Psychopharmacologia (PSYCHOPHARMACOLOGY)

Publications in this journal

• Article: Alcohol attenuates amygdala–frontal connectivity during processing social signals in heavy social drinkers

  Stephanie M. Gorka, Daniel A. Fitzgerald, Andrea C. King, K. Luan Phan
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  ABSTRACT: Rationale: Convergent evidence shows that alcohol exerts its effects on social behavior via modulation of amygdala reactivity to affective stimuli. Given that affective processing involves dynamic interactions between the amygdala and the prefrontal cortex (PFC), alcohol’s effects are likely to extend beyond regional changes in brain activity to changes that manifest on a broader functional circuit level. Objective: The current study examines alcohol’s effects on functional connectivity (i.e., "coupling") between the amygdala and the PFC during the processing of socio-emotional stimuli using functional magnetic resonance imaging (fMRI). Methods: In a randomized, double blind, placebo-controlled, within-subjects cross-over design, 12 heavy, social drinkers performed an fMRI task designed to probe amygdala response to socio-emotional stimuli (angry, fearful, and happy faces) following acute ingestion of alcohol or placebo. Functional connectivity between the amygdala and PFC was examined and compared between alcohol and placebo sessions using a conventional generalized psychophysiological interaction (gPPI) analysis. Results: Relative to placebo, alcohol reduced functional coupling between the amygdala and the right orbitofrontal cortex (OFC) during processing of both angry and fearful faces. Alcohol also reduced functional coupling between the amygdala and left OFC during processing of happy faces. Conclusions: These preliminary findings suggest that alcohol’s effects on social behavior may be mediated by alternations in functional connectivity between the amygdala and OFC during processing of emotional faces.
  Psychopharmacologia 04/2013;
• Article: Glutamatergic and GABAergic modulations of ultrasonic vocalizations during maternal separation distress in mouse pups

  Aki Takahashi, Jasmine J. Yap, Dawnya Zitzman Bohager, Sara Faccidomo, Terry Clayton, James M. Cook, Klaus A. Miczek
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  ABSTRACT: IntroductionDysregulation of GABAergic inhibition and glutamatergic excitation has been implicated in exaggerated anxiety. Mouse pups emit distress-like ultrasonic vocalizations (USVs) when they are separated from their dam/siblings, and this behavior is reduced by benzodiazepines (BZs) which modulate GABAergic inhibition. The roles of glutamate receptors on USVs remain to be investigated. Materials and methodsWe examined the roles of glutamate receptor subtypes on mouse pup USVs using N-methyl-d-aspartate (NMDA) receptor antagonists with different affinities [dizocilpine (MK-801), memantine, and neramexane] and group II metabotropic glutamate receptor agonist (LY-379268) and antagonist (LY-341495). These effects were compared with classic BZs: flunitrazepam, bromazepam, and chlordiazepoxide. To assess the role of GABAA receptor subunits on USVs, drugs that have preferential actions at different GABAA-α subunits (L-838417 and QH-ii-066) were tested. Seven-day-old CFW mouse pups were separated from their dam and littermates and placed individually on a 19°C test platform for 4min. Grid crossings and body rolls were measured in addition to USVs. ResultsDizocilpine dose-dependently reduced USVs, whereas memantine and neramexane showed biphasic effects and enhanced USVs at low to moderate doses. The NMDA receptor antagonists increased locomotion. LY-379268 reduced USVs but also suppressed locomotion. All BZs reduced USVs and increased motor incoordination. Neither L-838417 nor QH-ii-066 changed USVs, but both induced motor incoordination. ConclusionLow-affinity NMDA receptor antagonists, but not the high-affinity antagonist, enhanced mouse pup distress calls, which may be reflective of an anxiety-like state. BZs reduced USVs but also induced motor incoordination, possibly mediated by the α5 subunit containing GABAA receptors.
  Psychopharmacologia 02/2013; 204(1):61-71.
• Article: Zolmitriptan: A 5-HT1B/D agonist, alcohol, and aggression in mice.

  Rosa M. M. de Almeida, Ella M. Nikulina, Sara Faccidomo, Eric W. Fish, Klaus A. Miczek
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  ABSTRACT: Examined whether zolmitriptan (ZLM) has potential anti-aggressive effects. A 2nd objective was to study whether pre- or post-synaptic receptors mediate these anti-aggressive effects. The anti-aggressive effects of ZLM were studied in male CFW mice during 5-min resident-intruder confrontations. The ZLM dose-effect determinations were repeated after pretreatment with GR 127935. Mice were treated concurrently with alcohol and ZLM in order to compare the effects of this agonist on species-typical and alcohol-heightened aggression. Mice were infused with the neurotoxin 5,7-DHT into the raphé area to eliminate somatodendritic and presynaptic autoreceptors. The anti-aggressive effects of ZLM or CP-94,253 were assessed 10 days after the lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and prefrontal cortex. ZLM exerted behaviorally specific anti-aggressive effects. The reduction in aggression was antagonized by GR 127935, indicated by a rightward shift in the dose-effect curves of zolmitriptan, showing the specificity for the 5-HT 1B receptors. ZLM also decreased alcohol-heightened aggression with equal efficacy. The anti-aggressive effects of CP-94,253 and ZLM remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal 5-HT by 60–80%. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
  Psychopharmacologia 10/2012;
• Article: Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring

  James P. Kesby, Jonathan C. O’Loan, Suzanne Alexander, Chao Deng, Xu-Feng Huang, John J. McGrath, Darryl W. Eyles, Thomas H. J. Burne
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  ABSTRACT: RationaleDevelopmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. MethodsDVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. ResultsDVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. ConclusionsThese results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders. KeywordsSchizophrenia–MK-801–Vitamin D–Locomotion–Prepulse inhibition–Animal model–NMDA receptor
  Psychopharmacologia 04/2012; 220(3):455-463.
• Article: Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

  Christiaan H. Vinkers, Hendrikus Hendriksen, Ruud van Oorschot, James M. Cook, Sundari Rallipalli, Shengming Huang, Mark J. Millan, Berend Olivier, Lucianne Groenink
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  ABSTRACT: RationaleRepeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission. ObjectiveThe present study investigated molecular and functional alterations in GABAA receptor (GABAAR) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF. MethodsCRF1 receptor, GABAAR, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABAAR α subunits and mGluRs in the amygdala and hypothalamus. ResultsCRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF1 receptor antagonists CP154,526 and DMP695, the GABAAR α3-selective agonist TP003 (0–3mg/kg) and the mGluR2/3 agonist LY379268 (0–10mg/kg) in the SIH test. The hypothermic effect of the non-selective GABAAR agonist diazepam (0–4mg/kg) and the α1-subunit-selective GABAAR agonist zolpidem (0–10mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABAAR α5-subunit preferential compound SH-053-2′F-R-CH3 and mGluR5 antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABAAR α2 subunit and mGluR3 mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α1 and α5 GABAAR subunits. ConclusionsWe found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABAA and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission. KeywordsSIH–Corticotropin-releasing factor–Anxiety–Stress–Temperature–Emotional fever–Glutamate–Benzodiazepine–Mouse
  Psychopharmacologia 04/2012; 219(3):897-908.
• Article: Spatial memory alterations by activation of septal 5HT1A receptors: no implication of cholinergic septohippocampal neurons

  Julie Koenig, Lucas Lecourtier, Brigitte Cosquer, Patricia Marques Pereira, Jean-Christophe Cassel
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  ABSTRACT: IntroductionIn rats, activation of medial septum (MS) 5-HT1A receptors with the 5-HT1A/5-HT7 receptor agonist 8-OH-DPAT disrupts encoding and consolidation, but not retrieval of a spatial memory in the water maze task. These findings might be explained by an action of 8-OH-DPAT on 5-HT1A receptors located on cholinergic neurons which the drug could transiently hyperpolarise. If so, selective damage of these neurons should mimic the effects of 8-OH-DPAT, or, at least, synergistically interfere with them. MethodsTo test this hypothesis, rats were subjected to intraseptal infusions of 8-OH-DPAT (or phosphate-buffered saline) during acquisition of a water maze task before and/or after 192 IgG-saporin-induced MS cholinergic lesion (vs. sham-operated). ResultsWe confirmed that only pre-acquisition intraseptal 8-OH-DPAT infusions prevented learning and subsequent drug-free retrieval of the platform location in intact rats and found that (1) the cholinergic lesion did not prevent recall of the platform location, and (2) the impairing effects of 8-OH-DPAT were similar in sham-operated and lesioned rats, whether naïve or not, to the task before lesion surgery. ConclusionsAn action of 8-OH-DPAT on only MS cholinergic neurons is not sufficient to account for the drug-induced memory impairments. A concomitant 8-OH-DPAT-induced hyperpolarisation of cholinergic and/or GABAergic and/or glutamatergic neurons (intact rats), or of only GABAergic and/or glutamatergic ones after cholinergic lesion, might be necessary to obliterate task acquisition, confirming that, in the MS, (1) the three neuronal populations could cooperate to process hippocampal-dependent information, and (2) non-cholinergic septohippocampal neurons might be more important than cholinergic ones in serotonin-induced modulation of hippocampus-dependent memory processing. Keywords8-OH-DPAT–192 IgG-saporin–Hippocampus–Medial septum–Memory–Septohippocampal interface–Water maze
  Psychopharmacologia 04/2012; 214(2):437-454.
• Article: Alpha-lipoic acid, a scavenging agent for H2O2, reduces ethanol-stimulated locomotion in mice

  Juan Carlos Ledesma, Carlos M. G. Aragon
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  ABSTRACT: RationaleThe main system of central ethanol oxidation is mediated by the enzyme catalase. By reacting with H2O2, brain catalase forms compound I (the catalase–H2O2 system), which is able to oxidize ethanol to acetaldehyde in the brain. Previous studies have demonstrated that pharmacological manipulations of brain catalase activity modulate the stimulant effects of ethanol in mice. However, the role of H2O2 in the behavioral effects of ethanol has not yet been clearly addressed. ObjectivesIn the present study, we investigated the effects of alpha-lipoic acid (LA), a scavenging agent for H2O2, on ethanol-induced locomotor stimulation. MethodsCD-1 mice were pretreated with LA [0–100mg/kg, intraperitoneally (IP)] 0–60min prior to administration of ethanol (0–3.75g/kg, IP). In another experiment, animals were pretreated with LA (0, 25, or 50mg/kg, IP) 30min before cocaine (10mg/kg, IP), amphetamine (2mg/kg, IP), or caffeine (25mg/kg, IP). After these treatments the animals were placed in an open-field chamber and their locomotor activity was measured for 20min. ResultsLA 25, 50, and 100mg/kg IP prevented ethanol-induced locomotor stimulation. LA did not affect the locomotor-stimulating effects of cocaine, amphetamine, and caffeine. Additionally, we demonstrated that LA prevents the inactivation of brain catalase by 3-amino-1,2,4-triazole, thus indicating that H2O2 levels are reduced by LA. ConclusionsThese data support the idea that a decrease in cerebral H2O2 production by LA administration inhibits ethanol-stimulated locomotion. This study suggests that the brain catalase–H2O2 system, and by implication centrally formed acetaldehyde, plays a key role in the psychopharmacological effects of ethanol. KeywordsEthanol–Acetaldehyde–Catalase–Lipoic acid–H2O2 –Locomotor stimulation
  Psychopharmacologia 04/2012; 219(1):171-180.
• Article: fMRI of the brain’s response to stimuli experimentally paired with alcohol intoxication

  David A. Kareken, Nicholas Grahame, Mario Dzemidzic, Melissa J. Walker, Cari A. Lehigh, Sean J. O’Connor
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  ABSTRACT: RationaleIndividuals learn associations between alcohol’s sensory properties and intoxication, with such conditioned stimuli (CS) becoming involved in craving and relapse. However, these CS also carry idiosyncratic associations. ObjectivesThis study aimed to test brain responses to novel CS conditioned with alcohol intoxication. MethodsFourteen heavy drinkers (age 24.9 ± 3.2) performed a reaction time task with embedded novel geometric CS and were told only that the task was to measure alcohol’s effect on speed. Rapid intravenous alcohol infusion (the unconditioned stimulus; UCS) began with the appearance of a CS+, using pharmacokinetic modeling to increment breath alcohol by ~18mg% in 200s per each of six CS–UCS pairings. Placebo–saline infusion with CS− used the same infusion parameters in same-day randomized/counterbalanced sessions. The next morning subjects, connected to inactive intravenous pumps, underwent functional magnetic resonance imaging (fMRI) of the same task with mixed brief presentations of CS+, CS−, and irrelevant CS and were told that alcohol could be infused at any time during imaging. ResultsCS− responses were significantly greater than those of CS+ in medial frontal cortex. Notably, CS+ responses were negative, suggesting reduced neural activity. Negative activity was most pronounced in early scans, extinguishing with time. As subjects were told that alcohol could be administered in fMRI, a CS+ without alcohol is similar to a negative prediction error, with associated reduced frontal activity during withheld reward. ConclusionsNovel stimuli relatively free of demand characteristics can be classically conditioned to intermittent brain exposure of even low alcohol concentrations, permitting imaging studies of conditioned alcohol expectancies. KeywordsAlcohol–Alcoholism–Imaging–Brain–Frontal–Classical conditioning
  Psychopharmacologia 04/2012; 220(4):787-797.
• Article: Depot naltrexone decreases rewarding properties of sugar in patients with opioid dependence

  Daniel D. Langleben, Elliot L. Busch, Charles P. O’Brien, Igor Elman
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  ABSTRACT: BackgroundOpioid neurotransmission mediates hedonic value of sweet tastants; their intake may be exaggerated by the consumption of exogenous opioids (e.g., opioid dependence). Sweet Taste Test (STT) is a validated quantitative instrument assessing taste perception and hedonic features of sugar (sucrose) using a randomized and double-blind administration at five different sucrose concentrations ranging from 0.05 to 0.83M. MethodsThe STT and cue-induced craving procedure were administered to opioid-dependent patients (n = 15) before and 1week after the injection of a long-acting depot naltrexone (XRNT) preparation. ResultsAnalyses of covariance, employing sucrose concentration and its perceived taste as covariates, showed that XRNT therapy significantly reduced the self-reported hedonic and motivational characteristics of sucrose. Greater reductions in both these characteristics were associated with more diminution in the cue-induced opioid craving. ConclusionsOpioid antagonism in opioid-dependent subjects leads to a smaller sweet taste reward, which, in turn, may be proportional to decreased opioid craving. These pilot results support the heuristic value of the STT as a potential marker of the XRNT treatment response and call for further inquiry into potential clinical applications of the test. KeywordsNaltrexone–Glucose–Sucrose–Opioid–Antagonist–Reward–Motivation–Hedonic–Sweet taste test–Craving–Incentive sensitization
  Psychopharmacologia 04/2012; 220(3):559-564.
• Article: Mutual independence of 5-HT2 and α1 noradrenergic receptors in mediating deficits in sensorimotor gating

  Sarah K. Baisley, Katherine L. Fallace, Abha K. Rajbhandari, Vaishali P. Bakshi
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  ABSTRACT: RationalePrepulse inhibition (PPI), a preattentional information-filtering mechanism, is disrupted by serotonin (5-HT) or norepinephrine (NE) agonists to model deficits seen in schizophrenia, but whether this effect occurs through interactions between these systems is not known. ObjectivesThese studies investigated whether PPI/activity changes induced by agonists of one system were dependent on neurotransmission within the other. MethodsMale Sprague–Dawley rats received the 5-HT2 receptor agonist DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane) (0, 0.3mg/kg), with or without antagonists for α1 (prazosin:0, 0.3, or 1mg/kg) or β (timolol:0, 3, or 10mg/kg) receptors or their combination (0 or 0.3mg/kg prazosin + 3mg/kg timolol), or the 5-HT2 antagonist ritanserin (0, 2mg/kg). Separately, the α1-adrenergic receptor agonist cirazoline (0, 0.68mg/kg) was given with and without ritanserin (0, 0.5, or 2mg/kg) or the NE antagonists (0 or 0.3mg/kg prazosin + 3mg/kg timolol). Finally, combinations of subthreshold doses of DOI (0, 0.01, 0.025mg/kg) and cirazoline (0, 0.1, 0.25mg/kg) were tested for their ability to disrupt PPI, and concomitant administration of all three antagonists (0 vs. 0.3mg/kg prazosin + 3mg/kg timolol + 2mg/kg ritanserin) was assessed for its ability to modify PPI. Locomotion was assessed in an additional set of experiments. ResultsDoses/combinations of prazosin and timolol that reversed cirazoline-induced effects did not alter DOI-induced effects, and ritanserin did not affect cirazoline at doses that blocked DOI-mediated effects. Concomitant antagonism of α1 + β + 5-HT2 receptors did not modify PPI, nor did combinations of subthreshold doses of cirazoline and DOI. Conclusions5-HT2 receptors and α1 and β NE receptors may act through independent mechanisms to modulate sensorimotor gating and locomotor activity. KeywordsStartle–Schizophrenia–Noradrenergic–Serotonergic–Locomotion–Stereotypy
  Psychopharmacologia 04/2012; 220(3):465-479.
• Article: The role of conditioning history and reinforcer strength in the reinforcement enhancing effects of nicotine in rats

  Matthew I. Palmatier, Laura C. O’Brien, Melanie J. Hall
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  ABSTRACT: RationaleNicotine (NIC) administration can increase behaviors that result in delivery of non-drug reinforcers (e.g., salient sensory stimuli). However, little is known about the circumstances under which NIC increases these behaviors. ObjectiveThe present studies sought to extend the reinforcement enhancing effects of NIC to sucrose rewards for which intensity could be systematically manipulated. MethodIn Experiment 1, rats were trained to respond for sucrose (30% w/v) on a progressive ratio (PR) schedule of reinforcement and were pretreated with NIC (0.4mg/kg free-base) or physiological saline (SAL). The intensity of the sucrose reward was manipulated over subsequent testing sessions (0–60% w/v). Similar procedures were used in Experiment 2; however, each subject received only one sucrose concentration (0–20%) to control for conditioning history. In Experiment 3, a fixed ratio 3 (FR3) schedule of reinforcement was used to investigate putative activating effects of NIC. Experiment 4 investigated whether NIC pretreatment would reduce sucrose intake in limited-access drinks. ResultsIn Experiment 1, NIC increased the motivation to obtain all sucrose concentrations, including water. However, when conditioning history was controlled (Experiment 2) the reinforcement enhancing effects of NIC were systematically related to the strength of the reinforcer. In Experiment 3, NIC neither increased nor decreased responding for sucrose. In Experiment 4, NIC reduced sucrose intake, but only at concentrations that resulted in peak drink volumes (5–20%). ConclusionThe results suggest that the reinforcement enhancing effects of NIC depend on conditioning history and do not appear to be the result of simple behavioral activation. KeywordsAcetylcholine–Behavior–Dopamine–Drug abuse–Nicotine–Reward–Reinforcement
  Psychopharmacologia 04/2012; 219(4):1119-1131.
• Article: GABAB receptor blockade in the hippocampus affects sensory and sensorimotor gating in Long-Evans rats

  Jingyi Ma, L. Stan Leung
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  ABSTRACT: RationaleSensory and sensorimotor gating deficits are observed in schizophrenia. GABAB receptor deficiency is also detected in the hippocampus of schizophrenic patients. ObjectivesThe present study tested the hypothesis that GABAB receptors in the hippocampus contribute to paired-pulse gating of hippocampal auditory-evoked potentials (AEP) and auditory prepulse inhibition (PPI) in Long-Evans rats. MethodsGating of hippocampal AEP, or PPI, was examined before and after administration of GABAB receptor antagonist, CGP56999A or CGP35348, or saline was administered either systemically (intra-peritoneally (i.p.)) or infused bilaterally into the hippocampus 15min before gating measurements. ResultsSystemic injection of CGP56999A, at a dose of 0.2 and 0.4mg/kgi.p. resulted in reduced gating of hippocampal AEP in a dose-dependent manner. Reduced gating was found at conditioning-test interpulse intervals of 300–500ms, but not 100–200ms. Reduced gating of hippocampal AEP also followed bilateral infusion of CGP56999A into the hippocampus (0.1μg/μL/side). Gating loss was attributed to a decreased conditioning response and an increased test response after systemic or local injection of CGP56999A. Robust PPI was found at prepulse–pulse intervals of 30–100ms, and this PPI was reduced by hippocampal infusion of CGP56999A in a dose-dependent manner, as compared with saline infusion. ConclusionsBlockade of hippocampal GABAB receptors led to deficits in sensory and sensorimotor gating, which are symptoms of schizophrenia. KeywordsHippocampus–Auditory gating–Prepulse inhibition–GABAB receptors–Schizophrenia
  Psychopharmacologia 04/2012; 217(2):167-176.
• Article: Active cyamemazine metabolites in patients treated with cyamemazine (Tercian®): influence on cerebral dopamine D2 and serotonin 5-HT2A receptor occupancy as measured by positron emission tomography (PET)

  Yann Hodé, Amine Benyamina, Christophe Arbus, Matthias Reimold
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  ABSTRACT: RationaleCyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D2 receptors, which induces few extrapyramidal adverse effects, due to a potent antagonistic action at serotonin 5-HT2A receptors. In vitro studies showed that the desmethyl metabolite of cyamemazine (N-desmethyl cyamemazine) has similar affinity for 5-HT2A receptors as cyamemazine, whereas its D2 receptor affinity is eight times lower (Benyamina et al. in Eur J Pharmacol 578(2–3):142–147, 2008). Moreover, cyamemazine sulfoxide showed modest affinity for 5-HT2A receptors. ObjectivesThe objective of this study is to measure steady-state plasma levels of N-desmethyl cyamemazine and cyamemazine sulfoxide in patients treated with clinically relevant doses of cyamemazine and correlate them with dopamine D2 and serotonin 5-HT2A receptor occupancies (RO) assessed by positron emission tomography (PET). MethodsEight patients received Tercian® 37.5, 75, 150, or 300mg/day according to their symptoms. Dopamine D2 and serotonin 5-HT2A RO were assessed at steady-state cyamemazine plasma levels using [11C]raclopride and [11C]N-methyl-spiperone, respectively, for PET. Plasma levels of cyamemazine metabolites were determined using a validated high-performance liquid chromatography (PerkinElmer) associated with a mass spectrometry detection (API 365, PE SCIEX). The apparent equilibrium inhibition constant (K i) was estimated by fitting RO with plasma levels of cyamemazine metabolites at the time of the PET scan. ResultsAfter 6days of cyamemazine administration, plasma N-desmethyl cyamemazine reached steady-state levels at 2 to 12 times higher than those previously found for cyamemazine (Hode et al. in Psychopharmacology (Berl) 180:377–384, 2005). Plasma levels of N-desmethyl cyamemazine were closely related to striatal D2 RO (r 2 = 0.942) and extrastriatal 5-HT2A RO (r 2 = 0.901). The estimated K i(app) value of N-desmethyl cyamemazine for striatal D2 receptors was about fivefold higher than that for extrastriatal 5-HT2A receptors (48.7 vs. 10.6nM). Striatal D2 RO increased with the plasma levels of N-desmethyl cyamemazine but remained below 75% even at its highest levels. At steady state, plasma cyamemazine sulfoxide levels were about double those of N-desmethyl cyamemazine. However, these cyamemazine sulfoxide levels should not contribute significantly to in vivo 5-HT2A and D2 receptor occupancy. ConclusionsIn patients orally given cyamemazine, N-desmethyl cyamemazine, but not cyamemazine sulfoxide, should significantly contribute to in vivo frontal 5-HT2A and striatal D2 receptor occupancy. The higher in vivo affinity of cyamemazine and its desmethyl metabolite for serotonin 5-HT2A receptors compared with dopamine D2 receptors should explain the low incidence of extrapyramidal adverse effects. KeywordsPositron emission tomography (PET)–Cyamemazine–Metabolites–Dopamine D2 –Serotonin 5-HT2A –[11C]raclopride–[11C]N-methyl-spiperone–Receptor occupancy
  Psychopharmacologia 04/2012; 217(3):315-321.
• Article: Neuroprotection of paliperidone on SH-SY5Y cells against β-amyloid peptide25-35, N-methyl-4-phenylpyridinium ion, and hydrogen peroxide-induced cell death

  Ming-Chang Yang, For-Wey Lung
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  ABSTRACT: RationaleAntipsychotic drugs (APDs) were widely used in treating schizophrenia. Some APDs were reported to have neuroprotective effects against neurotoxicants in the cell level. ObjectivesThus, one typical APD (haloperidol) and three atypical APDs (paliperidone, olanzapine, and risperidone) were tested whether they provide neuroprotection against stressor-induced cell death of SH-SY5Y. MethodsHydrogen peroxide, N-methyl-4-phenylpyridinium ion, and β-amyloid peptide were used to treat cells with or without preconditioning by APDs; cell survival and indicators of oxidative stress were measured, respectively. ResultsPaliperidone has the lowest baseline cytotoxicity compared with other APDs at 24h; in addition, the paliperidone group showed a better survival than the other APD groups (P < 0.05). In stressor challenging, with a fixed concentration of stressors, olanzapine provided the best neuroprotection at 100μM against Aβ25-35 and MPP+ (P < 0.05). In contrast, paliperidone works finely at low concentrations (10 and 50μM) against Aβ25-35 and MPP+ and solely protected SH-SY5Y from hydrogen peroxide. At 100μM, paliperidone completely diminished cell reduction induced by different stressors, regardless of their dosages. Paliperidone was demonstrated with a higher oxidative stress-scavenging properties than other APDs in several aspects, such as generated bulk glutathione, low HNE, and protein carbonyl productions. Contradictorily, olanzapine, at 24h, also enhanced HNE and protein carbonyl productions, which may underlie its induced cytotoxicity. ConclusionsDifferent APDs exhibit variations against different stressors. Paliperidone might be useful not only in alleviating oxidative stress induced by Aβ25-35 and MPP+ but also in providing neuroprotection against hydrogen peroxide. KeywordsAtypical antipsychotics–β-amyloid– N-methyl-4-phenylpyridinium ion–Hydrogen peroxide–Cell death–Neuroprotection
  Psychopharmacologia 04/2012; 217(3):397-410.
• Article: Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit, Romano et al.

  Anthony G. Romano, Jennifer L. Quinn, Luchuan Li, Kuldip D. Dave, Emmanuelle A. Schindler, Vincent J. Aloyo, John A. Harvey
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  ABSTRACT: RationaleParenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT2A receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT2A-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning. ObjectiveThis study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT2A-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning. Materials and methodsLSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT2A receptor as measured by a decrease in DOI-elicited head bobs. ResultsAcute parenteral or intrahippocampal LSD elicited a 5-HT2A but not a 5-HT2C-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls. ConclusionsLSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT2A receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT2A receptor within the hippocampus as a result of repeated administration of its agonist (LSD). KeywordsHallucinogens-LSD-DOI-DOM-5-MeO-DHT-Learning-Eyeblink conditioning-Rabbit-Serotonin 5-HT2A receptor-Serotonin 5-HT2C receptor-Hippocampus
  Psychopharmacologia 04/2012; 212(3):441-448.
• Article: The N251K functional polymorphism in the α2A-adrenoceptor gene is not associated with depression: a study in suicide completers

  Idoia Martín-Guerrero, Luis F. Callado, Koldo Saitua, Guadalupe Rivero, África García-Orad, J. Javier Meana
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  ABSTRACT: Rationaleα2A-Adrenoceptor up-regulation and supersensitivity have been described in the postmortem brains of depressed suicide victims and in the platelets of depressed subjects. The C to G transversion at nucleotide 753 (Asn to Lys change at amino acid 251 or N251K) is a low-frequency polymorphism of the α2A-adrenoceptor gene that results in a gain-of-function phenotype. A previous study has suggested an association between completed suicide and this polymorphism. ObjectivesThe single functional polymorphism N251K was tested in a large sample (n=214) of completed suicides, controlling for the antemortem psychiatric diagnosis, and matched controls (n=176). MethodsPostmortem brain DNA was extracted and the α2A-adrenoceptor gene fragment was amplified by polymerase chain reaction, followed by a StyI restriction endonuclease digestion. Amplified products were sequenced to confirm the presence of the α2A-adrenoceptor gene fragment where the polymorphism is located. ResultsThe N251K polymorphism was absent in both suicide victim and control groups. No association between the polymorphism and suicide or depression was established. ConclusionsThe N251K polymorphism does not represent a genetic factor to explain the α2A-adrenoceptor hyperactivity in the brains of depressed suicide victims. Association between suicide and this polymorphism was not replicated.
  Psychopharmacologia 04/2012; 184(1):82-86.
• Article: Dipyridamole monotherapy in schizophrenia

  Ikwunga Wonodi, Hirekatur V. Gopinath, Judy Liu, Helene Adami, L. Elliot Hong, Robert Allen-Emerson, Robert P. McMahon, Gunvant K. Thaker
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  ABSTRACT: BackgroundEmerging data indicate the neuromodulator adenosine may play a role in the therapeutics of schizophrenia. Adenosine A2A receptor stimulation exerts a functional antagonism at postsynaptic D2 receptors. Data from animal models relevant to schizophrenia support a therapeutic effect of modulating adenosinergic transmission in the ventral striatum. One previous clinical trial showed superiority of adjunctive dipyridamole, an adenosine reuptake inhibitor, compared to placebo in ameliorating positive symptoms in schizophrenia patients. ObjectivesThe aim of this study was to examine the effects of dipyridamole monotherapy of 200mg/day on positive and negative symptoms, with the goal of determining dosing for future adjunctive studies in schizophrenia. MethodsTwenty symptomatic schizophrenia participants were randomized to a 6-week double-blind trial comparing olanzapine (20mg/day) to dipyridamole monotherapy (200mg/day). Thirteen participants completed the treatment phase (eight on dipyridamole; five on olanzapine). ResultsThe olanzapine group showed a trend (p = 0.08) for superiority on BPRS total scores (mean ± SD: total BPRS score decreasing from 36.8 ± 2.3 at week 1, to 33.2 ± 5.5 at the end of the study). The mean total BPRS scores decreased from 36.4 ± 5.3 to 34.0 ± 7.7 in the dipyridamole group. ConclusionsAlthough these pilot data do not support a significant antipsychotic effect of dipyridamole monotherapy, the results provide some evidence for examining dipyridamole (200mg/day) as adjunct to symptomatic antipsychotic-treated schizophrenia patients. KeywordsDipyridamole–Olanzapine–Adenosinergic–Dopaminergic–Purinergic–Positive symptoms–Schizophrenia–Proof of concept
  Psychopharmacologia 04/2012; 218(2):341-345.
• Article: Work aversion and associated changes in dopamine and serotonin transporter after methamphetamine exposure in rats

  Alisa R. Kosheleff, Millie Grimes, Steve J. O’Dell, John F. Marshall, Alicia Izquierdo
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  ABSTRACT: RationaleMethamphetamine (mAMPH) administration in animals can lead to a variety of cognitive and behavioral deficits. We previously reported non-acute reversal learning impairments after a single-day administration of mAMPH, providing evidence of this drug’s selective effects on inhibitory control. Effortful decision-making (i.e., how much effort to invest in rewards) is an aspect of cognition that has not yet been explored after mAMPH. ObjectivesGiven that frontostriatal circuitry mediating this type of choice is vulnerable to the effects of mAMPH, we tested the hypothesis that mAMPH may also affect decision-making involving effort, another form of cognitive flexibility. MethodsWe examined the non-acute effects of an experimenter-administered single day of mAMPH on effort discounting. In this task, rats previously treated with mAMPH or saline (SAL) could select a high reward at the cost of climbing over a tall barrier or a low reward with no barrier impeding its procurement. ResultsFollowing treatment, mAMPH rats were more work-averse than SAL rats. A control task showed there were no treatment group differences when the high and low rewards involved equal work: all rats chose the high reward preferentially. There were no significant treatment group differences in [125I]RTI-55 binding to dopamine and serotonin transporters (DAT, SERT) in any of the regions assayed; however, there were significant correlations of accumbens DAT and cingulate SERT with post-treatment performance. ConclusionsThese findings suggest that even modest dose mAMPH exposure has long-lasting effects on effortful decision-making and may do so through influences on forebrain monoaminergic systems. KeywordsCost–Reward processing–Decision-making–Cognitive flexibility–Dopamine transporter–Serotonin transporter
  Psychopharmacologia 04/2012; 219(2):411-420.