Exercise Improves Cognitive Responses to Psychological Stress through Enhancement of Epigenetic Mechanisms and Gene Expression in the Dentate Gyrus

Background We have shown previously that exercise benefits stress resistance and stress coping capabilities. Furthermore, we reported recently that epigenetic changes related to gene transcription are involved in memory formation of stressful events. In view of the enhanced coping capabilities in exercised subjects we investigated epigenetic, gene expression and behavioral changes in 4-weeks voluntarily exercised rats. Methodology/Principal Findings Exercised and control rats coped differently when exposed to a novel environment. Whereas the control rats explored the new cage for the complete 30-min period, exercised animals only did so during the first 15 min after which they returned to sleeping or resting behavior. Both groups of animals showed similar behavioral responses in the initial forced swim session. When re-tested 24 h later however the exercised rats showed significantly more immobility behavior and less struggling and swimming. If rats were killed at 2 h after novelty or the initial swim test, i.e. at the peak of histone H3 phospho-acetylation and c-Fos induction, then the exercised rats showed a significantly higher number of dentate granule neurons expressing the histone modifications and immediate-early gene induction. Conclusions/Significance Thus, irrespective of the behavioral response in the novel cage or initial forced swim session, the impact of the event at the dentate gyrus level was greater in exercised rats than in control animals. Furthermore, in view of our concept that the neuronal response in the dentate gyrus after forced swimming is involved in memory formation of the stressful event, the observations in exercised rats of enhanced neuronal responses as well as higher immobility responses in the re-test are consistent with the reportedly improved cognitive performance in these animals. Thus, improved stress coping in exercised subjects seems to involve enhanced cognitive capabilities possibly resulting from distinct epigenetic mechanisms in dentate gyrus neurons

Insertion of carbon fragments into P(III)-N bonds in aminophosphines and aminobis(phosophines): Synthesis, reactivity and coordination chemistry of resulting phosphine oxide derivatives. Crystal and molecular structures of (Ph2P(O)CH2)(2)NR (R = Me, Pr-n, Bu-n), Ph2P(O)CH(OH)Pr-n, and cis-[MoO2Cl2{(Ph2P(O)CH2)(2)NEt-kappa O,kappa O}]

Reactions of N-aryl and N-alicyclic derivatives of aminophosphines with paraformaldehyde lead to methylene insertion into P-N bond followed by oxidation of phosphorus from the P(III) to P(V) state. When N-alkyl derivatives are reacted with paraformaldehyde, dimerization takes place to afford bis(phosphine oxide)s of the type Ph2P(O)CH2N(R)CH2P(O)Ph-2 (R = Me, Pr-n, Bu-n). Aminobis(phosphines) also undergo methylene insertion when treated with paraformaldehyde to give bis(phosphine oxides) Ph2P(O)CH2N(R)CH2P(O)Ph-2 (R = Me, Et, Pr-n, Pr-i, Bu-n) in good yield. The reaction of aminophosphines with aromatic aldehydes ArCHO leads to insertion of "ArCH" into the P-N bond to give Ph2P(O)CH(R)N(H)Ph (R = C6H5, furfuryl, o-C6H4OH), but with aliphatic aldehydes such as butanal, P-N bond cleavage takes place to afford alpha-hydroxy phosphine oxide. The reaction of aminobis(phosphines) with both aromatic and aliphatic aldehydes leads to the formation of alpha-hydroxy phosphine oxides through P-N bond cleavage whereas the reaction with furfural leads to the P-N bond insertion. The structure of the alpha-hydroxy derivative Ph2P(O)CR(H)(OH)Pr-n shows intermolecular hydrogen bonding between OH and P=O oxygen. The phosphine oxide derivatives act as bidentate ligands and form chelate complexes with Co(II), Mo(VI), Th(IV), and U(VI) derivatives. The crystal structure of the molybdenum complex, cis-[MoO2Cl2{(OPPh2CH2)(2)NEt-kappaO,kappaO}], shows the distorted octahedral geometry around Mo with two oxo groups cis to each other

Copper(I) complexes of a thioether-functionalized short-bite aminobis(phosphonite), [PhN{P(-OC(10)H(6)(mu-S)C(10)H(6)O-)}(2)]

Copper(I) complexes of short-bite aminobis(phosphonite), PhN{P(-OC(10)H(6)(mu-S)C(10)H(6)O-)}(2) (1) have been synthesized. Reactions of 1 with an excess of CuX (X = Cl, Br, and I) afforded the ligand-bridged binuclear complexes, [PhN(PR-kappa P)(2){Cu(mu-X)(MeCN)}(2)] (2, X Cl; 3, X = Br; 4, X = 1; R = -OC(10)H(6)(mu-S)C(10)H(6)O-), whereas treatment with 0.5 equiv. of [Cu(MeCN)(4)]PF(6) produces the mononuclear bischelated cationic complex, [(PhN(PR-kappa P)(2)}(2)Cu](PF(6)) (5). Single crystal X-ray structures of complexes 3 and 4 are reported. Complex 3 shows strong pi-pi stacking interactions between the naphthyl moieties, whereas complex 4 shows ligand-supported Cu center dot center dot center dot Cu metallophilic interactions. (C) 200

Synthesis and transition metal chemistry of new bromo- and alkyl substituted phosphinite ligands

Ligands Ph2P(OAr) (Ar = 2,4,6-C6H2Br3, 1; Ar = C6H3(o-OMe)(p-C3H6), 2) were prepared by treating PPh2CI with tribromo phenol and eugenol, respectively, in good yields. The reaction of Ph2P(OAr) with Pd(COD)Cl-2] in 2:1 molar ratio yielded trans-[Pd{PPh2(OAr)}Cl-2] (4) and cis-[Pd{PPh2(OAr)}Cl-2] (5), respectively. The chloro-bridged dipalladium complex [Pd-2{PPh2(OAr)}(2)Cl-4 (6) was obtained in the 11 reaction between 2 and [Pd(COD)Cl-2], along with 5 as a minor product. Mononuclear complexes, [Au {PPh2(OAr)}Cl] (Ar = 2,4,6-C6H2Br3, 7; Ar = C6H3(o-OMe](p-C3H5), 8) and [(Ru(eta(6)-p-cym){PPh2(OAr)Cl (2)} (9) were prepared by reacting ligands 1 and 2 with [AuCl(SMe2)] and [(Ru(eta(6)-p-cym)Cl-2](2), respectively. All the complexes were characterized by P-31. H-1 NMR and elemental analyses data. (C) 2012 Elsevier Ltd. All rights reserved

Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala κ-Opioid Receptors

Chronic intermittent alcohol vapor exposure leads to increased dynorphin (DYN) A-like peptide expression and heightened kappa-opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA) and these neuroadaptive responses differentiate alcohol-dependent from non-dependent phenotypes. Important for therapeutic development efforts is understanding the nature of the stimulus that drives dependence-like phenotypes such as escalated alcohol self-administration. Accordingly, the present study examined the impact of intra-CeA KOR antagonism on escalated operant alcohol self-administration and physiological withdrawal symptoms during acute withdrawal and protracted abstinence in rats previously exposed to chronic intermittent alcohol vapor. Following operant training, rats were implanted with intra-CeA guide cannula and exposed to long-term intermittent alcohol vapor exposure that resulted in escalated alcohol self-administration and elevated physiological withdrawal signs during acute withdrawal. Animals received intra-CeA infusions of the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 2, 4, or 6 μg) prior to operant alcohol self-administration sessions and physiological withdrawal assessment during acute withdrawal and protracted abstinence. The results indicated that site-specific KOR antagonism in the CeA ameliorated escalated alcohol self-administration during both acute withdrawal and protracted abstinence test sessions, whereas KOR antagonism had no effect on physiological withdrawal scores at either time point. These results dissociate escalated alcohol self-administration from physiological withdrawal symptoms in relation to KOR signaling in the CeA and help clarify the nature of the stimulus that drives escalated alcohol self-administration during acute withdrawal and protracted abstinence

Affective Cue-Induced Escalation of Alcohol Self-Administration and Increased 22-kHz Ultrasonic Vocalizations during Alcohol Withdrawal: Role of Kappa-Opioid Receptors

Negative affect promotes dysregulated alcohol consumption in non-dependent and alcohol-dependent animals, and cues associated with negative affective states induce withdrawal-like symptoms in rats. This study was designed to test the hypotheses that: (1) the kappa-opioid receptor (KOR) system mediates phenotypes related to alcohol withdrawal and withdrawal-like negative affective states and (2) cues associated with negative affective states would result in dysregulated alcohol consumption when subsequently presented alone. To accomplish these goals, intracerebroventricular infusion of the KOR antagonist nor-binaltorphimine (nor-BNI) was assessed for the ability to attenuate the increase in 22-kHz ultrasonic vocalizations (USVs) associated with alcohol withdrawal and KOR activation in adult male wistar rats. Furthermore, cues associated with a KOR agonist-induced negative affective state were assessed for the ability to dysregulate alcohol consumption and the efficacy of intracerebroventricular KOR antagonism to reduce such dysregulation was evaluated. KOR antagonism blocked the increased number of 22-kHz USVs observed during acute alcohol withdrawal and a KOR agonist (U50,488) resulted in a nor-BNI reversible increase in 22-kHz USVs (mimicking an alcohol-dependent state). Additionally, cues associated with negative affective states resulted in escalated alcohol self-administration, an effect that was nor-BNI sensitive. Taken together, this study implicates negative affective states induced by both alcohol withdrawal and conditioned stimuli as being produced, in part, by activity of the DYN/KOR system

Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence

The purpose of this study was to test the hypothesis that activation of the dynorphin/kappa (kappa)-opioid system has a role in the increased consumption of ethanol in dependent animals. The effects of three opioid receptor antagonists with different effects on opioid receptors, naltrexone, nalmefene, and nor-binaltorphimine (nor-BNI), were compared in their ability to decrease ethanol self-administration in nondependent and ethanol-dependent male Wistar rats. Nalmefene and naltrexone are both opioid receptor ligands with comparable molecular weights and pharmacokinetic profiles, but differing specificity for the three opioid receptor subtypes at low doses, while nor-BNI is a selective kappa-opioid receptor antagonist. Dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 h per day. Subsequent to dependence induction, nalmefene, naltrexone, and nor-BNI were tested for their ability to modulate self-administration of ethanol in vapor-exposed and control rats. The results indicated that both nalmefene and naltrexone induced a significant dose-dependent decrease in the number of lever presses for ethanol in both groups of animals. However, in ethanol-dependent animals, nalmefene was significantly more effective in suppressing ethanol intake than naltrexone. Nor-BNI selectively attenuated ethanol-dependent self-administration while leaving nondependent ethanol self-administration intact. Because naltrexone is primarily selective for the mu-opioid receptor, and nalmefene is primarily selective for the mu- and kappa-opioid receptor subtypes, the fact that nalmefene demonstrates more suppression in dependent animals suggests that opioid systems distinct from the mu-regulated portion may be involved in the increased drinking seen during withdrawal in dependent animals. The results with nor-BNI confirm that kappa-opioid receptor antagonism selectively decreases dependence-induced ethanol self-administration, which supports the hypothesis that dynorphin/kappa-opioid systems are dysregulated in dependence and contribute to the increased drinking seen during acute withdrawal in dependent rats