D. Kontis

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.

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.

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.

P03-78 - No effects of polypharmacy and antipsychotic dose on spatial working memory in schizophrenia

Objectives Antipsychotic polypharmacy and high doses have been associated with poor outcome and increased adverse effects in schizophrenia. However, their relation to cognition has been poorly studied. Methods 40 right-handed patients (mean age: 42.87 years; SD:10.57) with DSM-IV schizophrenia, were recruited in an acute psychiatric ward. They were assessed on the Spatial Working Memory test (SWM) of the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Wechsler Adult Intelligence Scale (WAIS-III) at a time when they were able to cooperate with neuropsychological testing. The pattern of their pharmacological treatment was also assessed. Statistical correlation and Mann-Whitney tests were performed using the SPSS, as appropriate. Results 18 patients were receiving antipsychotic polypharmacy (≥2 antipsychotics) and 22 monotherapy. 13 patients received an excessive (≥1000 chloropromazine mEq(CmEq)/day), and 22 a normal antipsychotic dosage. No significant difference was detected on any of the SWM performance measures between the two groups of patients receiving either polypharmacy or monotherapy. These groups did not also differ in the WAIS full scale, performance or verbal IQ scores. When the patients were divided into two groups receiving either an excessive or a normal dose of antipsychotics, these two groups also showed a similar SWM and WAIS performance. The total antipsychotic dose showed negative but nonsignificant correlations with the SWM performance scores. Conclusions We did not detect any influence of antipsychotic polypharmacy or excessive dosing on spatial working memory in schizophrenia. This finding supports the independence of working memory deficits from the effects of treatment in schizophrenia.

P03-32 Directional persistence in the rewarded alternation model of obsessive-compulsive disorder is responsive to both dopaminergic and serotonergic manipulations

Rationale In the rewarded alternation model of obsessive compulsive disorder (OCD), the serotonin agonist m-chlorophenylpiperazine (mCPP) increases persistent behaviour, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI-fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increases, counteracted by mCPP pretreatment. Objectives This study a. further explores the apparent cross-tolerance between fluoxetine and mCPP and b. extends the model by investigating its sensitivity to dopaminergic manipulations (D2,3 agonism - quinpirole). Methods In both experiments, baseline and drug testing was carried out under daily T-maze alternation training. Exp.1 Matched group (n=8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration): 1. saline, 2. low-dose fluoxetine (2.5mg/kg), 3. low-dose mCPP (0.5mg/kg) or 4. combined fluoxetine+mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10mg/kg), the other with high-dose mCPP (2.5mg/kg). Exp.2 One group (n=12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg). Results ⁡ Exp.1 Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine+mCPP pretreatment afforded full protection from either challenge. Exp.2 Quinpirole significantly increased directional persistence after 13 administration days. Conclusions These results establish the sensitivity of the rewarded alternation OCD model to D2,3receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.

P03-33 An investigation of 5-HT2 involvement in the acute behavioural effects of fluoxetine and mCPP in an animal model of OCD

Background We reported that the non-specific 5HT agonist m-chlorophenylpiperazine (mCPP) and the SSRI fluoxetine (FLX) both cause acute persistence increases in the rewarded alternation (RA) model of OCD. Chronic pretreatment with either substance or their combined subclinical doses protects from this ‘pathogenic’ effect, so mCPP and fluoxetine exhibit cross-tolerance and synergy. Aims Using specific 5HT2A and 5HT2C receptor antagonists we investigated whether these receptors participate in a common mechanism of action mediating the acute mCPP/fluoxetine effect in our model. Methods Naive, male Wistars were used. Drugs used (intraperitoneally): FLX (10mg/kg), mCPP (2.5mg/kg), M100907 (5HT2A antagonist, 0.03mg/kg), SB242084 (5HT2C antagonist, 0.5mg/kg), vehicle. Experiments included a drug-free training/baseline phase in T-maze RA (group-matching for spontaneous persistence: SP). Experiment 1: Effects of M100907, SB242084, vehicle were assessed on 3 matched low SP and 3 high SP groups. Experiment 2: The acute effect of FLX, mCPP and saline were examined on RA in 3 SP-matched groups. Experiment 3: Effects of Vehicle+FLX, M100900+FLX, SB242084+FLX and Vehicle were examined on RA, in 4 SP-matched groups. Experiment 4: Correspondingly for mCPP. Results Experiment 1: Neither M100907 nor SB242084 affected high or low SP. Experiment 2 replicated the pathogenic effects of FLX/mCPP. Experiment 3: Neither M100907 nor SB242084 affected the pathogenic effect of FLX. Experiment 4: In contrast, SB242084 (but not M100907) significantly reduced the pathogenic mCPP effect. Conclusions The acute pathogenic action of mCPP, but not of FLX, involves 5HT2C but not 5HT2A receptors. The similar acute action of mCPP and FLX on persistence cannot be attributed to 5HT2 mediation.