Nikolaos Pitsikas

Objective: Caffeine could improve cognitive functions, but study protocols usually prohibit drinking coffee before cognitive testing. However, regular coffee consumers may experience withdrawal effects when they cannot drink their habitual coffee, which may impair cognitive performance. Therefore, we tested the effects of overnight coffee abstinence in regular coffee consumers: once allowing to drink their coffee and once not drinking coffee. The cognitive performance was compared with non‐regular coffee consumers. Methods: Thirty regular coffee consumers (RCCs) and 25 non‐regular consumers (N‐RCCs) took part in this study. RCCs were tested after their habitual morning coffee (c‐RCC) and after overnight abstinence (a‐RCC); N‐RCCs were tested once. A cognitive battery assessed reaction time (RT), processing speed (digit symbol substitution test), working memory, verbal learning/memory and executive function (Stroop). Sleep quality was included as a covariate. Results: Compared to c‐RCC, overnight coffee abstinence significantly slowed RTs but did not affect the performance in the other cognitive tasks. In the a‐RCC condition, but not the c‐RCC condition, the RTs were slower than those of the N‐RCCs, while accuracy measures were comparable across groups. Sleep quality did not alter these findings. Conclusions: Overnight coffee abstinence selectively slowed RT, and no statistical support was found for effects on memory or executive function. This suggests that overnight coffee abstinence protocols may introduce withdrawal‐related RT slowing as a confound in habitual consumers, whereas other cognitive domains may not be affected. Allowing habitual consumers to maintain normal coffee intake could reduce this bias, supporting tailored rather than uniform abstinence requirements based on the specific outcomes studied.

Rationale That exaggerated production of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia is well-documented. Therefore, compounds that can adjust nitrergic activity such as NO synthase (NOS) inhibitors might be useful for the treatment of schizophrenia. Objectives The purpose of the current study was to investigate in the rat the ability of the neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) in counteracting schizophrenia-like-deficits caused by blockade of the N-methyl-D-aspartate (NMDA) receptor. Methods 7NI’s capacity to attenuate social withdrawal, disruption of emotional and recognition memory induced by NMDA receptor antagonists, namely ketamine and MK-801, were evaluated using the social interaction, the step-through passive avoidance, the object recognition and the object location tests. The efficacy of the joint administration of sub-threshold doses of 7-NI with those of the atypical neuroleptics clozapine and risperidone in attenuating recognition memory deficits induced by ketamine was also tested. Results 7-NI (1 and 3 mg/kg) alleviated social withdrawal caused by ketamine (8 mg/kg), abolished emotional memory impairments caused by MK-801 (0.1 mg/kg) and counteracted ketamine (3 mg/kg)-induced recognition memory deficits. Finally, co-administration of inactive doses of 7-NI (0.1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) reduced the detrimental effects of ketamine (3 mg/kg) on recognition memory. Conclusions The present results indicate that 7-NI is sensitive to glutamate blockade since it decreased behavioural impairments resembling the negative symptoms and cognitive deficits of schizophrenia. Moreover, these findings corroborate the potential of 7-NI as an adjunctive molecule for the medication of schizophrenia.

Rationale: Anxiety is a chronic severe psychiatric disorder. In a series of studies, the implication of the gaseous molecule nitric oxide (NO) in anxiety has been evidenced. Further, the outcome of preclinical research suggests that different NO donors, including sodium nitroprusside (SNP), have expressed an anxiolytic profile revealed in animal models of anxiety. Regardless of this, it is not yet clarified the mechanism(s) of action by which SNP induces its beneficial effects on anxiety. In this context, it has been hypothesized that these effects might be attributed to a potential interaction of this NO donor with the GABA type A and the 5-HT_1A serotonergic receptors. Objectives: The current study was designed to investigate this issue in the male rat. Methods: To this end, the light/dark box and the open field tests were utilized. Results: SNP (1 mg/kg, i.p.) applied acutely induced an anti-anxiety-like effect evidenced either in the light/dark box or in the open field test. Either the GABA_A receptor antagonist flumazenil (10 mg/kg, i.p.) or the 5-HT_1A serotonin receptor agonist 8-OH-DPAT (0.25 mg/kg, i.p.) suppressed the above reported anxiolytic effects of SNP. Conclusions: The results here reported propose a functional interaction between SNP with the GABAergic and the serotonergic systems on anxiety and thus, might offer a plausible explanation for SNP’s anxiolytic effects.

Schizophrenia is a chronic devastating psychiatric disease characterized by a high recurrence rate. Pharmacological management of this disorder appears disappointing since it is associated with a lack of efficacy for negative symptoms and cognitive deficits, typical features of schizophrenia, and the presence of severe undesired side effects. Thus, novel molecules with high efficacy and low toxicity for the treatment of schizophrenia are urgently needed. The involvement of the gaseous molecule nitric oxide in the pathogenesis of schizophrenia is well documented since low concentrations of nitric oxide are associated with this psychiatric disease. Therefore, chemicals able to normalize nitric oxide levels, such as nitric oxide donors, might be useful for the management of this type of schizophrenia. Molsidomine is a nitric oxide donor and is under investigation as a novel antischizophrenia agent. The aim of this review is to critically evaluate the potential efficacy of this molecule for the treatment of schizophrenia.

Experimental evidence indicates that the noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists ketamine and MK‐801 induce schizophrenia‐like symptoms in rodents, including cognitive deficits. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders comprising schizophrenia. The present study was designed to evaluate the efficacy of the joint administration of sub‐effective doses of crocins with those of the atypical antipsychotics clozapine and risperidone in alleviating nonspatial recognition and emotional memory deficits induced either by ketamine (3 mg/kg) or MK‐801 (0.1 mg/kg) in the rat. To this end, the object recognition and the step‐through passive avoidance tests were used. Co‐administration of sub‐effective doses of crocins (5 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted nonspatial recognition and emotional memory deficits induced by NMDA receptor antagonists. The current findings suggest that this combinatorial treatment was efficacious in attenuating cognitive impairments related to the blockade of the NMDA receptor. In addition, the present results support the potential of crocins as an adjunctive drug for the therapy of schizophrenia.

Close to 19% of the world population suffers from anxiety. Current medications for this chronic mental disorder have improved treatment over the last half century or more, but the newer anxiolytics have proved disappointing, and enormous challenges remain. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of anxiety. In particular, excessive NO production might contribute to its pathology. This implies that it might be useful to reduce nitrergic activity; therefore, molecules aiming to downregulate NO production such as NO synthase inhibitors (NOSIs) might be candidates. Here, it was intended to critically review advances in research on these emerging molecules for the treatment of anxiety disorders. Current assessment indicates that, although NOSIs are implicated in anxiety, their potential anti-anxiety action remains to be established.

Rationale: Several lines of evidence indicate that the neurosteroid dehydroepiandrosterone (DHEA) is involved in anxiety. BNN27 is a new DHEA derivative lacking steroidogenic effects. The beneficial effects exerted by BNN27 in preclinical models of schizophrenia and memory disorders have been recently reported. Objectives: The present study was designed to investigate the effects of this DHEA novel analog on anxiety-like behavior in rats. Methods: To this end, the light/dark box, the open field, the contextual fear conditioning, and the excessive self-grooming induced by the serotonin 5-HT_2c receptor agonist mCPP tests were utilized. Results: Animals treated acutely with BNN27 (1, 3, and 6 mg/kg) dose dependently spent more time in the bright compartment of the light/dark box and in the central zone of the open field with respect to their vehicle-treated cohorts. Further, BNN27 reduced freezing behavior and weakened the mCPP-induced excessive self-grooming. Conclusions: Our data indicate that BNN27 is a highly potent anxiolytic agent, as in all studied paradigms it showed anxiolytic-like effects in male rats.

Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It has been previously shown that the NO donor molsidomine attenuated schizophrenia-like behavioral deficits caused by glutamate hypofunction in rats. The aim of the current study was to investigate the efficacy of molsidomine and that of the joint administration of this NO donor with sub-effective doses of the non-typical antipsychotics clozapine and risperidone to counteract memory deficits associated with dysregulation of the brain dopaminergic system in rats. Molsidomine (2 and 4 mg/kg) attenuated spatial recognition and emotional memory deficits induced by the mixed dopamine (DA) D₁/D₂ receptor agonist apomorphine (0.5 mg/kg). Further, the joint administration of sub-effective doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted non-spatial recognition memory impairments caused by apomorphine. The present findings propose that molsidomine is sensitive to DA dysregulation since it attenuates memory deficits induced by apomorphine. Further, the current findings reinforce the potential of molsidomine as a complementary molecule for the treatment of schizophrenia.