Laís F. Berro

Short-term social isolation induces depressive-like behaviour and reinstates the retrieval of an aversive task: mood-congruent memory in male mice?

BACKGROUND Although mood-congruent memory (MCM), or the tendency to recall information consistent with ones mood, is a robust phenomenon in human depression, to our knowledge, it has never been demonstrated in animals. METHODS Mice were subjected to social isolation (SI) or crowding for 12 hours and had their depressive-like behaviour (evaluated by the forced swim, tail suspension, sucrose preference and splash tests) or their serum corticosterone concentrations evaluated. In addition, we determined the temporal forgetting curve of the plus-maze discriminative avoidance task (PM-DAT) and examined the effects of SI or crowding on memory retrieval in the PM-DAT. Finally, we verified the effects of metyrapone pretreatment on reinstatement of memory retrieval or on the increase of corticosterone levels induced by SI. RESULTS Twelve hours of SI produced depressive-like behaviour, enhanced corticosterone concentration and reinstated retrieval of a forgotten discriminative aversive (i.e., negatively valenced) task. Depressive-like behaviour was critical for this facilitative effect of SI because 12 hours of crowding neither induced depressive-like behaviour nor enhanced retrieval, although it increased corticosterone levels at the same magnitude as SI. However, corticosterone increase was a necessary condition for MCM in mice, in that the corticosterone synthesis inhibitor metyrapone abolished SI-induced retrieval reinstatement. LIMITATIONS Our study did not investigate the effects of the social manipulations proposed here in a positively valenced task. CONCLUSION To our knowledge, the present paper provides the first evidence of MCM in animal models.

Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys

RationaleAccumulating evidence shows that the serotonergic system plays a major role in psychostimulant abuse through its interactions with the dopaminergic system. Studies indicate that serotonin 5-HT2C receptors are one of the main classes of receptors involved in mediating the influence of serotonin in drug abuse.ObjectiveThe aim of the present study was to evaluate the effects of the selective serotonin 5-HT2C receptor agonist WAY163909 on the behavioral neuropharmacology of cocaine and methamphetamine in adult rhesus macaques.MethodsCocaine or methamphetamine self-administration and reinstatement were evaluated under second-order and fixed-ratio schedules of reinforcement, respectively. Cocaine- and methamphetamine-induced increases in dopamine were assessed through in vivo microdialysis targeting the nucleus accumbens.ResultsPretreatment with WAY163909 dose-dependently attenuated cocaine and methamphetamine self-administration and drug-induced reinstatement of extinguished behavior previously maintained by cocaine or methamphetamine delivery. In an additional experiment, WAY163909 induced a dose-dependent attenuation of cocaine- or methamphetamine-induced dopamine overflow in the nucleus accumbens.ConclusionsOur data indicate that selective 5-HT2C receptor activation decreases drug intake and drug-seeking behavior in nonhuman primate models of psychostimulant abuse through neurochemical mechanisms involved in the modulation of mesolimbic dopamine.

Effects of acute and long‐term typical or atypical neuroleptics on morphine‐induced behavioural effects in mice

It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long‐term administration of haloperidol and/or ziprasidone on morphine‐induced open‐field behaviour in mice. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open‐field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine‐induced behaviours in the open‐field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy‐two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open‐field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine‐induced locomotor stimulation. Withdrawal from haloperidol or ziprasidone did not modify morphine‐elicited behaviours in the open‐field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients.

Actigraphy-based sleep parameters during the reinstatement of methamphetamine self-administration in rhesus monkeys.

The objective of this study was to investigate nighttime activity of nonhuman primates during extinction and cue- and drug-primed reinstatement of methamphetamine self-administration. Adult rhesus monkeys (Macaca mulatta; n = 5) self-administered methamphetamine (0.01 mg/kg/injection, i.v.) under a fixed-ratio 20 schedule of reinforcement. Saline infusions were then substituted for methamphetamine and stimulus light (drug-conditioned stimulus presented during drug self-administration) withheld until subjects reached extinction criteria. Drug- and cue-induced reinstatement effects were evaluated after i.v. noncontingent priming injections of methamphetamine (0.03, 0.1, or 0.3 mg/kg). Activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline nighttime activity parameters) and throughout the protocol. Although methamphetamine self-administration did not significantly affect nighttime activity compared to baseline, sleeplike parameters were improved during extinction compared to self-administration maintenance. Priming injection of 0.1 mg/kg methamphetamine, but not 0.03 or 0.3 mg/kg, induced significant reinstatement effects. These behavioral responses were accompanied by nighttime outcomes, with increased sleep fragmentation and decreased sleep efficiency in the night following 0.1 mg/kg methamphetamine-induced reinstatement. In the absence of both drug and drug-paired cues (extinction conditions), nighttime activity decreased compared to self-administration maintenance. Additionally, effective reinstatement conditions impaired sleeplike measures. Our data indicate that the reintroduction of the stimulus light as a drug-paired cue increased nighttime activity.

Re: Safety and efficacy of testosterone replacement therapy in adolescents with Klinefelter syndrome: A. Mehta, T. Clearman and D. A. Paduch. J Urol 2014; 191: 1527-1531.

Reply by Authors: The comments of Das et al regarding the contribution of the fibers from the superior hypogastric and inferior mesenteric plexus to renal innervation are largely consistent with those reported in the literature and appear generally correct. However, our article focused entirely on evaluation of the autonomic nervous system from the main renal vessels deep into the renal cortex. We did not evaluate the more proximal nerve distribution on the main renal artery because this anatomy is well described in the literature. Indeed, the references cited by Das et al beautifully characterize the autonomic nerve distribution outside the kidney but make no mention of the intrarenal nerve distribution. After an extensive literature search we affirm that the methodology that allowed us to redefine intrarenal anatomy is unique and has never been previously reported. This anatomy is extremely important during catheter based renal denervation for resistant renovascular hypertension. Furthermore, we agree that our work is preliminary and that human anatomical distribution of the renal nerves may vary by gender, body type and anatomical malformations. Further studies with a greater number of cadavers are warranted to confirm our pilot data. Indeed, this limitation was clearly documented in the article.

Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) and R(-) MDMA on actigraphy-based daytime activity and sleep parameters in rhesus monkeys.

3,4-Methylenedioxymethamphetamine (MDMA) affects monoaminergic pathways that play a critical role in sleep-wake cycles. Dopaminergic mechanisms are thought to mediate the sleep-disrupting effects of stimulant drugs. However, the mechanisms underlying the effects of MDMA on sleep-wake cycles and the effects of R(-) MDMA, a stereoisomer that lacks dopaminergic activity, on sleep remain unknown. The aim of the present study was to investigate the effects of racemic MDMA and R(-) MDMA on daytime activity and sleep-like parameters evaluated with actigraphy in adult rhesus macaques (Macaca mulatta, n = 6). Actiwatch monitors were attached to the monkeys’ collars and actigraphy recording was conducted during baseline conditions and after the administration of acute intramuscular injections of saline (vehicle), racemic MDMA (0.3, 1.0, or 1.7 mg/kg), or R(-) MDMA (0.3, 1.0, or 1.7 mg/kg) at 9 or 16 h (3 h before “lights off”). Morning treatments had no effects on sleep-like parameters. Racemic MDMA decreased general daytime activity during the first hour after injection and increased daytime activity at 3 hr posttreatment. Although afternoon administration of racemic MDMA increased sleep latency, it improved other sleep parameters, decreasing wake time after sleep onset (WASO) and increasing sleep efficiency for subjects with low baseline sleep efficiency. Afternoon treatment with R(-) MDMA improved sleep measures, increasing sleep efficiency and decreasing sleep latency and WASO, while having no effects on daytime activity. The stimulant and sleep-disrupting effects of racemic MDMA are likely mediated by dopaminergic and noradrenergic mechanisms, while serotonergic pathways appear to be involved in the sleep-promoting effects of MDMA.

Sleep impairment: the possible link between childhood ADHD, sensation seeking, and cocaine dependence.

Dear Editor, Ballon, Brunault, and Cortese (in press) recently showed that, opposed to 5% of control individuals, 56% of cocainedependent adults had a history of probable childhood ADHD. In addition, ADHD history was associated with higher levels of sensation seeking among cocaine dependents, who showed higher sensation-seeking scores than non-dependent ones. ADHD presents several comorbid conditions, including sleep disturbances. There is a bidirectional relationship between sleep impairment and ADHD. Difficulty in falling and staying asleep and poor sleep quality are frequently observed in ADHD patients, and these conditions currently result in ADHD-like daytime behaviors (Ganelin-Cohen & Ashkenasi, 2013). Interestingly, substance abuse and sleep disorders also show a bidirectional relationship, with a high prevalence of sleep problems in dependent individuals (Mahfoud, Talih, Streem, & Budur, 2009) and individuals with history of childhood sleep problems showing a higher risk of developing drug abuse (Wong, Brower, Nigg, & Zucker, 2010). Thus, one could raise the hypothesis that sleep problems might be the link between ADHD and cocaine dependence. Ballon et al. showed that this relationship seem to be mediated by high levels of sensation seeking. In this scenario, sleep impairment amplifies the reactivity of brain networks that mediate reactivity to pleasurable and rewarding sensations, and a lack of sufficient sleep has been linked to both impulsivity and changes in reward-related decision making (Gujar, Yoo, Hu, & Walker, 2011; Schmidt, Gay, & Van der Linden, 2008). Ultimately, sleep impairment potentiates the neural mechanisms responsible for sensation seeking in humans (Joseph, Liu, Jiang, Lynam, & Kelly, 2009). Because sleep problems are a common feature in children with ADHD and sleep loss potentiates neural networks associated with rewarding sensations and may predispose the development of addiction, we propose a potential contribution of sleep problems to cocaine dependence in individuals with ADHD. We highlight that clinical evaluations of children with ADHD should assess sleep disorders, with possibilities for prevention of future undesirable outcomes. Declaration of Conflicting Interests

Do Naps and Nocturnal Sleep Impact Gastroesophageal Reflux Disease Differently

Reply. Multiple studies have confirmed that chronic abdominal pain (CAP) is the most frequent reason esophagogastroduodenoscopies (EGDs) are being performed in children. The use of EGD for CAP seems to be increasing, along with the number of biopsies performed during EGD. With clinical guidelines suggesting that most children with CAP have functional disorders, we sought to determine if these EGDs are largely unnecessary or if EGDs offer some value in children with CAP. We discovered substantial gaps in the existing evidence. The letter from Dr Mones states that “nighttime wakening is no longer considered an alarm symptom,” however, the Rome III criteria clearly state that “pain that wakes the child from sleep” is an alarm feature. Our study was designed to examine the yield of EGD in CAP, therefore we did not examine the yield of “simple, noninvasive tests.” Dr Mones also suggests noninvasive testing for patients with celiac and inflammatory bowel diseases, however, clinical guidelines state both of these conditions require an EGD. Although the presence of esophagitis orHelicobacter pylori as determined by biopsy specimen is not necessarily believed to cause abdominal pain, the evidence is either limited or inconclusive. Dr Bourke cautions against building multiple endoscopy units based on our study findings. However, there is a flaw in his calculations; our study is not applicable to all children who have CAP. Our study population includes only children with CAP who are referred to a gastroenterologist and selected for an EGD. This would include a small percentage of the total number of children with CAP. We agree that our observational study cannot account for a placebo effect or determine causality. However, our finding of a 38% diagnostic yield is not an exaggeration. Sheiko et al also reported abnormal findings in 35% of EGDs. Our multicenter retrospective analysis of 1190 EGDs confirmed a 38% yield in children referred to a gastroenterologist for CAP. Our message is as follows: more studies are needed to uncover the possible utility of EGD in a subset of children with CAP. By defining this subset, we may be able to better use clinical reasoning, laboratory examinations, and empiric drug adjustment to avoid invasive procedures. We must not be afraid to “challenge long held beliefs and clinical experience suggesting that children with CAP invariably have functional, nonorganic disorders.” The case of eosinophilic esophagitis illustrates that the findings and implications of biopsy specimens taken during EGD can change over time, so we must constantly evaluate our practices and beliefs.