Sintocalmy, a Passiflora incarnata Based Herbal, Attenuates Morphine Withdrawal in Mice.

Chronic opioid use changes brain chemistry in areas related to reward processes, memory, decision-making, and addiction. Both neurons and astrocytes are affected, ultimately leading to dependence. Passiflora incarnata L. (Passifloraceae) is the basis of frequently used herbals to manage anxiety and insomnia, with proven central nervous system depressant effects. Anti-addiction properties of P. incarnata have been reported. The aim of this study was to investigate the effect of a commercial extract of Passiflora incarnata (Sintocalmy®, Aché Laboratory) in the naloxone-induced jumping mice model of morphine withdrawal. In addition, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) levels were assessed in the frontal cortex and hippocampus, and DNA damage was verified on blood cells. In order to improve solubilization a Sintocalmy methanol extract (SME) was used. SME is mainly composed by flavonoids isovitexin and vitexin. The effects of SME 50, 100 and 200 mg/kg (i.p.) were evaluated in the naloxone-induced withdrawal syndrome in mice. SME 50 and SME 100 mg/kg decreased naloxone-induced jumping in morphine-dependent mice without reducing locomotor activity. No alterations were found in GFAP levels, however SME 50 mg/kg prevented the S100B increase in the frontal cortex and DNA damage. This study shows anti-addiction effects for a commercial standardized extract of P. incarnata and suggests the relevance of proper clinical assessment.

Plants with Anti-Addictive Potential.

Drug addiction is prevalent among individuals of modern society, being a major cause of disability and premature loss of life. Although the drug addiction have profound social, economical and health impact in the world population, its management remains a challenge as available pharmacological treatments remains ineffective for most people. The limited efficacy and adverse effects have led to a search for alternative therapies to treat drug addiction. In this context, natural products are an important source for new chemical substances with a potential therapeutic applicability. Therefore, this chapter will present data obtained after an extensive literature search regarding the use of medicinal plants as a pharmacological alternative for drug addiction treatment.

N-acetylcysteine Prevents Alcohol Related Neuroinflammation in Rats.

Alcoholism has been characterized as a systemic pro-inflammatory condition and alcohol withdrawal has been linked to various changes in the brain homeostasis, including oxidative stress and glutamate hyperactivity. N-acetylcysteine (NAC) is an anti-inflammatory and antioxidant multi-target drug with promising results in psychiatry, including drug addiction. We assessed the effects of NAC on the serum and brain inflammatory cytokines after cessation of chronic alcohol treatment in rats. Male Wistar rats received 2 g/kg alcohol or vehicle twice a day by oral gavage for 30 days. Rats were treated, from day 31 to 34, with NAC (60 or 90 mg/kg) or saline, intraperitoneally, once daily. Rats were sacrificed at day 35, trunk blood was collected and the frontal cortex and hippocampus dissected for assessment of TNF-α, IL-1ß, IL-6, IL-18, IL-10. NAC prevented the increase of pro-inflammatory cytokines and the decrease of anti-inflammatory cytokine in the frontal cortex and hippocampus. No changes were observed on serum cytokines. We conclude that NAC protects against inflammation induced by chronic (30 days) alcohol ingestion followed by 5 days cessation in two rat brain areas. Because inflammation has been documented and associated with craving and relapse in alcoholics, the data revealed by this study points to the validity of NAC clinical evaluation in the context of alcohol detoxification and withdrawal.

AMPA glutamate receptors mediate the antidepressant-like effects of N-acetylcysteine in the mouse tail suspension test.

The aim of this study was to investigate the involvement of noradrenaline, serotonin, and subtypes of glutamate receptors in the antidepressant-like effects of N-acetylcysteine (NAC). The tail suspension test was used with male CF1 albino mice. D,L-α-methyl-ρ-tyrosine and ρ-chlorophenylalanine methyl ester hydrochloride were used as synthesis inhibitors of noradrenaline and serotonin, respectively. N-methyl-D-aspartate (NMDA) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione were used as an NMDA receptor agonist and an α-amino acid-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptor antagonist, respectively. NAC (10, 25, and 50 mg/kg intraperitoneally) significantly (P<0.05) decreased tail suspension test immobility time, whereas pretreatment with D,L-α-methyl-ρ-tyrosine, ρ-chlorophenylalanine methyl ester hydrochloride, and NMDA partially prevented (P<0.05) the effects of NAC (25 mg/kg), and pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione completely abolished (P<0.01) this effect. The study corroborates the antidepressant-like effects of NAC in the TST, a model with a well-established predictive value. The results point to the key role of AMPA receptors in the mechanism of the antidepressant-like action of NAC. Like other AMPA potentiators, NAC indirectly modulates noradrenaline and serotonin pathways. It is suggested that the value of NAC as an antidepressant arises from combined and intertwined effects on a variety of pathways.

6­Sulfatoxymelatonin as a predictor of clinical outcome in depressive patients.

OBJECTIVES: This study established the value of the 6­sulfatoxymelatonin (aMT6s) urine concentration as a predictor of the therapeutic response to noradrenaline reuptake inhibitors in depressive patients. METHODS: Twenty-two women aged 18-60 years were selected. Depressive symptoms were assessed by using the Hamilton Depression Scale. Urine samples were collected at 0600-1200 h, 1200-1800 h, 1800-2400 h, and 2400-0600 h intervals, 1 day before and 1 day after starting on the nortriptyline treatment. Urine aMT6s concentration was analyzed by a one-way analysis of variance/Bonferroni test. Spearman's rank correlation coefficient was used to analyze the correlation between depressive symptoms after 2 weeks of antidepressant treatment and the increase in aMT6s urine concentration. RESULTS: Higher and lower size effect groups were compared by independent Student's t-tests. At baseline, the 2400­ to 0600­h interval differed from all other intervals presenting a significantly higher aMT6s urine concentration. A significant difference in aMT6s urine concentrations was found 1 day after treatment in all four intervals. Higher size effect group had lower levels of depressive symptoms 2 weeks after the treatment. A positive correlation between depressive symptoms and the delta of aMT6s in the 2400-0600 h interval was observed. CONCLUSION: Our results reinforce the hypothesis that aMT6s excretion is a predictor of clinical outcome in depression, especially in regard to noradrenaline reuptake inhibitors.

Alstonine as an antipsychotic: effects on brain amines and metabolic changes.

Managing schizophrenia has never been a trivial matter. Furthermore, while classical antipsychotics induce extrapyramidal side effects and hyperprolactinaemia, atypical antipsychotics lead to diabetes, hyperlipidaemia, and weight gain. Moreover, even with newer drugs, a sizable proportion of patients do not show significant improvement. Alstonine is an indole alkaloid identified as the major component of a plant-based remedy used in Nigeria to treat the mentally ill. Alstonine presents a clear antipsychotic profile in rodents, apparently with differential effects in distinct dopaminergic pathways. The aim of this study was to complement the antipsychotic profile of alstonine, verifying its effects on brain amines in mouse frontal cortex and striatum. Additionally, we examined if alstonine induces some hormonal and metabolic changes common to antipsychotics. HPLC data reveal that alstonine increases serotonergic transmission and increases intraneuronal dopamine catabolism. In relation to possible side effects, preliminary data suggest that alstonine does not affect prolactin levels, does not induce gains in body weight, but prevents the expected fasting-induced decrease in glucose levels. Overall, this study reinforces the proposal that alstonine is a potential innovative antipsychotic, and that a comprehensive understanding of its neurochemical basis may open new avenues to developing newer antipsychotic medications.

Melatonin and Depression: A Translational Perspective From Animal Models to Clinical Studies.

Daily rhythm of melatonin synchronizes the body to the light/dark environmental cycle. Several hypotheses have been raised to understand the intersections between melatonin and depression, in which changes in rest-activity and sleep patterns are prominent. This review describes key experimental and clinical evidence that link melatonin with the etiopathology and symptomatology of depressive states, its role in the follow up of therapeutic response to antidepressants, as well as the clinical evidence of melatonin as MDD treatment. Melatonin, as an internal temporal cue contributing to circadian organization and best studied in the context of circadian misalignment, is also implicated in neuroplasticity. The monoaminergic systems that underly MDD and melatonin production overlap. In addition, the urinary metabolite 6-sulfatoxymelatonin (aMT6) has been proposed as biomarker for antidepressant responders, by revealing whether the blockage of noradrenaline uptake has taken place within 24 h from the first antidepressant dose. Even though animal models show benefits from melatonin supplementation on depressive-like behavior, clinical evidence is inconsistent vis-à-vis prophylactic or therapeutic benefits of melatonin or melatonin agonists in depression. We argue that the study of melatonin in MDD or other psychiatric disorders must take into account the specificities of melatonin as an integrating molecule, inextricably linked to entrainment, metabolism, immunity, neurotransmission, and cell homeostasis.

Post-weaning social isolation impairs purinergic signaling in rat brain.

Early life stressors, such as social isolation (SI), can disrupt brain development contributing to behavioral and neurochemical alterations in adulthood. Purinergic receptors and ectonucleotidases are key regulators of brain development in embryonic and postnatal periods, and they are involved in several psychiatric disorders, including schizophrenia. The extracellular ATP drives purinergic signaling by activating P2X and P2Y receptors and it is hydrolyzed by ectonucleotidases in adenosine, which activates P1 receptors. The purpose of this study was to investigate if SI, a rodent model used to replicate abnormal behavior relevant to schizophrenia, impacts purinergic signaling. Male Wistar rats were reared from weaning in group-housed or SI conditions for 8 weeks. SI rats exhibited impairment in prepulse inhibition and social interaction. SI presented increased ADP levels in cerebrospinal fluid and ADP hydrolysis in the hippocampus and striatum synaptosomes. Purinergic receptor expressions were upregulated in the prefrontal cortex and downregulated in the hippocampus and striatum. A2A receptors were differentially expressed in SI prefrontal cortex and the striatum, suggesting distinct roles in these brain structures. SI also presented decreased ADP, adenosine, and guanosine levels in the cerebrospinal fluid in response to D-amphetamine. Like patients with schizophrenia, uric acid levels were prominently increased in SI rats after D-amphetamine challenge. We suggest that the SI-induced deficits in prepulse inhibition might be related to the SI-induced changes in purinergic signaling. We provide new evidence that purinergic signaling is markedly affected in a rat model relevant to schizophrenia, pointing out the importance of purinergic system in psychiatry conditions.

Antidepressant-Like Effects of Chronic Guanosine in the Olfactory Bulbectomy Mouse Model.

Major depressive disorder (MDD) leads to pervasive changes in the health of afflicted patients. Despite advances in the understanding of MDD and its treatment, profound innovation is needed to develop fast-onset antidepressants with higher effectiveness. When acutely administered, the endogenous nucleoside guanosine (GUO) shows fast-onset antidepressant-like effects in several mouse models, including the olfactory bulbectomy (OBX) rodent model. OBX is advocated to possess translational value and be suitable to assess the time course of depressive-like behavior in rodents. This study aimed at investigating the long-term behavioral and neurochemical effects of GUO in a mouse model of depression induced by bilateral bulbectomy (OBX). Mice were submitted to OBX and, after 14 days of recovery, received daily (ip) administration of 7.5 mg/kg GUO or 40 mg/kg imipramine (IMI) for 45 days. GUO and IMI reversed the OBX-induced hyperlocomotion and recognition memory impairment, hippocampal BDNF increase, and redox imbalance (ROS, NO, and GSH levels). GUO also mitigated the OBX-induced hippocampal neuroinflammation (IL-1, IL-6, TNF-α, INF-γ, and IL-10). Brain microPET imaging ([18F]FDG) shows that GUO also prevented the OBX-induced increase in hippocampal FDG metabolism. These results provide additional evidence for GUO antidepressant-like effects, associated with beneficial neurochemical outcomes relevant to counteract depression.

Guanosine fast onset antidepressant-like effects in the olfactory bulbectomy mice model.

The treatment of major depressive disorder (MDD) is still a challenge. In the search for novel antidepressants, glutamatergic neuromodulators have been investigated as possible fast-acting antidepressants. Innovative studies suggest that the purine cycle and/or the purinergic signaling can be dysregulated in MDD, and the endogenous nucleoside guanosine has gained attention due to its extracellular effects. This study aimed to verify if guanosine produces fast-onset effects in the well-validated, reliable and sensitive olfactory bulbectomy (OBX) model of depression. The involvement of the mTOR pathway, a key target for the fast-onset effect of ketamine, was also investigated. Results show that a single i.p. injection of guanosine, or ketamine, completely reversed the OBX-induced anhedonic-like behavior 24 or 48 h post treatment, as well as the short-term recognition memory impairment 48 h post treatment. The antidepressant-like effects of guanosine and ketamine were completely abolished by rapamycin. This study shows, for the first time, that guanosine, in a way similar to ketamine, is able to elicit a fast antidepressant response in the OBX model in mice. The results support the notion that guanosine represents a new road for therapeutic improvement in MDD.

Effects of N-acetylcysteine amide on anxiety and stress behavior in zebrafish.

Anxiety disorders are highly prevalent and a leading cause of disability worldwide. Their etiology is related to stress, an adaptive response of the organism to restore homeostasis, in which oxidative stress and glutamatergic hyperactivity are involved. N-Acetylcysteine (NAC) is a multitarget approved drug proved to be beneficial in the treatment of various mental disorders. Nevertheless, NAC has low membrane permeability and poor bioavailability and its limited delivery to the brain may explain inconsistencies in the literature. N-Acetylcysteine amide (AD4) is a synthetic derivative of NAC in which the carboxyl group was modified to an amide. The amidation of AD4 improved lipophilicity and blood-brain barrier permeability and enhanced its antioxidant properties. The purpose of this study was to investigate the effects of AD4 on behavioral and biochemical parameters in zebrafish anxiety models. Neither AD4 nor NAC induced effects on locomotion and anxiety-related parameters in the novel tank test. However, in the light/dark test, AD4 (0.001 mg/L) increased the time spent in the lit side in a concentration 100 times lower than NAC (0.1 mg/L). In the acute restraint stress protocol, NAC and AD4 (0.001 mg/L) showed anxiolytic properties without meaningful effects on oxidative status. The study suggests that AD4 has anxiolytic effects in zebrafish with higher potency than the parent compound. Additional studies are warranted to characterize the anxiolytic profile of AD4 and its potential in the management of anxiety disorders.

The NMDA antagonist MK-801 induces hyperalgesia and increases CSF excitatory amino acids in rats: reversal by guanosine.

Excitatory amino acids (EAAs) and their receptors play a central role in the mechanisms underlying pain transmission. NMDA-receptor antagonists such as MK-801 produce antinociceptive effects against experimental models of chronic pain, but results in acute pain models are conflicting, perhaps due to increased glutamate availability induced by the NMDA-receptor antagonists. Since guanosine and riluzole have recently been shown to stimulate glutamate uptake, the aim of this study was to examine the effects of guanosine or riluzole on changes in nociceptive signaling induced by MK-801 in an acute pain model. Rats received an i.p. injection of vehicle, morphine, guanosine, riluzole or MK-801 or a combined treatment (vehicle, morphine, guanosine or riluzole+MK-801) and were evaluated in the tail flick test, or had a CSF sample drawn after 30 min. Riluzole, guanosine, and MK-801 (0.01 or 0.1 mg/kg) did not affect basal nociceptive responses or CSF EAAs levels. However, MK-801 (0.5 mg/kg) induced hyperalgesia and increased the CSF EAAs levels; both effects were prevented by guanosine, riluzole or morphine. Hyperalgesia was correlated with CSF aspartate and glutamate levels. This study provides additional evidence for the mechanism of action of MK-801, showing that MK-801 induces hyperalgesia with parallel increase in CSF EAAs levels.

Antidepressant profile of Ptychopetalum olacoides Bentham (Marapuama) in mice.

Depression has become of universal major importance, and it is therefore vital to expand the armamentarium for treating the condition. Lack of motivation and lassitude are major symptoms treated with the use of Marapuama (Ptychopetalum olacoides, PO) remedies by communities in the Brazilian Amazon. Considering the prominence of such symptoms in depression, the present study was designed to verify the effects of a standardized PO ethanol extract (POEE) on the forced swimming (FST) and tail suspension tests (TST). POEE i.p. (15-100 mg/kg) and oral (300 mg/kg) resulted in a significant and dose-related anti-immobility effect. We further examined the involvement of dopamine, noradrenaline and serotonin in these antidepressant-like effects. POEE effects were prevented when catecholamine synthesis was inhibited by -alpha-methyl-rho-tyrosine (AMPT) (100 mg/kg, i.p.), while inhibition of serotonin synthesis with rho-chlorophenylalanine methyl ester hydrochloride (PCPA) (100 mg/kg, i.p.) was devoid of effect. The blockade of beta-adrenergic (propranolol 2 mg/kg, i.p.) and D(1) dopamine (SCH 23390 0.5 mg/kg, i.p.) receptors prevented POEE anti-immobility effects; by contrast, blockade of D(2) dopamine (sulpiride 2 and 50 mg/kg, i.p.) receptors was ineffective. Consistent with traditional use, the results indicate that POEE possesses antidepressant-like effects, possibly mediated by beta-adrenergic and D(1) dopamine receptors.

Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review.

OBJECTIVE: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. METHODS: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. RESULTS: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. CONCLUSION: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

Is chronodisruption a vulnerability factor to stress?

Since the circadian system seems to modulate stress responses, this study aimed to evaluate if the combination of circadian strain and stress amplifies changes expected from each factor alone. Control Balb/c mice (12:12-NS) kept in standard 12:12 light:dark cycles (LD) and submitted to no stress procedures (NS) were compared to groups submitted to shortened LD (10:10-NS), chronic mild stress (CMS) but no circadian strain (12:12-CMS), or shortened LD followed by CMS (10:10-CMS). Rest-activity/temperature rhythms and body weight were assessed throughout the experiments. In Experiment 1 mice were submitted to 3 weeks of CMS; in Experiment 2 sucrose preference and light-dark tests were performed. Also, blood samples were collected at the end of Experiment 2 to assess metabolic parameters. Relative amplitude of temperature after CMS was increased only in the 10:10-CMS group, while body weight change was reduced during CMS regardless of LD intervention. During the CMS, the relative amplitude of temperature was negatively correlated with body weight gain. No differences in behavior and metabolic parameters were seen among groups. Identifying suitable research designs to investigate our hypothesis that circadian disturbances may increase vulnerability to stress-induced depression and anxiety is warranted.

Antinociceptive effects of intracerebroventricular administration of guanine-based purines in mice: evidences for the mechanism of action.

It is well known that adenine-based purines exert multiple effects on pain transmission. However, less attention has been given to the potential effects of guanine-based purines (GBPs) on pain transmission. The aim of this study was to investigate the effects of intracerebroventricular (i.c.v.) guanosine and GMP on mice pain models. Mice received an i.c.v. injection of vehicle (saline or 10 muM NaOH), guanosine (5 to 400 nmol), or GMP (240 to 960 nmol). Additional groups were also pre-treated with i.c.v. injection of the A(1)/A(2A) antagonist caffeine (15 nmol), the non-selective opioid antagonist naloxone (12.5 nmol), or the 5'-nucleotidase inhibitor AOPCP (1 nmol). Measurements of CSF purine levels and cortical glutamate uptake were performed after treatments. Guanosine and GMP produced dose-dependent antinociceptive effects. Neither caffeine nor naloxone affected guanosine antinociception. Pre-treatment with AOPCP completely prevented GMP antinociception, indicating that conversion of GMP to guanosine is required for its antinociceptive effects. Intracerebroventricular administration of guanosine and GMP induced, respectively, a 180- and 1800-fold increase on CSF guanosine levels. Guanosine was able to prevent the decrease on cortical glutamate uptake induced by intraplantar capsaicin. This study provides new evidence on the mechanism of action of GBPs, with guanosine and GMP presenting antinociceptive effects in mice. This effect seems to be independent of adenosine and opioid receptors; it is, however, at least partially associated with modulation of the glutamatergic system by guanosine.

The putative antipsychotic alstonine reverses social interaction withdrawal in mice.

Negative symptoms of schizophrenia are particularly problematic due to their deleterious impact on a patient's social life. The indol alkaloid alstonine, the major component of traditional remedies used for treating mental illnesses in Nigeria, presents a clear antipsychotic-like profile in mice, as well as anxiolytic properties. Considering that social interaction is the core of negative symptoms, and that anxiolytic drugs can improve social interaction behavior, the aim of this study was to evaluate the effects of alstonine in the social interaction and MK801-induced social withdrawal models in mice. Sub-chronic (but not acute) treatment with alstonine 0.5 mg/kg (but not 1.0 mg/kg) significantly increased social interaction in mice. Moreover, MK801-induced social withdrawal was completely prevented by sulpiride (10 mg/kg) and alstonine 1.0 mg/kg, and partially prevented by alstonine 0.5 mg/kg. The study indicates that alstonine not only increases social interaction in normal mice, but also averts social deficits attributable to negative symptoms of schizophrenia. This study reinforces and complements the antipsychotic-like profile of alstonine, and emphasizes its potential as a drug useful for the management of negative symptoms in schizophrenia.

Serotonin receptors contribute to the promnesic effects of P. olacoides (Marapuama).

Nootropic, antioxidant, and neuroprotective properties have been shown in a standardized ethanol extract of Ptychopetalum olacoides (POEE), a medicinal plant traditionally used by the Amazonian elderly population. It has been revealed that POEE mechanisms of action include anticholinesterase effects, and involve beta-adrenergic and dopamine D(1) receptors. The purpose of this study was to verify the role of serotonin receptors in the promnesic effects of this standardized extract. The step-down task in mice and selective serotonin antagonists were used. The study reveals that POEE promnesic effects on short-term (acquisition, consolidation and retrieval) and long-term (retrieval) declarative aversive memories are increased by 5HT(2A) (but not 5HT(1A)) serotonin antagonists (spiperone and pindolol, respectively). The observed synergism between POEE and spiperone can be interpreted as the combined effects of two subeffective doses of two 5HT antagonists, or the known synergism between an acetylcholinesterase inhibitor (POEE) and a 5HT antagonist. In conclusion it is suggested that 5HT(2A) serotonin receptors are relevant for the promnesic effects of this extract, adding to its multiple mechanisms of action.

Effects of Marapuama in the chronic mild stress model: further indication of antidepressant properties.

ETHNOPHARMACOLOGY RELEVANCE: Ptychopetalum olacoides Bentham (PO) (Olacaceae), known as Marapuama, is regarded as a "nerve tonic" in the Amazon. Traditional uses include states of lassitude with noticeable lack of desire/motivation, and to manage particularly stressful (physical and/or psychological) circumstances. Suggestive of antidepressant activity, we have established that a specific PO ethanol extract (POEE) significantly decreases immobility in the tail suspension and forced swimming tests. AIM OF THE STUDY: The aim of this study was to verify the effects of POEE in the unpredictable chronic mild stress (UCMS) depression model in mice, given the construct and face values of the UCMS as an experimental model of depression and the traditional use of this species. MATERIALS AND METHODS: Over 6 weeks BALB/c mice were subjected to the UCMS protocol. The effects of POEE (50, 100, 300mg/kg, p.o.) and imipramine (20mg/kg, i.p.) were evaluated in relation to coat state, splash-test grooming, and corticosterone levels. RESULTS: The coat state degradation, decreased grooming and increased serum corticosterone induced by UCMS were prevented by POEE and imipramine treatments. CONCLUSION: In addition to supporting traditional claims and previously reported antidepressant properties for POEE, this study shows that POEE prevents stress-induced HPA hyperactivity.

Effects of N-acetylcysteine on amphetamine-induced sensitization in mice.

OBJECTIVE: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. METHODS: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. RESULTS: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. CONCLUSION: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.