European Neuropsychopharmacology (v.18, #4)

Antidepressant drugs and memory: Insights from animal studies by Santiago Monleón; Concepción Vinader-Caerols; M. Carmen Arenas; Andrés Parra (235-248).
This is a selective review of the literature concerning the effects of antidepressant drugs on animal memory, which was performed with the aid of the PubMed database. Monoamine oxidase inhibitors tend to either have no effect on memory or result in its improvement. Studies with cyclic antidepressants have reported no effect or, more often, memory impairments. Pre-training administration of selective serotonin reuptake inhibitors (SSRIs) has been shown to have either no effect on memory or undermine it (with some isolated exceptions, in which improvements have been recorded), while post-training administration of SSRIs has been demonstrated to improve memory or have no effect. A small group formed by the remaining antidepressants has been shown to improve memory, with the exception of trazodone, which impairs memory. These findings are discussed in the light of knowledge regarding the actions of antidepressants on several neurotransmission systems. The possibility that the effects of antidepressants on memory are the core of the therapeutic effects of these drugs is also considered.
Keywords: Antidepressants; Memory; Learning; Rats; Mice;

Platelet 18 kDa Translocator Protein density is reduced in depressed patients with adult separation anxiety by Beatrice Chelli; Stefano Pini; Marianna Abelli; Alessandra Cardini; Lisa Lari; Matteo Muti; Camilla Gesi; Giovanni B. Cassano; Antonio Lucacchini; Claudia Martini (249-254).
Recent studies indicate that Adult Separation Anxiety Disorder (ASAD) may represent a discrete diagnostic entity worthy of attention. Adults with separation anxiety report extreme anxiety and fear about separations from major attachment figures (partner, children or parents). These symptoms affect individual's behavior, lead to severe impairment in social relationships and are not better accounted for by the presence of agoraphobia. In a previous study we found platelet expression reduction of the 18 kDa Translocator Protein (TSPO) (the new nomenclature for the peripheral-type benzodiazepine receptor) in patients with panic disorder who also fulfilled the diagnostic criteria for ASAD.To explore whether separation anxiety might be a factor differentiating TSPO expression in a sample of patients with major depression.The equilibrium binding parameters of the specific TSPO ligand [3H]PK 11195 were estimated on platelet membranes from 40 adult outpatients with DSM-IV diagnosis of MDD, with or without separation anxiety symptoms, and 20 healthy controls. Patients were assessed by SCID-I, HAM-D, the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS-A) and the Adult Separation Anxiety Self-report Checklist (ASA-27).A significant reduction of platelet TSPO density mean value was found in depressed patients with associated ASAD symptoms, while no significant differences were found between depressed patients without ASAD and the control group. Individual TSPO density values were significantly and negatively correlated with both SCI-SAS-A and ASA-27 total scores, but not with HAM-D total score or HAM-D anxiety/somatization factor score.The reduction of platelet TSPO density in our sample of patients with depression was specifically related to the presence of ASAD. These data suggest that TSPO expression evaluation is a useful biological marker of ASAD.
Keywords: Translocator Protein (18 kDa); Major depressive disorder; Adult separation anxiety; Platelets; Radioligand binding assay; PK 11195;

Dehydroepiandrosterone and monoamines in the limbic system of a genetic animal model of childhood depression by O. Malkesman; Y. Braw; E. Ram; R. Maayan; A. Weizman; N. Kinor; G. Yadid; A. Weller (255-261).
Monoamines and dehydroepiandrosterone (DHEA) levels were measured in a genetic animal model for childhood depression in four subcortical structures: nucleus accumbens (Nac), ventral tegmental area (VTA), amygdala and hypothalamus. The “depressive-like” strain was the Flinders Sensitive Line (FSL), compared to their controls, Sprague–Dawley (SD) rats. Prepubertal FSL rats showed abnormal levels of only a few monoamines and their metabolites in these brain regions. This is in contrast to former studies, in which adult FSL rats exhibited significantly higher levels of all the monoamines and their metabolites measured. These different abnormal monoamine patterns between the “depressed” prepubertal rats and their adults, may help to explain why depressed children and adolescents fail to respond to antidepressant treatment as well as adults do. On the other hand, FSL prepubertal rats exhibited the same pattern of abnormal DHEA basal levels as was found in adults in previous experiments. The results from the current study may imply that treatment with DHEA could be a promising novel therapeutic option for depressed children and adolescents that fail to respond to common (monoaminergic) antidepressant treatments.
Keywords: Childhood depression; Monoamines; DHEA; Limbic system; Animal model; FSL;

Opiate addiction is a chronic disorder characterized by relapse behaviour, often preceded by craving and anhedonia. Chronic craving and anhedonia have been associated with low availability of dopamine D2 receptors (D2Rs) and cue-elicited craving has been linked with endogenous dopamine release. We studied D2R availability and cue-elicited endogenous dopamine release in 12 abstinent opiate-dependent males and 18 age-matched male controls with [123I]IBZM SPECT. Craving was manipulated with a video containing heroin-related stimuli. Moreover, chronic craving, anhedonia and cue-elicited craving were measured. We found lower baseline D2R availability in opiate-dependent subjects than controls in the left caudate nucleus. D2R availability in the putamen correlated negatively with years of opiate use. Opiate-dependent subjects demonstrated higher dopamine release after cue-exposure in the right putamen than controls. Chronic craving and anhedonia were positively correlated with DA release. Treatment strategies that increase D2Rs may, therefore, be an interesting approach to prevent relapse in opiate addiction.
Keywords: Opiate; Addiction; Dopamine; Striatum; Craving; D2 receptor;

Evidence exists for a dopaminergic system dysregulation in mood disorders. In particular, depression may be accompanied by a relative fall of brain dopamine (DA) availability, while the increase of dopamine D2/D3 receptors (D2R/D3R) binding may reflect a compensatory change following primary reduction of mesolimbic DA levels. It is well established that D3Rs, acting as autoreceptors, inhibit DA synthesis and release, although lack of selective compounds have limited the progress in understanding D3Rs role in mood disorders. Aim of this study was to assess the behavioral responses of D3R-deficient (D3 −/−) mice tested in the forced swim test (FST) and to evaluate their sensitivity to the treatment with different antidepressant drugs. Different groups of mice received one injection of the tricyclic compound, clomipramine (1, 5 and 10 mg/kg) or of one the selective serotonin reuptake inhibitors (SSRIs), paroxetine, sertraline or citalopram (1, 4 and 16 mg/kg), 30 min prior the behavioral test. Vehicle-injected wild type (WT) mice and D3 −/− animals were used as controls and submitted to the same experimental procedure. In a preliminary experiment, vehicle-injected D3 −/− mice, but not their littermates, failed to show an increased immobility time in FST as compared to intact controls, suggesting an increased resistance to injection-induced stress in the former. Clomipramine 1 mg/kg failed to affect behavioral responses of both D3 −/− mice and WT animals. After the 5 mg/kg dose, D3 −/− and WT mice showed a better performance in FST than vehicle-injected controls, with a lower immobility time exhibited by D3 −/− mice than that shown by WT animals. No difference was found between WT mice treated with the highest dose of clomipramine (10 mg/kg) and the respective controls, although D3 −/− mice exhibited a decreased immobility time as compared to vehicle-injected controls. In contrast to WT animals, when treated with 1 mg/kg sertraline and the 4 mg/kg dose of every SSRI D3 −/− mice exhibited a decreased immobility time in FST in comparison to vehicle-injected controls. Furthermore, 16 mg/kg doses of citalopram, paroxetine or sertraline induced a greater reduction of immobility time in D3 −/− mice than in WT-treated animals as compared to their respective controls. These data suggest that D3 −/− mice, as being more resistant to stressful procedure than WT littermates, are more sensitive to antidepressants in FST paradigm than the former. Although the present data do not allow any conclusion on the neurochemical base of this difference, it might be possible that the greater sensitivity to antidepressants depends on a higher DA levels in mesolimbic pathways following the lack of D3Rs.
Keywords: Dopamine D3 receptors; Knockout mice; Forced swim test (FST); Antidepressant drugs;

Cerebral blood flow effects of acute intravenous heroin administration by Markus Kosel; Roger S. Noss; Robert Hämmig; Peter Wielepp; Petra Bundeli; Rebeca Heidbreder; Jane A. Kinser; Rudolf Brenneisen; Hans-Ulrich Fisch; Sarah Kayser; Thomas E. Schlaepfer (278-285).
We examined acute effects of intravenous diacetylmorphine (heroin) administration — which induces a characteristic biphasic response: A short rush-sensation associated with intense pleasurable feelings followed by a subjectively different period of euphoria on cerebral blood flow. This was assessed in nine male heroin dependent patients participating in a heroin maintenance program in a setting resembling everyday pattern of heroin abuse. 99mTc-HMPAO was administered 45 s (rush) and 15 min (euphoria) after administration of i.v. heroin and 45 s after administration of saline (placebo). Plasma concentration of diacetylmorphine and its metabolites were measured with high-pressure liquid chromatography (HPLC). Compared to the euphoria condition, rush was associated with blood flow increase in the left posterior cerebellar lobe, left anterior cingulate gyrus and right precuneus. Our results are in line with recent reports indicating that the cerebellum is an important component in functional brain systems subserving sensory and motor integration, learning, modulation of affect, motivation and social behaviour, which all play important roles in reinforcing properties of opioids.
Keywords: Heroin; Diacetylmorphine; Opioid; Single photon emission computed tomography; Addiction; Cerebellum;

We evaluated the involvement of dorsal hippocampus (DH) 5-HT1A receptors in the mediation of the behavioral effects caused by the pharmacological manipulation of 5-HT neurons in the median raphe nucleus (MRN). To this end, we used the rat elevated T-maze test of anxiety. The results showed that intra-DH injection of the 5-HT1A/7 agonist 8-OH-DPAT facilitated inhibitory avoidance, an anxiogenic effect, without affecting escape. Microinjection of the 5-HT1A antagonist WAY-100635 was ineffective. In the elevated T-maze, inhibitory avoidance and escape have been related to generalized anxiety and panic disorders, respectively. Intra-MRN administration of the excitatory aminoacid kainic acid, which non-selectively stimulates 5-HT neurons in this brain area facilitated inhibitory avoidance and impaired escape performance, but also affected locomotion. Intra-MRN injection of WAY-100635, which has a disinhibitory effect on the activity of 5-HT neurons in this midbrain area, only facilitated inhibitory avoidance. Pre-administration of WAY-100635 into the DH blocked the behavioral effect of intra-MRN injection of WAY-100635, but not of kainic acid. These results indicate that DH 5-HT1A receptors mediate the anxiogenic effect induced by the selective stimulation of 5-HT neurons in the MRN.
Keywords: Median raphe nucleus; Dorsal hippocampus; 5-HT1A receptors; Serotonin; Generalized anxiety and panic;

Global DNA methylation is influenced by smoking behaviour by Thomas Hillemacher; Helge Frieling; Susanna Moskau; Marc A.N. Muschler; Alexander Semmler; Johannes Kornhuber; Thomas Klockgether; Stefan Bleich; Michael Linnebank (295-298).
The level of epigenetic DNA methylation is an important factor in the pathogenesis of various human diseases. As smoking may influence DNA methylation, we investigated the effect of smoking habits on global DNA methylation in 298 genomic DNA samples (73 fathers, 69 mothers and 156 offspring). We did not find a direct effect of smoking on global DNA methylation. However, there was an association of the offspring's DNA methylation with paternal DNA methylation that was strongest if both had never smoked (R 2 corr  = 0.41, Beta = 0.68, p  = 0.02) and completely vanished if the offspring smoked or had ever smoked. These findings suggest an association between smoking behaviour and global DNA methylation, which may be of importance for a wide range of diseases.
Keywords: Epigenetics; Global DNA methylation; Nicotine; Smoking; Heredity; Imprinting;

Guanosine possesses specific modulatory effects on NMDA receptor-mediated neurotransmission in intact mice by Stephen I. Deutsch; Richard B. Rosse; Katrice D. Long; Brooke L. Gaskins; John Mastropaolo (299-302).
Guanosine, a purine nucleotide, promotes the reuptake of l-glutamate by astrocytes; astrocytic reuptake of glutamate is a major mechanism of its synaptic inactivation. The current experiments showed that guanosine reduced the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor “open-channel” blocker, to raise the threshold voltage for electrically-precipitated tonic hindlimb extension in unstressed intact mice. This modulatory effect may be due to guanosine's removal of glutamate from the synaptic cleft, resulting in a reduced proportion of NMDA receptor-associated ion channels in the open configuration. The modulatory effect of guanosine on MK-801's ability to disrupt rotorod performance in unstressed mice or antagonize electrically-precipitated seizures in stressed mice was not seen. The inability to demonstrate modulation in the rotorod paradigm may reflect the sensitivity of this measure of motor incoordination to MK-801's disruptive effects. Whereas failure to see this effect in our incremental electroconvulsive shock paradigm in stressed mice may be due to the fact that stress and guanosine act in the same direction to reduce MK-801's antiseizure efficacy. Given the phencyclidine model of schizophrenia and its pharmacological actions as a noncompetitive NMDA receptor “open-channel” blocker and guanosine's antagonistic effect on MK-801's antiseizure efficacy in unstressed mice, the current data support development of guanine-based purines for the treatment of at least some aspects of schizophrenia.
Keywords: Guanosine; Glutamate; Schizophrenia;

α1-Noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access by Sunmee Wee; Chitra D. Mandyam; Dusan M. Lekic; George F. Koob (303-311).
In rodents, extended access to cocaine produces an escalation in cocaine self-administration that has face and construct validity for human compulsive drug intake. Here we report that rats with six-hour access (long access, LgA) to cocaine self-administration produced a higher breakpoint for cocaine using a progressive-ratio schedule than rats with one-hour access (short access, ShA), and prazosin (α1 receptor antagonist) reduced the higher breakpoint for cocaine in LgA rats. Additionally, the number of neurons with α1-adrenergic receptor-like immunoreactivity in the bed nucleus of stria terminalis (BNST) was found to be much lower in LgA rats than in ShA and drug-naive rats. In contrast, UK14304 (α2 receptor agonist) and betaxolol (β1 receptor antagonist) had no effect on cocaine self-administration in either group. The data suggest that activation of the α1-noradrenergic system, perhaps in the BNST, is associated with increased motivation for cocaine in rats with extended access.
Keywords: Cocaine; Self-administration; Escalation; Alpha-1 noradrenergic receptor; Rats; Bed nucleus of stria terminalis;

Hypothalamus volume in twin pairs discordant for schizophrenia by P. Cédric M.P. Koolschijn; Neeltje E.M. van Haren; Hilleke E. Hulshoff Pol; René S. Kahn (312-315).
Monozygotic and same-sex dizygotic twin pairs discordant for schizophrenia were compared with matched control twin pairs in order to disentangle genetic and environmental contributions to variation in hypothalamus volume. A decrease in hypothalamus volume was found in patients or discordant twin pairs compared to healthy controls which could be attributed to the decrease in total brain volume. Higher within-twin pair similarities in monozygotic compared to dizygotic twin pairs, suggests that hypothalamus volume might be partly genetically controlled.
Keywords: Schizophrenia; Twins; Hypothalamus; Discordant; Genetic risk; Magnetic resonance imaging;