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Inflammation, oxidative and nitrosative stress underlie depression being assessed in rodents by the systemic administration of lipopolysacharide (LPS). There is an increasing body of evidence of an involvement of nitric oxide (NO) pathway in depression, but this issue was not investigated in LPS-induced model. Thus, herein we evaluated the effects of NO-pathway-modulating drugs, named aminoguanidine, l-NAME, sildenafil and l-arginine, on the behavioral (forced swimming test [FST], sucrose preference [SPT] and prepulse inhibition [PPI] of the startle) and neurochemical (glutathione [GSH], lipid peroxidation, IL-1β) alterations in the prefrontal cortex, hippocampus and striatum as well as in BDNF levels in the hippocampus 24h after LPS (0.5mg/kg, i.p.) administration, a time-point related to depressive-like behavior. Twenty-four hours post LPS there was an increase in immobility time in the FST, decrease in sucrose preference and PPI levels accompanied by a decrease in GSH levels and an increase in lipid peroxidation, IL-1β and hippocampal BDNF levels suggestive of a depressive-like state. The pretreatment with the NOS inhibitors, l-NAME and aminoguanidine as well as sildenafil prevented the behavioral and neurochemical alterations induced by LPS, although sildenafil and l-NAME were not able to prevent the increase in hippocampal BDNF levels induced by LPS. The iNOS inhibitor, aminoguanidine, and imipramine prevented all behavioral and neurochemical alterations induced by LPS. l-arginine did not prevent the alterations in immobility time, sucrose preference and GSH induced by LPS. Taken together our results show that the NO-cGMP pathway is important in the modulation of the depressive-like alterations induced by LPS., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Antiretroviral therapy has revolutionized the treatment of the human immunodeficiency virus because it has improved the clinical outcomes of patients. It is essential that these drugs cross the blood-brain barrier, since the virus is present in the central nervous system (CNS). Efavirenz passes through this barrier satisfactorily and can reduce the deleterious central effects of the human immunodeficiency virus. However, patients treated with efavirenz have been observed to experience psychiatric symptoms such as mania, depression, suicidal thoughts, psychosis, and hallucinations. The aim of this review is to describe the pharmacokinetic and pharmacodynamic properties of efavirenz and its major neuropsychiatric symptoms and the neurochemical pathways associated with these changes in the CNS. The databases Medline and Lilacs were used to search for review articles and preclinical and clinical research articles published from January 1996 to 2010. The search terms used were efavirenz, central nervous system, neuropsychiatry, neurotransmitters, adverse effects, and neurochemistry. Subject categories considered included effects on viral replication, pharmacokinetic and pharmacodynamic properties of efavirenz, and neuropsychiatric adverse effects including time course, duration, and probable mechanisms involved. The mechanisms involved in these changes include interference with cytochrome P450 enzymes, cytokines, tryptophan-2-3-dioxygenase, and brain creatine kinase.

: Oxidative stress has been implicated in a large number of human degenerative diseases, including epilepsy. Levetiracetam (LEV) is a new antiepileptic agent with broad-spectrum effects on seizures and animal models of epilepsy. Recently, it was demonstrated that the mechanism of LEV differs from that of conventional antiepileptic drugs. Objectifying to investigate if LEV mechanism of action involves antioxidant properties, lipid peroxidation levels, nitrite-nitrate formation, catalase activity, and glutathione (GSH) content were measured in adult mice brain. The neurochemical analyses were carried out in hippocampus of animals pretreated with LEV (200 mg/kg, i.p.) 60 min before pilocarpine-induced seizures (400 mg/kg, s.c.). The administration of alone pilocarpine, 400 mg/kg, s.c. (P400) produced a significant increase of lipid peroxidation level in hippocampus. LEV pretreatment was able to counteract this increase, preserving the lipid peroxidation level in normal value. P400 administration also produced increase in the nitrite-nitrate formation and catalase activity in hippocampus, beyond a decrease in GSH levels. LEV administration before P400 prevented the P400-induced alteration in nitrite-nitrate levels and preserved normal values of catalase activity in hippocampus. Moreover, LEV administration prevented the P400-induced loss of GSH in this cerebral area. The present data suggest that the protective effects of LEV against pilocarpine-induced seizures can be mediated, at least in part, by reduction of lipid peroxidation and hippocampal oxidative stress.

1. The study of changes that persist after drug discontinuation could be fundamental to understand the mechanisms involved in craving and relapse. 2. In this work the changes occurring in muscarinic, D1- and D2-like receptors after 30 min (immediate), 1 day (early), 5 and 30 days (late) withdrawal periods were studied, in the striatum of rats treated once a day for 7 days with cocaine 20 and 30 mg/kg, i.p. 3. Binding assays were performed in 10% homogenates and ligands used were [3H]-N-methylscopolamine, [3H]-SCH 23390, and [3H]-spiroperidol for muscarinic (M1 + M2-like), D1-, and D2-like receptors, respectively. 4. Muscarinic receptors presented a downregulation at all doses and discontinuation times, while the dissociation constant (Kd) for this receptor decreased after 30 min, 5 and 30 days abstinence times. In relation to D1-like receptors we found an antagonistic effect with 100% increase in receptor number 30 min after the last cocaine injection, but after 1-day withdrawal a downregulation was observed with both doses that persisted up to 30 days, only with the higher dose. The dissociation constant value (Kd) for this receptor showed a decrease only with 5 and 30 days withdrawal. An increase occurred with D2-like receptors at all doses and withdrawal periods studied, while Kd increased in 30-min, 5, and 30 days withdrawal. 5. In this work we found that the subchronic cocaine treatment produces early and long-lasting modifications in cholinergic muscarinic as well in dopaminergic receptors that persist up to 30 days of cocaine withdrawal.

Pilocarpine and lithium-pilocarpine can induce seizures and brain damage in adult rats. However, manifestation of cerebral lesions seems to be an age-related phenomenon suggesting that maturational states of neurocircuitry may be involved. We have studied behavior changes, cerebral histopathology, and muscarinic and dopaminergic receptors density in rodents subjected to lithium-pilocarpine treatment. Wistar rats, at two different ages (21 days and 2 months), were treated with pilocarpine (15 mg/kg, SC), lithium (3 mEq/kg, IP), atropine (50 mg/kg, IP) and the combination of lithium to pilocarpine. Histopathologic studies showed that younger animals were more resistant to the development of cerebral changes and there was a preferential involvement of the striatum (Wilcoxon p = 0.02) as opposed to more generalized areas in adult animals such as hippocampus and neocortex. Lithium treatment induced an upregulation of muscarinic receptors at both ages, and this effect was reversed in younger animals after pilocarpine administration. Lithium also induced an upregulation of dopaminergic receptors in the striatum at both ages (p < 0.05), and this effect was not reversed after pilocarpine administration. Our data confirm that young animals show less brain damage after lithium-pilocarpine, and main alterations in dopaminergic receptors density occur in young and older animals after treatment with lithium and lithium combined to a low dose of pilocarpine.

The mechanism of action of lithium (Li) alone or with pilocarpine (Pilo), focusing on muscarinic and dopaminergic systems and also on phosphoinositide metabolism was studied. Li (3 mEq/kg) administered to rats once (1 d) or daily for 7 days (7 d), 24 h before Pilo (15 mg/kg), exacerbated cholinergic signs, leading to tremors. convulsions and brain lesions. Increases in muscarinic receptors (MR) of 29 and 49% were observed in the hippocampus after atropine (Atro) and Li-Atro-Pilo treatments, respectively, as compared to controls (Atro) and the Li-Pilo group (Li-Atro-Pilo). In the striatum, except for the 37% increase in the Li-Atro (50 mg/kg)-Pilo group as compared to the Li-Pilo one, no other changes were observed in MR. A decrease of 32% on average in D2-like receptors (D2R) was detected in the hippocampus in the group Li-7d. On the contrary, in the striatum an increase (25%) in the Li-7d group was observed and this effect was blocked by Li-Pilo. As far as inositol phosphates (IP) and phosphatidylinositol-4,5-biphosphate (PIP2) metabolism is concerned, Li caused a decrease (28%) and an increase (60%) in IP and PIP2 accumulations, respectively, in hippocampus slices while Pilo only altered IP accumulation (32% decrease). In this area the association of Li-Atro (10 mg/kg)-Pilo also caused a decrease (36%) in PIP2 as compared to the Li-Pilo group. In striatal slices, except for the Li, Atro (10 mg/kg) and Li-Atro (10 mg/kg)-Pilo groups which showed a decrease (33 40%) in IP accumulation, no other alteration was detected. The potentiation of the effect of Pilo by Li does not seem to depend on the PI metabolism, but instead on its involvement with muscarinic and dopaminergic systems.