Prenatal Restraint Stress Generates Two Distinct Behavioral and Neurochemical Profiles in Male and Female Rats

Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS ("PRS rats'') showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females. [Zuena, Anna Rita; Mairesse, Jerome; Morley-Fletcher, Sara; Maccari, Stefania] Univ Lille 1, Perinatal Stress Lab, F-59655 Villeneuve Dascq, France; [Zuena, Anna Rita; Mairesse, Jerome; Casolini, Paola; Cinque, Carlo; Alema, Giovanni Sebastiano; Chiodi, Valentina; Catalani, Assia; Nicoletti, Ferdinando; Maccari, Stefania] Univ Roma La Sapienza, Dept Human Physiol & Pharmacol, Rome, Italy; [Gradini, Roberto; Nicoletti, Ferdinando] Ist Neurol Mediterraneo Neuromed, Pozzilli, Italy; [Spagnoli, Luigi Giusto] Tor Vergata Univ, Inst Anatom Pathol, Rome, Italy; [Gradini, Roberto] Univ Roma La Sapienza, Dept Expt Med, Rome, Italy Zuena, AR (reprint author), Univ Lille 1, Perinatal Stress Lab, F-59655 Villeneuve Dascq, France. [email protected] Alema, Giovanni Sebastiano/D-2672-2009 Alema, Giovanni Sebastiano/0000-0003-2350-6365 University of Lille 1; Sapienza University of Rome; Ministere des Affaires Etrangers; Lavoisier, EGIDE This research was supported by the University of Lille 1 and the Sapienza University of Rome (under the framework of an agreement signed between the 2 universities on 15/02/2007). Anna Rita Zuena was funded by the Ministere des Affaires Etrangers. Jerome Mairesse was funded by the Lavoisier, EGIDE. 116 85 86 PUBLIC LIBRARY SCIENCE SAN FRANCISCO 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA 1932-6203 PLOS ONE PLoS One MAY 14 2008 3 5 e2170 10.1371/journal.pone.0002170 13 Multidisciplinary Sciences Science & Technology - Other Topics 390OE WOS:000262172800035 J Trezza, V; Cuomo, V; Vanderschuren, LJMJ Trezza, Viviana; Cuomo, Vincenzo; Vanderschuren, Louk J. M. J. Cannabis and the developing brain: Insights from behavior EUROPEAN JOURNAL OF PHARMACOLOGY English Review cannabis; behavior; development; pregnancy; adolescence PRENATAL MARIJUANA EXPOSURE; MESSENGER-RNA EXPRESSION; MU-OPIOID RECEPTORS; HUMAN FETAL-BRAIN; ILLICIT DRUG-USE; RAT-BRAIN; ADULT RATS; PERINATAL EXPOSURE; ENDOCANNABINOID SYSTEM; GENE-EXPRESSION The isolation and identification, in 1964, of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, opened the door to a whole new field of medical research. The exploration of the therapeutic potential of THC and other natural and synthetic cannabinoid compounds was paralleled by the discovery of the endocannabinoid system, comprising cannabinoid receptors and their endogenous ligands, which offered exciting new insights into brain function. Besides its well-known involvement in specific brain functions, such as control of movement, memory and emotions, the endocannabinoid system plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation. For this reason, changes in its activity during stages of high neuronal plasticity, such as the perinatal and the adolescent period, can have long-lasting neurobehavioral consequences. Here, we summarize human and animal studies examining the behavioral and neurobiological effects of in utero and adolescent exposure to cannabis. Since cannabis preparations are widely used and abused by young people, including pregnant women, understanding how cannabinoid compounds affect the developing brain, leading to neurobehavioral alterations or neuropsychiatric disorders later in life, is a serious health issue. In addition, since the endocannabinoid system is emerging as a novel therapeutic target for the treatment of several neuropsychiatric diseases, a detailed investigation of possible adverse effects of cannabinoid compounds on the central nervous system (CNS) of immature individuals is warranted. (C) 2008 Elsevier B.V. All rights reserved. [Trezza, Viviana; Vanderschuren, Louk J. M. J.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurosci & Pharmacol, NL-3584 CG Utrecht, Netherlands; [Cuomo, Vincenzo] Univ Rome Sapienza, Dept Human Physiool & Pharmacol, Rome, Italy Trezza, V (reprint author), Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurosci & Pharmacol, Univ Weg 100, NL-3584 CG Utrecht, Netherlands. [email protected] Cuomo, Vincenzo/D-2772-2009; cuomo, vincenzo/J-6777-2012 159 31 32 ELSEVIER SCIENCE BV AMSTERDAM PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS 0014-2999 EUR J PHARMACOL Eur. J. Pharmacol. MAY 13 2008 585 2-3 441 452 10.1016/j.ejphar.2008.01.058 12 Pharmacology & Pharmacy Pharmacology & Pharmacy 304ZD WOS:000256146700024 J Amato, MP; Goretti, B; Ghezzi, A; Lori, S; Zipoli, V; Portaccio, E; Moiola, L; Falautano, M; De Caro, MF; Lopez, M; Patti, F; Vecchio, R; Pozzilli, C; Bianchi, V; Roscio, M; Comi, G; Trojano, M Amato, M. P.; Goretti, B.; Ghezzi, A.; Lori, S.; Zipoli, V.; Portaccio, E.; Moiola, L.; Falautano, M.; De Caro, M. F.; Lopez, M.; Patti, F.; Vecchio, R.; Pozzilli, C.; Bianchi, V.; Roscio, M.; Comi, G.; Trojano, M. Italian Neurological Soc Cognitive and psychosocial features of childhood and juvenile MS NEUROLOGY English Article PEDIATRIC MULTIPLE-SCLEROSIS; IMPAIRMENT; CHILDREN; DYSFUNCTION; DIAGNOSIS; FATIGUE; DISABILITY; IMPACT; SCALE; LIFE Objective: To assess the impact of multiple sclerosis (MS) on cognitive and psychosocial functioning in childhood and juvenile cases. Methods: We used an extensive neuropsychological battery assessing IQ, memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. Performance of cases was compared with that of demographically matched healthy controls. Results: Sixty-three patients and 57 healthy controls were assessed. Five patients (8%) exhibited a particularly low IQ (< 70). Criteria for cognitive impairment (failure on at least three tests) were fulfilled in 19 patients (31%), whereas 32 patients (53%) failed at least two tests. Beyond deficits in memory, complex attention, and executive functions, the profile of deficits was characterized by involvement of linguistic abilities. In the regression analysis, the only significant predictor of cognitive impairment was an IQ score lower than 90 (odds ratio [OR] 18.2,95% CI 4.6-71.7, p < 0.001). Considering the IQ score as a dependent variable, the only significant predictor was represented by younger age at onset (OR 0.7, 95% CI 0.5-0.9, p = 0.009). Depressive symptoms were reported by 6% of the cases, and fatigue was reported by 73% of the cases. MS negatively affected school and everyday activities in 56% of the subjects. Conclusions: In childhood and juvenile cases, multiple sclerosis (MS) is associated with cognitive impairment and low IQ scores, the latter related to younger age at onset. These aspects are of critical importance in helping children and adolescents with MS to manage their difficulties and psychosocial challenges. [Amato, M. P.; Goretti, B.; Zipoli, V.; Portaccio, E.] Univ Florence, Dept Neurol, I-50134 Florence, Italy; [Lori, S.] Meyer Hosp, Neurol Unit, Florence, Italy; [Moiola, L.; Falautano, M.; Comi, G.] Ist Sci San Raffaele, Dept Neurol, I-20132 Milan, Italy; [De Caro, M. F.; Lopez, M.; Trojano, M.] Univ Bari, Dept Neurol, I-70121 Bari, Italy; [Patti, F.; Vecchio, R.] Univ Catania, Dept Neurol, I-95124 Catania, Italy; [Pozzilli, C.; Bianchi, V.] Univ Roma La Sapienza, Dept Neurol Sci, Rome, Italy Amato, MP (reprint author), Univ Florence, Dept Neurol, Viale Morgagni 85, I-50134 Florence, Italy. [email protected] Patti, Francesco/C-3300-2011 38 70 71 LIPPINCOTT WILLIAMS & WILKINS PHILADELPHIA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA 0028-3878 NEUROLOGY Neurology MAY 13 2008 70 20 1891 1897 10.1212/01.wnl.0000312276.23177.fa 7 Clinical Neurology Neurosciences & Neurology 312YC WOS:000256707300005 J Domenici, F; Castellano, C; Congiu, A; Pompeo, G; Felici, R Domenici, F.; Castellano, C.; Congiu, A.; Pompeo, G.; Felici, R. Ordering and lyotropic behavior of a silicon-supported cationic and neutral lipid system studied by neutron reflectivity APPLIED PHYSICS LETTERS English Article DIOCTADECYLDIMETHYLAMMONIUM BROMIDE; X-RAY; MEMBRANES; BILAYERS; INTERFACES; VESICLES Self-assembling of amphipathic lipid films on solid support allows the structural investigation of important biological model systems, such as the vectorlike lipid membranes, in order to improve DNA transfection in nonviral gene therapy. We present a neutron reflectivity study of a binary lipid system composed of dioleoylphosphatidylcholine (DOPC) and dimethyldioctadecylammonium bromide (DDAB) deposited on [100] silicon support by means of spin coating technique. We underline their lyotropic behavior under saturated deuterium oxide (D(2)O) vapor thus pointing out that the lipid mixture is organized in ordered domains composed of plane lamellar bilayers of noninteractive DOPC and DDAB. (c) 2008 American Institute of Physics. [Domenici, F.; Castellano, C.; Congiu, A.] Univ Roma La Sapienza, Dipartimento Fis, I-00185 Rome, Italy; [Pompeo, G.] Ist Struttura Mat, Sezione Tor Vergata, I-00133 Rome, Italy; [Felici, R.] European Synchrotron Radiat Facil, F-38043 Grenoble, France Domenici, F (reprint author), Univ Roma La Sapienza, Dipartimento Fis, Ple A Moro 2, I-00185 Rome, Italy. [email protected]; [email protected] 30 1 1 AMER INST PHYSICS MELVILLE CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA 0003-6951 APPL PHYS LETT Appl. Phys. Lett. MAY 12 2008 92 19 193901 10.1063/1.2917807 3 Physics, Applied Physics 310XN WOS:000256564200111 J Ribeiro, MCC; Scopigno, T; Ruocco, G Ribeiro, Mauro C. C.; Scopigno, Tullio; Ruocco, Giancarlo Fragility and glassy dynamics of 2Ca(NO(3))(2)center dot 3KNO(3) under pressure: Molecular dynamics simulations JOURNAL OF CHEMICAL PHYSICS English Article FORMING LIQUIDS; NITRATE MELTS; TRANSITION; RELAXATION; CA0.4K0.6(NO3)(1.4); TEMPERATURE; DEPENDENCE; TRANSPORT Molecular dynamics simulations of the glass-forming liquid 2Ca(NO(3))(2)center dot 3KNO(3) (CKN) were performed from high temperature liquid states down to low temperature glassy states at six different pressures from 10(-4) to 5.0 GPa. The temperature dependence of the structural relaxation time indicates that the fragility of liquid CKN changes with pressure. In line with recent proposal [Scopigno , Science 302, 849 (2003)], the change on liquid fragility is followed by a proportional change of the nonergodicity factor of the corresponding glass at low temperature. (c) 2008 American Institute of Physics. [Ribeiro, Mauro C. C.] Univ Sao Paulo, Inst Quim, Lab Espect Mol, BR-05513970 Sao Paulo, Brazil; [Scopigno, Tullio; Ruocco, Giancarlo] Univ Roma La Sapienza, Ist Nazl Fis Mat, I-00185 Rome, Italy; [Scopigno, Tullio; Ruocco, Giancarlo] Univ Roma La Sapienza, Dept Fis, I-00185 Rome, Italy Ribeiro, MCC (reprint author), Univ Sao Paulo, Inst Quim, Lab Espect Mol, CP 26077, BR-05513970 Sao Paulo, Brazil. [email protected] Ruocco, Giancarlo/A-6245-2010; Scopigno, Tullio/A-1778-2010; Ribeiro, Mauro/C-4820-2012 Ruocco, Giancarlo/0000-0002-2762-9533; 26 7 7 AMER INST PHYSICS MELVILLE CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA 0021-9606 J CHEM PHYS J. Chem. Phys. MAY 12 2008 128 19 191104 10.1063/1.2931525 4 Physics, Atomic, Molecular & Chemical Physics 305VF WOS:000256205200004 J Celani, F; Isidori, A; Marconi, L Celani, F.; Isidori, A.; Marconi, L. A reduction paradigm for output regulation INTERNATIONAL JOURNAL OF ROBUST AND NONLINEAR CONTROL English Article output regulation; nonlinear systems; linear systems; non-minimum-phase systems NONLINEAR INTERNAL-MODELS; SEMIGLOBAL STABILIZATION; FEEDBACK STABILIZATION; SYSTEMS; TOOL The goal of this paper is to provide a reduction paradigm for the design of output regulators which can be of interest for nonlinear as well as linear uncertain systems. The main motivation of the work is to provide a systematic design tool to deal with non-minimum-phase uncertain systems for which conventional high-gain stabilization methods are not effective. The contribution of the work is two-fold. First, this work extends a previous reduction paradigm for output regulation of nonlinear systems. Furthermore, in the case of the uncertain controlled dynamics being linear, we show how the proposed framework leads to a number of systematic design tools of interest for non-minimum-phase linear systems affected by severe uncertainties. A numerical control example of a linearized model of an inverted pendulum on a cart is presented. Copyright (c) 2007 John Wiley & Sons, Ltd. [Celani, F.; Isidori, A.] Univ Roma La Sapienza, Dipartimento Informat & Sistemist Antonio Ruberti, I-00185 Rome, Italy; [Isidori, A.] Washington Univ, Dept Elect & Syst Engn, St Louis, MO 63130 USA; [Isidori, A.; Marconi, L.] Univ Bologna, Dipartimento Elettr Informat & Sistemist, Ctr Res Complex Automated Syst Giuseppe Evangelis, I-40123 Bologna, Italy Celani, F (reprint author), Univ Roma La Sapienza, Dipartimento Informat & Sistemist Antonio Ruberti, Via Ariosto 25, I-00185 Rome, Italy. [email protected] Celani, Fabio/F-1397-2011; Isidori, Alberto/F-5825-2011 19 3 3 WILEY-BLACKWELL MALDEN COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA 1049-8923 INT J ROBUST NONLIN Int. J. Robust Nonlinear Control MAY 10 2008 18 7 756 781 10.1002/rnc.1262 26 Automation & Control Systems; Engineering, Electrical & Electronic; Mathematics, Applied Automation & Control Systems; Engineering; Mathematics 294BP WOS:000255379400004 J Serrilli, AM; Ramunno, A; Amicucci, F; Chicarella, V; Santoni, S; Ballero, M; Serafini, M; Bianco, A Serrilli, Anna Maria; Ramunno, Alessia; Amicucci, Francesca; Chicarella, Valentina; Santoni, Sabrina; Ballero, Mauro; Serafini, Mauro; Bianco, Armandodoriano Iridoidic pattern in endemic Sardinian plants: the case of Galium species NATURAL PRODUCT RESEARCH English Article Rubiaceae; Galium corsicum; Galium schmidii; Galium glaucophyllum; monoterpenoids : iridoid glycosides; Sardinia GLUCOSIDES; SPECTROSCOPY; RUBIACEAE The monoterpenoid fractions of three endemic Galium ssp. (Rubiaceae) from Sardinia Island were examined and compared with the iridoidic pattern yet known in Galium species. This comparison evidenced theirs endemic characters. In particular, in G.corsicum and in G. glaucophyllum loganic acid was isolated and identified for the first time in Galium genus. In G. schmidii a rare iridoid is present, 10-hydroxy-loganin, whose presence in this genus was evidenced only in G. mollugo and loganin isolated for the first time. [Serrilli, Anna Maria; Ramunno, Alessia; Amicucci, Francesca; Chicarella, Valentina; Santoni, Sabrina; Bianco, Armandodoriano] Univ Roma La Sapienza, Dipartimento Chim, I-00185 Rome, Italy; [Ballero, Mauro] Univ Cagliari, Dipartimento Sci Bot, I-09124 Cagliari, Italy; [Serrilli, Anna Maria; Ramunno, Alessia; Amicucci, Francesca; Chicarella, Valentina; Santoni, Sabrina; Ballero, Mauro; Serafini, Mauro; Bianco, Armandodoriano] COSMESE Consorzio Interuniv Studio Metab Secondar, Cagliari, Italy Serrilli, AM (reprint author), Univ Roma La Sapienza, Dipartimento Chim, P A Moro 5, I-00185 Rome, Italy. [email protected] 14 1 1 TAYLOR & FRANCIS LTD ABINGDON 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND 1478-6419 NAT PROD RES Nat. Prod. Res. MAY 10 2008 22 7 618 622 10.1080/14786410701614135 5 Chemistry, Applied; Chemistry, Medicinal Chemistry; Pharmacology & Pharmacy 314JD WOS:000256804800009 J Zenchuk, AI; Santini, PM Zenchuk, A. I.; Santini, P. M. The remarkable relations among PDEs integrable by the inverse spectral transform method, by the method of characteristics and by the Hopf-Cole transformation JOURNAL OF PHYSICS A-MATHEMATICAL AND THEORETICAL English Article KADOMTSEV-PETVIASHVILI EQUATION; NONLINEAR EVOLUTION EQUATIONS; DEPENDENT SCHRODINGER-EQUATION; PARTIAL-DIFFERENTIAL EQUATIONS; SCATTERING TRANSFORM; DRESSING METHOD; CAUCHY-PROBLEM; HIERARCHIES; ALGEBRAS; FIELDS We establish deep and remarkable connections among partial differential equations (PDEs) integrable by different methods: the inverse spectral transform method, the method of characteristics and the Hopf-Cole transformation. More concretely, (1) we show that the integrability properties (Lax pair, infinitely-many commuting symmetries, large classes of analytic solutions) of (2+1)-dimensional PDEs integrable by the inverse scattering transform method (S-integrable) can be generated by the integrability properties of the (1+1)-dimensional matrix Burgers hierarchy, integrable by the matrix Hopf-Cole transformation (C-integrable). (2) We show that the integrability properties (i) of S-integrable PDEs in (1+1) dimensions, (ii) of the multidimensional generalizations of the GL(M, C) self-dual Yang-Mills equations and (iii) of the multidimensional Calogero equations can be generated by the integrability properties of a recently introduced multidimensional matrix equation solvable by the method of characteristics. To establish the above links, we consider a block Frobenius matrix reduction of the relevant matrix fields, leading to integrable chains of matrix equations for the blocks of such a Frobenius matrix, followed by a systematic elimination procedure of some of these blocks. The construction of large classes of solutions of the soliton equations from solutions of the matrix Burgers hierarchy turns out to be intimately related to the construction of solutions in Sato theory. (3) Finally, we show that suitable generalizations of the block Frobenius matrix reduction of the matrix Burgers hierarchy generates PDEs exhibiting integrability properties in common with both S- and C-integrable equations. [Zenchuk, A. I.] Landau Inst Theoret Phys, Int Inst Nonlinear Sci, Ctr Nonlinear Studies, Moscow 119334, Russia; [Santini, P. M.] Univ Roma La Sapienza, Dipartimento Fis, I-00185 Rome, Italy; [Santini, P. M.] Ist Nazl Fis Nucl, I-00185 Rome, Italy Zenchuk, AI (reprint author), Landau Inst Theoret Phys, Int Inst Nonlinear Sci, Ctr Nonlinear Studies, Kosygina 2, Moscow 119334, Russia. [email protected]; [email protected] 52 6 6 IOP PUBLISHING LTD BRISTOL TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND 1751-8113 J PHYS A-MATH THEOR J. Phys. A-Math. Theor. MAY 9 2008 41 18 185209 10.1088/1751-8113/41/18/185209 28 Physics, Multidisciplinary; Physics, Mathematical Physics 298AZ WOS:000255659900016 J Aaltonen, T; Adelman, J; Akimoto, T; Albrow, MG; Gonzalez, BA; Amerio, S; Amidei, D; Anastassov, A; Annovi, A; Antos, J; Aoki, M; Apollinari, G; Apresyan, A; Arisawa, T; Artikov, A; Ashmanskas, W; Attal, A; Aurisano, A; Azfar, F; Azzi-Bacchetta, P; Azzurri, P; Bacchetta, N; Badgett, W; Barbaro-Galtieri, A; Barnes, VE; Barnett, BA; Baroiant, S; Bartsch, V; Bauer, G; Beauchemin, PH; Bedeschi, F; Bednar, P; Behari, S; Bellettini, G; Bellinger, J; Belloni, A; Benjamin, D; Beretvas, A; Beringer, J; Berry, T; Bhatti, A; Binkley, M; Bisello, D; Bizjak, I; Blair, RE; Blocker, C; Blumenfeld, B; Bocci, A; Bodek, A; Boisvert, V; Bolla, G; Bolshov, A; Bortoletto, D; Boudreau, J; Boveia, A; Brau, B; Bridgeman, A; Brigliadori, L; Bromberg, C; Brubaker, E; Budagov, J; Budd, HS; Budd, S; Burkett, K; Busetto, G; Bussey, P; Buzatu, A; Byrum, KL; Cabrera, S; Campanelli, M; Campbell, M; Canelli, F; Canepa, A; Carlsmith, D; Carosi, R; Carrillo, S; Carron, S; Casal, B; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chang, SH; Chen, YC; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, K; Chokheli, D; Chou, JP; Choudalakis, G; Chuang, SH; Chung, K; Chung, WH; Chung, YS; Ciobanu, CI; Ciocci, MA; Clark, A; Clark, D; Compostella, G; Convery, ME; Conway, J; Cooper, B; Copic, K; Cordelli, M; Cortiana, G; Crescioli, F; Almenar, CC; Cuevas, J; Culbertson, R; Cully, JC; Dagenhart, D; Datta, M; Davies, T; de Barbaro, P; De Cecco, S; Deisher, A; De Lentdecker, G; De Lorenzo, G; Dell'Orso, M; Demortier, L; Deng, J; Deninno, M; De Pedis, D; Derwent, PF; Di Giovanni, GP; Dionisi, C; Di Ruzza, B; Dittmann, JR; D'Onofrio, M; Donati, S; Dong, P; Donini, J; Dorigo, T; Dube, S; E

Attenuation of the anxiogenic effects of cocaine by 5-HT1B autoreceptor stimulation in the bed nucleus of the stria terminalis of rats

RATIONALE: Cocaine produces significant aversive/anxiogenic actions whose underlying neurobiology remains unclear. A possible substrate contributing to these actions is the serotonergic (5-HT) pathway projecting from the dorsal raphé (DRN) to regions of the extended amygdala, including the Bed Nucleus of the Stria Terminalis (BNST) which have been implicated in the production of anxiogenic states. OBJECTIVES: The present study examined the contribution of 5-HT signaling within the BNST to the anxiogenic effects of cocaine as measured in a runway model of drug self-administration. METHODS: Male Sprague-Dawley rats were fitted with bilateral infusion cannula aimed at the BNST and then trained to traverse a straight alley once a day for a single 1mg/kg i.v. cocaine infusion delivered upon goal-box entry on each of 16 consecutive days/trials. Intracranial infusions of CP 94,253 (0, 0.25, 0.5, or 1.0μg/side) were administered to inhibit local 5-HT release via activation of 5-HT(1B) autoreceptors. To confirm receptor specificity, the effects of this treatment were then challenged by co-administration of the selective 5-HT(1B) antagonist NAS-181. RESULTS: Intra-BNST infusions of the 5-HT(1B) autoreceptor agonist attenuated the anxiogenic effects of cocaine as reflected by a decrease in runway approach-avoidance conflict behavior. This effect was reversed by the 5-HT(1B) antagonist. Neither start latencies (a measure of the subject’s motivation to seek cocaine) nor spontaneous locomotor activity (an index of motoric capacity) were altered by either treatment. CONCLUSIONS: Inhibition of 5-HT(1B) signaling within the BNST selectively attenuated the anxiogenic effects of cocaine, while leaving unaffected the positive incentive properties of the drug