Eleftheria Tsaltas

Reinforced Spatial Alternation as an Animal Model of Obsessive-Compulsive Disorder (OCD): Investigation of 5-HT2C and 5-HT1D Receptor Involvement in OCD Pathophysiology

BACKGROUND This study introduces a laboratory model of compulsive behavior based on persistence in the context of rewarded spatial alternation. METHODS Rats were screened for spontaneous persistence during T-maze reinforced alternation. Experiment 1: One high and one low spontaneous persistence group (n = 8) received 20 injections of fluoxetine, a matched pair saline, both followed by 4 days of meta-chlorophenylpiperazine (mCPP) challenge. Experiment 2: Five matched groups of rats (n = 9) received pretreatment (20 injections) with fluoxetine, mCPP, desipramine, diazepam or saline, followed by 4 days of mCPP challenge (fluoxetine in mCPP group). After washout, animals received 2 days of naratriptan, followed by another 2-day mCPP challenge. RESULTS In both experiments mCPP significantly increased persistence in saline controls. Fluoxetine also acutely increased persistence scores: after a gradual return to baseline, these scores showed tolerance to mCPP. Experiment 1: This pattern was significant in high but not low initial persistence groups. Experiment 2: Fluoxetine and mCPP showed cross-tolerance. Neither desipramine nor diazepam protected against mCPP challenge. Persistence scores returned to baseline during washout and naratriptan and were thereafter increased by another mCPP challenge in all but the fluoxetine and mCPP groups, suggesting 5-HT2C receptor mediation. CONCLUSIONS This model is based on spontaneous persistence behavior showing pharmacological responses concordant with those of compulsive symptomatology.

Serotonergic and dopaminergic modulation of attentional processes

Disturbances in attentional processes are a common feature of several psychiatric disorders such as schizophrenia, attention deficit/hyperactivity disorder and Huntingtons disease. The use of animal models has been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic and vice-versa. In this chapter, a comparative and integrated account is provided on the neuroanatomical and neurochemical modulation of basic behavioural operations such as selective attention, vigilance, set-shifting and executive control focusing on the comparative functions of the serotonin and dopamine systems in the cognitive control exerted by the prefrontal cortex. Specifically, we have reviewed evidence emerging from several behavioural paradigms in experimental animals and humans each of which centres on a different aspect of the attentional function. These paradigms offering both human and animal variants include the five-choice serial reaction time task (5CSRTT), attentional set-shifting and stop-signal reaction time task. In each case, the types of operation that are measured by the given paradigm and their neural correlates are defined. Then, the role of the ascending dopaminergic and serotonergic systems in the neurochemical modulation of its behavioural output are examined, and reference is made to clinical implications for neurological and neuropsychiatric disorders which exhibit deficits in these cognitive tests.

Enhancing effects of chronic lithium on memory in the rat

BACKGROUND In spite of recent enrichment of neurochemical and behavioural data establishing a neuroprotective role for lithium, its primary effects on cognitive functioning remain ambiguous. This study examines chronic lithium effects on spatial working memory and long-term retention. METHODS In three discrete experiments, rats subjected to 30 daily intraperitoneal injections (2mmol/kg) of lithium (lithium groups: serum lithium=0.5+/-0.4mEq/l, 12h post-injection) or saline (controls) were trained in 0-s delay T-maze alternation and then tested in 30-, 45- and 60-s delay alternation (Experiments 1, 2, 3, respectively). Animals from Experiment 1 were further tested in one-trial step-through passive avoidance under mild shock parameters (0.5mA, 1s). Retention was assessed 6h later. Daily lithium or saline injections continued throughout behavioural testing. RESULTS Lithium animals were indistinguishable from controls during 0-delay alternation baseline (Experiments 1-3, accuracy>88%) but showed significantly higher accuracy than controls at 30- and 45-s delays (93% versus 85% and 92% versus 82%, Experiments 1 and 2, respectively). At 60-s delay (Experiment 3) this beneficial effect of lithium was no longer apparent (lithium and control accuracy=78%). In Experiment 4, the shock used did not support 6-h passive avoidance retention in controls, whereas lithium animals showed significant step-through latency increases. CONCLUSIONS Chronic lithium enhanced spatial working memory and promoted long-term retention of a weak aversive contingency. The results suggest that lithium may have potential as a cognitive enhancer.

Lithium and cognitive enhancement: leave it or take it?

RationaleLithium is established as an effective treatment of acute mania, bipolar and unipolar depression and as prophylaxis against bipolar disorder. Accumulating evidence is also delineating a neuroprotective and neurotrophic role for lithium. However, its primary effects on cognitive functioning remain ambiguous.ObjectivesThe aim of this paper is to review and combine the relevant translational studies, focusing on the putative cognitive enhancement properties of lithium, specifically on learning, memory, and attention.DiscussionThese properties are also discussed in reference to research demonstrating a protective action of lithium against cognitive deficits induced by various challenges to the nervous system, such as stress, trauma, neurodegenerative disorders, and psychiatric disorders.ConclusionsIt is suggested on the basis of the evidence that the cognitive effects of lithium are best expressed and should, therefore, be sought under conditions of functional or biological challenge to the nervous system.

Neuropsychological and hypothalamic–pituitary-axis function in female patients with melancholic and non-melancholic depression

BackgroundExecutive function deficits in depression implicate involvement of frontal–striatal circuits. However, studies of hypothalamic–pituitary-axis (HPA) function suggest that stress-related brain changes of hippocampus may also implicate prefrontal–hippocampal circuits, which may explain the profile of both executive dysfunction and memory deficits. In this study we examined the performance of patients with major depressive disorder (MDD) on tasks of memory and executive function in relation to melancholic features and to cortisol levels. Our hypothesis was that raised cortisol levels in melancholic patients would correlate with these deficits.MethodForty female MDD patients, 20 having melancholic features (MEL vs. Non-MEL), and 20 sex- age- and education-matched normal controls were investigated using the Cambridge neuropsychological test automated battery (CANTAB), to assess memory (paired associative learning, PAL; short-term recognition memory, SRM) and executive (intradimensional/ extradimensional set-shifting, ID/ED; Stockings of Cambridge, SOC) functions. Plasma and salivary cortisol levels were measured.ResultsThe MDD patients performed worse than controls on PAL and both executive tasks. The MEL group differed from controls on all tests, and differed from the non-MEL only at the ED stage of the ID/ED task. Patient cortisol levels were within the normal range and did not correlate with neuropsychological performance for any group.ConclusionsMDD patients showed neuropsychological deficits on tasks of executive function and memory, supporting the model of frontal-temporal dysfunction. MEL vs. non-MEL performed worse overall and demonstrated a qualitative difference in set shifting, perhaps implicating more extensive prefrontal involvement. Cortisol levels did not correlate with depression severity or the observed deficits.

Doubtful association of antipsychotic polypharmacy and high dosage with cognition in chronic schizophrenia

Despite consistent recommendations for antipsychotic monotherapy, antipsychotic polypharmacy (the use of two or more antipsychotic agents) and the administration of excessive doses (higher than 1000 mgr/day of chloropromazine equivalents) is a common practice in schizophrenia. The therapeutic and adverse effects of this practice are poorly studied, in particular with regards to the cognitive symptoms of the disease. In this cross-sectional study we investigated the cognitive effects of antipsychotic polypharmacy and excessive doses in 53 patients with chronic schizophrenia using non-verbal cognitive tasks involving speed of movement, memory and executive functions. No significant difference in performance scores was found between the groups under polypharmacy and monotherapy, or the groups receiving either excessive or normal doses of antipsychotics. Since these groups did not also differ in demographic, clinical, other pharmacologic parameters, in the relative anticholinergic potency of antipsychotics, or in intelligence scores, we raise doubts about the association of polypharmacy and excessive doses with non-verbal cognitive performance in chronic schizophrenia.

Enhancing effects of lithium on memory are not by-products of learning or attentional deficits

We recently reported that chronic lithium (LiCl), at therapeutic plasma levels, enhanced spatial working memory and retention of an aversive contingency. Here we examine the possibility that these effects be secondary to LiCl effects on the ability to ignore irrelevant stimuli or on fear conditioning. In Experiment 1, rats subjected to >30 daily intraperitoneal injections of LiCl (2mmol/kg) or saline underwent conditioned emotional response training (CER: 2 CS pairings with 1-s, 1-mA shock) after 40 pre-exposures either to the CS (latent inhibition-LiCl/latent inhibition-saline, n=8) or to another stimulus (control-LiCl/control-saline, n=8). In Experiment 2, eight LiCl and eight saline animals were trained in on-the-baseline (VI-60s) CER (1-s, 0.15-mA shock in CS-signalled periods) in the Skinner box. In Experiment 1, LiCl animals showed normal latent inhibition. In both experiments, their fear conditioning was unimpaired. Therefore, the previously reported memory improvement under chronic lithium cannot be attributed to changes in the ability to ignore irrelevant stimuli or in fear conditioning.

5-HT2C receptor involvement in the control of persistence in the Reinforced Spatial Alternation animal model of obsessive-compulsive disorder

OBJECTIVE The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. METHODS Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. RESULTS Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. CONCLUSIONS These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD.

Contrasting patterns of deficits in visuospatial memory and executive function in patients with major depression with and without ECT referral

BACKGROUND The pretreatment neuropsychological profile of drug-resistant patients with major depressive disorder (MDD) referred for electroconvulsive therapy (ECT) may differ from that of their drug-respondent MDD counterparts. Such differences could help in identifying distinct MDD subtypes, thus offering insights into the neuropathology underlying differential treatment responses. METHOD Depressed patients with ECT referral (ECTs), depressed patients with no ECT referral (NECTs) and non-psychiatric Controls (matched groups, n=15) were assessed with memory and executive function tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS ECTs scored significantly lower than NECTs in the Mini-Mental State Examination (MMSE; p=0.01). NECTs performed worse than Controls in the Paired Associates Learning (PAL) task (p<0.03; Control/NECT p<0.01) and the Spatial Recognition Memory (SRM) task (p<0.05; Controls/NECTs p<0.05); ECTs performed between Controls and NECTs, not differing from either. In the Intra/Extradimensional (IED) set-shifting task, ECTs performed worse that Controls and NECTS (IED: p<0.01; Controls/ECTs p<0.01), particularly in the shift phases, which suggests reduced attentional flexibility. In Stockings of Cambridge (SOC), ECTs abandoned the test early more often than Controls and NECTs (H=11, p<0.01) but ECTs who completed SOC performed comparably to the other two groups. CONCLUSIONS A double dissociation emerged from the comparison of cognitive profiles of ECT and NECT patients. ECTs showed executive deficits, particularly in attentional flexibility, but mild deficits in tests of visuospatial memory. NECTs presented the opposite pattern. This suggests predominantly frontostriatal involvement in ECT versus temporal involvement in NECT depressives.

Cognitive effects of pregabalin in the treatment of long-term benzodiazepine-use and dependence.

Long‐term benzodiazepine (BDZ) use and dependence affect cognitive functioning adversely and partly irreversibly. Emerging evidence suggests that pregabalin (PGB) might be a safe and efficacious treatment of long‐term BDZ use. The aim of the present study was to investigate the changes in several core cognitive functions after successful treatment of long‐term BDZ use and dependence with PGB.