European Neuropsychopharmacology (v.24, #6)

Contents (OBC).

Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood by Arlette F. Buchmann; Nathalie Holz; Regina Boecker; Dorothea Blomeyer; Marcella Rietschel; Stephanie H. Witt; Martin H. Schmidt; Günter Esser; Tobias Banaschewski; Daniel Brandeis; Ulrich S. Zimmermann; Manfred Laucht (837-845).
Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus–pituitary–adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress regulation related to childhood maltreatment, which have been suggested to represent a premorbid risk or resilience factor in the context of stress-related disorders.
Keywords: FKBP5; Stress; HPA; Cortisol; Childhood adversity;

Intranasal desmopressin as an adjunct to risperidone for negative symptoms of schizophrenia: A randomized, double-blind, placebo-controlled, clinical trial by Seyed Mohammad Reza Hosseini; Mehdi Farokhnia; Farzin Rezaei; Amirhossein Gougol; Habibeh Yekehtaz; Negar Iranpour; Bahman Salehi; Mina Tabrizi; Masih Tajdini; Ali Ghaleiha; Shahin Akhondzadeh (846-855).
Considering the role of neurohypophyseal peptides in normal development and function of higher cortical processes along with their proven abnormalities in schizophrenic patients, these pathways have recently attracted greater attention as treatment targets for schizophrenia. Desmopressin (DDAVP) is a synthetic analog of vasopressin. This study aimed to evaluate the efficacy and safety of DDAVP nasal spray as an adjunct to risperidone in improving negative symptoms of schizophrenia. In this randomized double-blind placebo-controlled clinical trial, forty patients aged 18–50 years with a DSM IV-TR diagnosis of chronic schizophrenia and a minimum score of 60 on positive and negative syndrome scale (PANSS) were equally randomized to receive DDAVP nasal spray (20 mcg/day) or placebo in addition to risperidone for 8 weeks. Patients were partially stabilized and treated with a stable dose of risperidone (5 or 6 mg/day) for at least four weeks prior to entry. Participants were rated by PANSS every two weeks and decrease in the PANSS negative subscale score was considered as our primary outcome. By the study endpoint, DDAVP-treated patients showed significantly greater improvement in the negative symptoms (P=0.001) as well as the PANSS total and general psychopathology subscale scores (P=0.005 and P=0.003; respectively) compared to the placebo group. Treatment group was the strongest predictor of changes in negative symptoms (β=−0.48, t=−3.67, P=001). No serious adverse event or fluid/electrolyte imbalance was reported in this trial. In conclusion, DDAVP nasal spray showed to be an effective and safe medication for improving negative symptoms in patients with chronic schizophrenia.
Keywords: Desmopressin; DDAVP; Negative symptoms; Schizophrenia; Vasopressin;

Adolescent intermittent ethanol exposure diminishes anhedonia during ethanol withdrawal in adulthood by Nathalie Boutros; Svetlana Semenova; Athina Markou (856-864).
Adolescent alcohol use may interfere with neurodevelopment, increasing the likelihood of adult alcohol use disorders (AUDs). We investigated whether adolescent intermittent ethanol (AIE) exposure alters the adult reward response to ethanol. Adolescent rats were administered ethanol once (moderate exposure; Cohort 1) or three times per day (severe exposure; Cohort 2) in a 2 days on/2 days off pattern. In adulthood, subjects responded for electrical stimulation directed at the posterior lateral hypothalamus in a discrete-trial intracranial self-stimulation (ICSS) procedure that provides current-intensity thresholds as a measure of brain reward function. The effects of ethanol administration and withdrawal were assessed. Control rats showed dose-dependent threshold elevations after acute ethanol, indicating reward deficits. A majority of moderately AIE-exposed rats (Cohort 1) showed threshold lowering after ethanol, suggesting ethanol-induced reward enhancement in this sub-set of rats. Rats exposed to severe AIE (Cohort 2) showed no threshold elevation or lowering, suggesting a blunted affective ethanol response. Daily ethanol induced threshold elevations 24 h after administration in control rats but not in either group of AIE-exposed rats, suggesting decreased sensitivity to the negative affective state of ethanol withdrawal. Withdrawal from a 4-day ethanol binge produced robust and enduring threshold elevations in all rats, although threshold elevations were diminished in rats exposed to severe AIE. These results indicate that AIE exposure diminished reward deficits associated with ethanol intoxication and withdrawal and may have increased ethanol-induced reward enhancement in a sub-set of rats. In humans, enhanced ethanol reward accompanied by reduced withdrawal severity may contribute to the development of AUDs.
Keywords: Adolescent; Binge drinking ethanol; Self-stimulation; Wistar rats;

Adolescents at ultra-high risk for psychosis: Long-term outcome of individuals who recover from their at-risk state by S. de Wit; P.F. Schothorst; B. Oranje; T.B. Ziermans; S. Durston; R.S. Kahn (865-873).
Studies of individuals at ultra-high risk (UHR) for psychosis have mostly reported on long-term outcome of those individuals who develop psychosis compared to those who do not. However, these studies show that a large number of UHR individuals no longer meet criteria for UHR at follow-up. Therefore, this study aimed to investigate functioning at 6-year follow-up in remitted individuals, and to explore the course of their clinical symptoms. Forty-four UHR adolescents completed extensive clinical assessments at baseline and participated in long-term follow-up approximately six years later. UHR adolescents who had either converted to psychosis or who still met UHR criteria (n=26) at follow-up were compared to individuals who had remitted from their UHR status (n=18) on clinical and psychosocial variables. Results show that more than 40% of UHR individuals had fully remitted from their UHR status. At six-year follow-up, remitted individuals had improved clinically on most symptoms. The course of their symptoms showed that the most substantial reduction in positive symptoms occurred within the first two years, while improvements in general, mood and anxiety symptoms occurred at a later stage. Baseline socio-demographic characteristics and clinical symptoms did not distinguish between remitters and non-remitters. Although remitters no longer met criteria for UHR, they did meet diagnostic criteria for a wide range of psychiatric disorders. Our findings suggest that, when related to long-term outcome, UHR criteria capture non-specific psychotic symptoms rather than risk for psychosis per se and relate more to general psychopathology.
Keywords: Psychosis; Ultra-high risk; Remission; Long-term outcome; Clinical diagnosis;

Recruitment for clinical studies presents a serious challenge in terms of meeting both time and budget constraints. The internet offers a potentially powerful means for quick and effective recruitment—either as an add-on or as alternative to traditional methods. We developed a Google search based solution which enhances patient recruitment. Recruitment via internet was associated with greater exposure to relevant applicants and better response to treatment as compared to traditional printed ads.
Keywords: Recruitment; Online recruitment; Clinical trials; Internet;

Schizophrenia and bipolar disorder are associated with neurocognitive symptoms including deficits in attentional set shifting (changing attentional focus from one perceptual dimension to another) and reversal learning (learning a reversed stimulus/outcome contingency). Maternal infection during gestation and chronically flattened glucocorticoid rhythm are aetiological risk factors for schizophrenia and bipolar disorder. We hypothesised that these factors are causative in the neurocognitive deficits observed in schizophrenia and bipolar disorder. Here we used maternal immune activation (MIA) as a rat model of maternal infection, and sub-chronic low dose corticosterone treatment as a rat model of flattened glucocorticoid rhythm. For comparison we examined the effects of sub-chronic phencyclidine – a widely used rodent model of schizophrenia pathology. The effects of these three treatments on neurocognition were explored using the attentional set shifting task – a multistage test of executive functions. As expected, phencyclidine treatment selectively impaired set shifting ability. In contrast, MIA caused a marked and selective impairment of reversal learning. Corticosterone treatment impaired reversal learning but in addition also impaired rule abstraction and prevented the animals from forming an attentional set. The reversal learning deficits induced by MIA and corticosterone treatment were due to increases in non-perseverative rather than perseverative errors. Our data indicate that the cognitive deficits of schizophrenia and bipolar disorder may be explained by aetiological factors including maternal infection and glucocorticoid abnormalities and moreover suggest that the particular spectrum of cognitive deficits in individual patients may depend on the specific underlying aetiology of the disorder.
Keywords: Psychiatric aetiology; Phencyclidine; Glucocorticoids; Maternal immune activation; Executive dysfunction;

IGF-I levels and depressive disorders: Results from the Study of Health in Pomerania (SHIP) by C. Sievers; M.K. Auer; J. Klotsche; A.P. Athanasoulia; H.J. Schneider; M. Nauck; H. Völzke; U. John; A. Schulz; H.J. Freyberger; N. Friedrich; R. Biffar; G.K. Stalla; H. Wallaschofski; H.J. Grabe (890-896).
In vitro and in vivo models revealed that the somatotropic system exerts central effects on the central nervous system. Disturbances to this system such as in the case of growth hormone deficiency or growth hormone excess, are associated with a wide range of psychiatric disorders. Nonetheless, there is no epidemiological data available regarding the influence of growth hormone and its mediator, insulin-like growth factor I (IGF-I), on depressive disorders. The objective of this study was to investigate whether endogenous IGF-I levels may predict depression in humans. We included 4079 adult subjects from the Study of Health in Pomerania (SHIP), a population-based study with a 5-year follow-up period. The main predictor was the baseline IGF-I value categorized in three levels as <10th percentile, between the 10th and the 90th percentile (the reference group) and >90th percentile. The outcome measure was the incidence of depressive disorders according to the Composite International Diagnostic-Screener (CID-S). After adjustment for potential confounding variables, females with IGF-I levels below the 10th percentile had a higher incidence of depressive disorders during follow-up (OR 2.70 95% CI 1.38–5.28, p=0.004) compared to females within the reference group (10th–90th percentile). Among males, those with IGF-I levels above the 90th percentile had a higher risk of depressive disorder (OR 3.26 95% CI 1.52–6.98, p=0.002) than those within the 10th–90th percentile. In conclusion we can demonstrate that low IGF-I levels in females and high IGF-I levels in males predict the development of depressive disorders in this general adult population sample.
Keywords: Depression; Depressive disorders; Affective disorders; IGF-I; Growth hormone;

Methylphenidate and brain activity in a reward/conflict paradigm: Role of the insula in task performance by Iliyan Ivanov; Xun Liu; Suzanne Clerkin; Kurt Schulz; Jin Fan; Karl Friston; Edythe D. London; Jeffrey Schwartz; Jeffrey H. Newcorn (897-906).
Psychostimulants, such as methylphenidate, are thought to improve information processing in motivation–reward and attention-activation networks by enhancing the effects of more relevant signals and suppressing those of less relevant ones; however the nature of such reciprocal influences remains poorly understood. To explore this question, we tested the effect of methylphenidate on performance and associated brain activity in the Anticipation, Conflict, Reward (ACR) task. Sixteen healthy adult volunteers, ages 21–45, were scanned twice using functional magnetic resonance imaging (fMRI) as they performed the ACR task under placebo and methylphenidate conditions. A three-way repeated measures analysis of variance, with cue (reward vs. non-reward), target (congruent vs. incongruent) and medication condition (methylphenidate vs. placebo) as the factors, was used to analyze behaviors on the task. Blood oxygen level dependent (BOLD) signals, reflecting task-related neural activity, were evaluated using linear contrasts. Participants exhibited significantly greater accuracy in the methylphenidate condition than the placebo condition. Compared with placebo, the methylphenidate condition also was associated with lesser task-related activity in components of attention-activation systems irrespective of the reward cue, and less task-related activity in components of the reward–motivation system, particularly the insula, during reward trials irrespective of target difficulty. These results suggest that methylphenidate enhances task performance by improving efficiency of information processing in both reward–motivation and in attention-activation systems.
Keywords: fMRI; Stimulants; Insula; Reward; Attention;

Evidence supporting the match/mismatch hypothesis of psychiatric disorders by Sara Santarelli; Sylvie L. Lesuis; Xiao-Dong Wang; Klaus V. Wagner; Jakob Hartmann; Christiana Labermaier; Sebastian H. Scharf; Marianne B. Müller; Florian Holsboer; Mathias V. Schmidt (907-918).
Chronic stress is one of the predominant environmental risk factors for a number of psychiatric disorders, particularly for major depression. Different hypotheses have been formulated to address the interaction between early and adult chronic stress in psychiatric disease vulnerability. The match/mismatch hypothesis of psychiatric disease states that the early life environment shapes coping strategies in a manner that enables individuals to optimally face similar environments later in life. We tested this hypothesis in female Balb/c mice that underwent either stress or enrichment early in life and were in adulthood further subdivided in single or group housed, in order to provide aversive or positive adult environments, respectively. We studied the effects of the environmental manipulation on anxiety-like, depressive-like and sociability behaviors and gene expression profiles. We show that continuous exposure to adverse environments (matched condition) is not necessarily resulting in an opposite phenotype compared to a continuous supportive environment (matched condition). Rather, animals with mismatched environmental conditions behaved differently from animals with matched environments on anxious, social and depressive like phenotypes. These results further support the match/mismatch hypothesis and illustrate how mild or moderate aversive conditions during development can shape an individual to be optimally adapted to similar conditions later in life.
Keywords: Match/mismatch hypothesis; Cumulative stress hypothesis; Stress vulnerability; Mouse; Behavior; Depression;

Blood serotonin levels in autism spectrum disorder: A systematic review and meta-analysis by Stefano Gabriele; Roberto Sacco; Antonio M. Persico (919-929).
Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1–5.2); P=1.0×10−12], and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8–3.9); P=2.7×10−7]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2–2–0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use.
Keywords: 5-HT; Autism; Biomarker; Endophenotype; Meta-analysis;

Impact of variation in the BDNF gene on social stress sensitivity and the buffering impact of positive emotions: Replication and extension of a gene–environment interaction by Mark van Winkel; Frenk Peeters; Ruud van Winkel; Gunter Kenis; Dina Collip; Nicole Geschwind; Nele Jacobs; Catherine Derom; Evert Thiery; Jim van Os; Inez Myin-Germeys; Marieke Wichers (930-938).
A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factorVal66Met (BDNF rs6265) genotype. Additionally, positive emotions partially neutralize this moderating effect. The current study aimed to: (i) replicate in a new independent sample of subjects with residual depressive symptoms the moderating effect of BDNFVal66Met genotype on social stress sensitivity, (ii) replicate the neutralizing impact of positive emotions, (iii) extend these analyses to other variations in the BDNF gene in the new independent sample and the original sample of non-depressed individuals.Previous findings were replicated in an experience sampling method (ESM) study. Negative Affect (NA) responses to social stress were stronger in “Val/Met” carriers of BDNFVal66Met compared to “Val/Val” carriers. Positive emotions neutralized the moderating effect of BDNFVal66Met genotype on social stress sensitivity in a dose–response fashion. Finally, two of four additional BDNF SNPs (rs11030101, rs2049046) showed similar moderating effects on social stress-sensitivity across both samples. The neutralizing effect of positive emotions on the moderating effects of these two additional SNPs was found in one sample.In conclusion, ESM has important advantages in gene–environment (GxE) research and may attribute to more consistent findings in future GxE research. This study shows how the impact of BDNF genetic variation on depressive symptoms may be explained by its impact on subtle daily life responses to social stress. Further, it shows that the generation of positive affect (PA) can buffer social stress sensitivity and partially undo the genetic susceptibility.
Keywords: BDNF genotype; Gene–environment interaction; Stress sensitivity; Experience sampling method (ESM); Positive emotions; Major depressive disorder (MDD);

Agomelatine but not melatonin improves fatigue perception: A longitudinal proof-of-concept study by M. Pardini; C. Cordano; F. Benassi; C. Mattei; D. Sassos; S. Guida; C. Serrati; A. Primavera; M. Amore; L. Cocito; L. Emberti Gialloreti (939-944).
Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep–wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition. Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50 mg u.i.d. with sustained release melatonin 10 mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study. Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects. Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.
Keywords: Fatigue; Dopamine; Noradrenaline; Agomelatine; Melatonin;

The behavioral characterization of animal models of psychiatric disorders is often based upon independent traits measured at adult age. To model the neurodevelopmental aspects of psychiatric pathogenesis, we introduce a novel approach for a developmental behavioral analysis in mice. C57BL/6J (C57) mice were used as a reference strain and compared with 129S1/SvImJ (129Sv), BTBR T+tf/J (BTBR) and A/J (AJ) strains as marker strains for aberrant development. Mice were assessed at pre-adolescence (4 weeks), adolescence (6 weeks), early adulthood (8 weeks) and in adulthood (10–12 weeks) on a series of behavioral tasks measuring general health, neurological reflexes, locomotor activity, anxiety, short- and long-term memory and cognitive flexibility. Developmental delays in short-term object memory were associated with either a hypo-reactive profile in 129Sv mice or a hyper-reactive profile in BTBR mice. Furthermore, BTBR mice showed persistent high levels of repetitive grooming behavior during all developmental stages that was associated with the adult expression of cognitive rigidity. In addition, strain differences in development were observed in puberty onset, touch escape, and body position. These data showed that this longitudinal testing battery provides sufficient behavioral and cognitive resolution during different development stages and offers the opportunity to address the behavioral developmental trajectory in genetic mouse models for neurodevelopmental disorders. Furthermore, the data revealed that the assessment of multiple behavioral and cognitive domains at different developmental stages is critical to determine confounding factors (e.g., impaired motor behavior) that may interfere with the behavioral testing performance in mouse models for brain disorders.
Keywords: Developmental trajectories; Mouse models; Cognitive flexibility; Repetitive behavior; BTBR;

Neuropeptide Y in the central nucleus of amygdala regulates the anxiolytic effect of agmatine in rats by Brijesh G. Taksande; Nandkishor R. Kotagale; Dinesh Y. Gawande; Ashish P. Bharne; Chandrabhan T. Chopde; Dadasaheb M. Kokare (955-963).
In the present study, modulation of anxiolytic action of agmatine by neuropeptide Y (NPY) in the central nucleus of amygdala (CeA) is evaluated employing Vogel's conflict test (VCT) in rats. The intra-CeA administration of agmatine (0.6 and 1.2 µmol/rat), NPY (10 and 20 pmol/rat) or NPY Y1/Y5 receptors agonist [Leu31, Pro34]-NPY (30 and 60 pmol/rat) significantly increased the number of punished drinking licks following 15 min of treatment. Combination treatment of subeffective dose of NPY (5 pmol/rat) or [Leu31, Pro34]-NPY (15 pmol/rat) and agmatine (0.3 µmol/rat) produced synergistic anxiolytic-like effect. However, intra-CeA administration of selective NPY Y1 receptor antagonist, BIBP3226 (0.25 and 0.5 mmol/rat) produced anxiogenic effect. In separate set of experiment, pretreatment with BIBP3226 (0.12 mmol/rat) reversed the anxiolytic effect of agmatine (0.6 µmol/rat). Furthermore, we evaluated the effect of intraperitoneal injection of agmatine (40 mg/kg) on NPY-immunoreactivity in the nucleus accumbens shell (AcbSh), lateral part of bed nucleus of stria terminalis (BNSTl) and CeA. While agmatine treatment significantly decreased the fibers density in BNSTl, increase was noticed in AcbSh. In addition, agmatine reduced NPY-immunoreactive cells in the AcbSh and CeA. Immunohistochemical data suggest the enhanced transmission of NPY from the AcbSh and CeA. Taken together, this study suggests that agmatine produced anxiolytic effect which might be regulated via modulation of NPYergic system particularly in the CeA.
Keywords: Agmatine; Neuropeptide Y; Central nucleus of amygdala; Vogel's conflict test; Anxiety;

Many physiological systems in mammals are linked to the body’s master circadian rhythm in the sleep/wake cycle and dysfunctions in this rhythm has been associated with neurological diseases such as major depression, Alzheimer’s Disease and schizophrenia. There is some evidence that nicotinic cholinergic input to the master circadian pacemaker, the suprachiasmatic nucleus, may modulate circadian activity rhythms, but data employing in vivo preparations is sparse. Therefore we examined the ability of intraperitoneally applied nicotinic agonists and antagonists relatively selective for the α7 nicotinic receptor to modulate light-induced phase shifts of hamster circadian wheel running rhythms. Hamsters were maintained in constant darkness and exposed to light pulses early and late in their active period, mimicking dusk and dawn respectively, which elicited phase delays and advances of their circadian wheel running rhythms. The α7 receptor antagonists bPiDDB (0.03–3 mg/kg) and methyllacaconitine (0.1–1 mg/kg) inhibited both light- induced phase advances and delays of circadian wheel running rhythms by as much as 75% versus vehicle injections. In contrast, systemic injections of the α7 agonists PHA 543613 and ABT107, both at 0.156–2.5 mg/kg, had no effect on light induced phase advances or delays. Further, α7 nicotinic receptors were identified in the hamster suprachiasmatic nucleus using an antibody that recognizes α7 nicotinic receptors. These results clearly identify the ability of α7 nicotinic receptor antagonists to inhibit light-entrainment of the hamster circadian pacemaker. Therefore, nicotinic compounds may be useful for the treatment of circadian dysfunction associated with neurological diseases.
Keywords: Nicotine; Circadian rhythms; Major depression; Suprachiasmatic nucleus;

Juvenile cannabinoid treatment induces frontostriatal gliogenesis in Lewis rats by Marco Bortolato; Valentina Bini; Roberto Frau; Paola Devoto; Alessandra Pardu; Yijun Fan; Marylou V. Solbrig (974-985).
Cannabis abuse in adolescence is associated with a broad array of phenotypical consequences, including a higher risk for schizophrenia and other mental disturbances related to dopamine (DA) imbalances. The great variability of these sequelae likely depends on the key influence of diverse genetic vulnerability factors. Inbred rodent strains afford a highly informative tool to study the contribution of genetic determinants to the long-term effects of juvenile cannabinoid exposure. In this study, we analyzed the phenotypical impact of the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 2 mg/kg/day from postnatal day 35–48) in adolescent Lewis rats, an inbred strain exhibiting resistance to psychotomimetic effects of environmental manipulations. At the end of this treatment, WIN-injected animals displayed increased survival of new cells (mainly oligodendroglia precursors) in the striatum and prefrontal cortex (PFC), two key terminal fields of DAergic pathways. To test whether these changes may be associated with enduring behavioral alterations, we examined the consequences of adolescent WIN treatment in adulthood (postnatal days 60–70), with respect to DA levels and metabolism as well as multiple behavioral paradigms. Rats injected with WIN exhibited increased turnover, but not levels, of striatal DA. In addition, cannabinoid-treated animals displayed increases in acoustic startle latency and novel-object exploration; however, WIN treatment failed to induce overt deficits of sensorimotor gating and social interaction. These results indicate that, in Lewis rats, juvenile cannabinoid exposure leads to alterations in frontostriatal gliogenesis, as well as select behavioral alterations time-locked to high DAergic metabolism, but not overt schizophrenia-related deficits.
Keywords: Cannabinoids; Adolescent exposure; Dopamine; Gliogenesis; Lewis rats;

Delayed BDNF alterations in the prefrontal cortex of rats exposed to prenatal stress: Preventive effect of lurasidone treatment during adolescence by A. Luoni; A. Berry; F. Calabrese; S. Capoccia; V. Bellisario; P. Gass; F. Cirulli; M.A. Riva (986-995).
Psychiatric diseases may often represent the consequence of exposure to adverse events early in life. Accordingly, exposure to stress during gestation in rats has a strong impact on development and can cause long-term abnormalities in adult behavior. Considering that neuronal plasticity has emerged as a major vulnerability element in psychiatric disorders, we investigated the postnatal developmental profile of Brain-Derived Neurotrophic Factor expression (BDNF), an important mediator for long-term functional deterioration associated to mental illness, in male and female rats following exposure to prenatal stress (PNS). Since we found that the majority of alterations became fully manifest at early adulthood, we tried to prevent these abnormalities with an early pharmacological intervention. To address this point, we treated rats during adolescence with the multi-receptor antipsychotic lurasidone, which was proven to be effective in animal models of schizophrenia. Interestingly, we show that lurasidone treatment was able to prevent the reduction of BDNF expression in adult rats that were exposed to PNS.Collectively, our results provide further support to the notion that exposure to early life stress has a negative impact on neuronal plasticity and that pharmacological intervention during critical time windows may prove effective in preventing neuroplastic dysfunction, leading to long-term beneficial effects on brain function.
Keywords: Gestational stress; BDNF; Lurasidone; Postnatal development;

Pain exacerbates chronic mild stress-induced changes in noradrenergic transmission in rats by Lidia Bravo; Sonia Torres-Sanchez; Cristina Alba-Delgado; Juan A. Mico; Esther Berrocoso (996-1003).
Depression can influence pain and vice versa, yet the biological mechanisms underlying how one influences the pathophysiology of the other remains unclear. Dysregulation of locus coeruleus-noradrenergic transmission is implicated in both conditions, although it is not known whether this effect is exacerbated in cases of co-morbid depression and chronic pain. We studied locus coeruleus activity using immunofluorescence and electrophysiological approaches in rats subjected to unpredictable chronic mild stress (CMS, an experimental model of depression) and/or chronic constriction injury (CCI, a model of chronic neuropathic pain) for 2 weeks. CCI alone had no effect on any of the locus coeruleus parameters studied, while CMS led to a slight reduction in the electrophysiological activity of the locus coeruleus. Furthermore, CMS was associated with an increase in the number of tyrosine hydroxylase-positive cells in the locus coeruleus, although they were smaller in size. Interestingly, these effects of CMS were exacerbated when combined with CCI, even though no changes in the α2-adrenoreceptors or the noradrenaline transporter were observed in any group. Together, these findings suggest that CMS triggers several modifications in locus coeruleus-noradrenergic transmission that are exacerbated by co-morbid chronic pain.
Keywords: Depression; Stress; Pain; Comorbidity; Locus coeruleus; Tyrosine hydroxylase;