(1)-opioid antagonist nor-binaltorphamine. Correspondingly, AS ODN probes directed against either exons 1 and 2, but not 3 of the kappa-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 kappa(3)-like opioid receptor clone (KOR-3/ORL-1) also attenuated dynorphin-induced feeding. Although the selective mu-antagonist beta-funaltrexamine (20-80 nmol) reduced dynorphin-induced feeding, an AS ODN probe directed only against exon 1 of the mu-opioid receptor clone was transiently effective. Neither general (naltrexone, 80 nmol) nor delta (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 delta-opioid receptor clone failed to significantly reduce dynorphin-induced feeding. These converging antagonist and AS ODN data firmly implicate the kappa(1)-opioid receptor and the KOR-1 and KOR-3/ORL-1 opioid receptor genes in the mediation of dynorphin-induced feeding.

Endogenous opiates and behavior: 2001.

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).