Interrelated involvement of the endocannabinoid/endovanilloid (TRPV1) systems and epigenetic processes in anxiety- and working memory impairment-related behavioural effects of nicotine as a stressor.

The addictive use of nicotine contained in tobacco is associated with stressor-like emotional and cognitive effects such as anxiety and working memory impairment, and the involvement of epigenetic mechanisms such as histone acetylation has recently been reported. Although the precise nature of behavioural plasticity remains unclear, both anxiogenic- and working memory impairment-like effects were observed in the present experimental model of mice treated with repeated subcutaneous nicotine and/or immobilization stress, and these effects were commonly attenuated by the histone deacetylase (HDAC) inhibitors that induce histone acetylation. Such HDAC inhibitor-induced resilience was mimicked by ligands for the endocannabinoid (ECB) system, a neurotransmitter system that is closely associated with nicotine-induced addiction-related behaviours: the anxiogenic-like effects were mitigated by the cannabinoid type 1 (CB1) agonist arachidonylcyclopropylamide (ACPA), whereas the working memory impairment-like effects were mitigated by the CB1 antagonist SR 141716A. Moreover, the effects of the HDAC inhibitors were also mimicked by ligands for the endovanilloid (transient receptor potential vanilloid 1 [TRPV1]) system, a system that shares common characteristics with the ECB system: the anxiogenic-like effects were mitigated by the TRPV1 antagonist capsazepine, whereas the working memory impairment-like effects were mitigated by the TRPV1 agonist olvanil. Notably, the HDAC inhibitor-induced anxiolytic-like effects were attenuated by SR 141716A, which were further counteracted by capsazepine, whereas the working memory improvement-like effects were attenuated by capsazepine, which were further counteracted by SR 141716A. These results suggest the contribution of interrelated control of the ECB/TRPV1 systems and epigenetic processes such as histone acetylation to novel therapeutic approaches.

Epigenetic mechanisms associated with addiction-related behavioural effects of nicotine and/or cocaine: implication of the endocannabinoid system.

The addictive use of nicotine (NC) and cocaine (COC) continues to be a major public health problem, and their combined use has been reported, particularly during adolescence. In neural plasticity, commonly induced by NC and COC, as well as behavioural plasticity related to the use of these two drugs, the involvement of epigenetic mechanisms, in which the reversible regulation of gene expression occurs independently of the DNA sequence, has recently been reported. Furthermore, on the basis of intense interactions with the target neurotransmitter systems, the endocannabinoid (ECB) system has been considered pivotal for eliciting the effects of NC or COC. The combined use of marijuana with NC and/or COC has also been reported. This article presents the addiction-related behavioural effects of NC and/or COC, based on the common behavioural/neural plasticity and combined use of NC/COC, and reviews the interacting role of the ECB system. The epigenetic processes inseparable from the effects of NC and/or COC (i.e. DNA methylation, histone modifications and alterations in microRNAs) and the putative therapeutic involvement of the ECB system at the epigenetic level are also discussed.

Putative Epigenetic Involvement of the Endocannabinoid System in Anxiety- and Depression-Related Behaviors Caused by Nicotine as a Stressor.

Like various stressors, the addictive use of nicotine (NC) is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB) system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC) inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM). Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test) and depression-like (forced swimming test) behaviors, which were observed in mice treated with repeated (4 days) NC (subcutaneous 0.8 mg/kg) and/or IM (10 min), were blocked by the HDAC inhibitors sodium butyrate (SB) and valproic acid (VA). The cannabinoid type 1 (CB1) agonist ACPA (arachidonylcyclopropylamide; AC) also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR), which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor-induced antidepressant-like effects may reflect the characteristic involvement of histone acetylation within the NC-related neurotransmitter systems other than the ECB system.

Working memory- and anxiety-related behavioral effects of repeated nicotine as a stressor: the role of cannabinoid receptors.

BACKGROUND: Like emotional symptoms such as anxiety, modulations in working memory are among the frequently-reported but controversial psychiatric symptoms associated with nicotine (NC) administration. In the present study, repeated NC-induced modulations in working memory, along with concurrently-observed anxiety-related behavioral alterations, were investigated in mice, and compared with the effects of a typical cognition-impairing stressor, immobilization stress (IM). Furthermore, considering the structural and functional contributions of brain cannabinoid (CB) receptors in NC-induced psychiatric symptoms including emotional symptoms, the interactive effects of brain CB receptor ligands (CB ligands) and NC and/or IM on the working memory- and anxiety-related behaviors were examined. RESULTS: Statistically significant working memory impairment-like behavioral alterations in the Y-maze test and anxiety-like behavioral alterations in the elevated plus-maze (EPM) test were observed in the groups of mice treated with 0.8 mg/kg NC (subcutaneous (s.c.) 0.8 mg/kg treatment, 4 days) and/or IM (10 min treatment, 4 days). In the group of mice treated with NC plus IM (NC-IM group), an enhancement of the behavioral alterations was observed. Among the CB type 1 (CB1) antagonist AM 251 (AM), the non-selective CB agonist CP 55,940 (CP), and the CB1 partial agonist/antagonist virodhamine (VD), significant recovering effects were provided by AM (0.2-2.5 mg/kg) and VD (5 mg/kg) against the working memory impairment-like behaviors, whereas significant anxiolytic-like effects (recoveries from both attenuated percentage of entries into open arms and attenuated percentage of time spent on open arms) were provided by VD (1-10 mg/kg) and CP (2 mg/kg) against the anxiety-like behaviors. CONCLUSIONS: Although working memory impairment- and anxiety-like behavioral alterations were commonly induced in the NC, IM, and NC-IM groups and the therapeutic involvement of CB receptors was shown, there were discrepancies in the types of effective CB ligands between the working memory- and anxiety-related behaviors. The differential involvements of CB receptor subtypes and indirectly activated neurotransmitter systems may contribute to these discrepancies.

Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors.

BACKGROUND: The contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. In the present study, the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alterations in a mouse model in order to elucidate the "antidepressant-like" contributions of TRPV1 receptors against the NC-induced "depression" observed in various types of tobacco abuse. RESULTS: Repeated subcutaneous NC treatments (NC group: 0.3 mg/kg, 4 days), like repeated immobilization stress (IM) (IM group: 10 min, 4 days), caused depression-like behavioral alterations in both the forced swimming (reduced swimming behaviors) and the tail suspension (increased immobility times) tests, at the 2 h time point after the last treatment. In both NC and IM groups, the TRPV1 agonists capsaicin (CP) and olvanil (OL) administered intraperitoneally provided significant antidepressant-like attenuation against these behavioral alterations, whereas the TRPV1 antagonist capsazepine (CZ) did not attenuate any depression-like behaviors. Furthermore, the endogenous TRPV1-agonistic CB1 agonists anandamide (AEA) and N-arachidonyldopamine (NADA) did not have any antidepressant-like effects. Nevertheless, a synthetic "hybrid" agonist of CB1 and TRPV1 receptors, arvanil (AR), caused significant antidepressant-like effects. The antidepressant-like effects of CP and OL were antagonized by the TRPV1 antagonist CZ. However, the antidepressant-like effects of AR were not antagonized by either CZ or the CB1 antagonist AM 251 (AM). CONCLUSIONS: The antidepressant-like effects of TRPV1 agonists shown in the present study suggest a characteristic involvement of TRPV1 receptors in NC-induced depression-like behaviors, similar to those caused by IM. The strong antidepressant-like effects of the potent TRPV1 plus CB1 agonist AR, which has been reported to cause part of its TRPV1-mimetic and cannabimimetic effects presumably via non-TRPV1 or non-CB1 mechanisms support a contribution from other sites of action which may play a therapeutically important role in the treatment of NC abuse.

Depression-related anhedonic behaviors caused by immobilization stress: a comparison with nicotine-induced depression-like behavioral alterations and effects of nicotine and/or "antidepressant" drugs.

Anhedonia, an affective symptom related to the inability to experience pleasure, is one of the representative symptoms observed in depression. In the present study, considering that repeated nicotine (NC) also causes "depressive" symptoms, the depression-related anhedonic behavioral alterations caused by a typical depression-inducing stressor, immobilization stress (IM), combined with or without NC administration, were examined in mice and compared with the depression-like behavioral alterations caused by NC. In the repeated IM (10 min, 4 days) group, as well as the repeated NC (0.3 mg/kg, s.c., 4 days) group, depression-related behavioral despair was observed in both forced swimming and tail suspension tests. Depression-related anhedonic behavioral alterations, as judged in the sucrose test, were observed only in the IM group. In the group treated with IM plus NC (IM-NC group), NC antagonized the IM-induced anhedonic attenuation of sucrose consumption in the sucrose test. Furthermore, in the IM-NC group, NC attenuated the effects of antidepressants which inhibit the reuptake of monoamines in the forced swimming test. Against the IM-induced anhedonia in the sucrose test, the cannabinoid agonists anandamide and CP 55940, in addition to the antidepressants previously reported, restored the preference for sucrose to control levels, with or without NC co-treatment. The absence of anhedonic behavioral alterations, the antidepressant-like anti-anhedonic effects against IM, and the effects against some antidepressant drugs all seemed to be characteristic of the effects of NC. Neural mechanisms other than those involved in the depression-like effects of NC seemed to contribute to the IM-induced anhedonic component of depression.

Nicotine (NC)-induced "depressive" behavioral symptoms and effects of antidepressants including cannabinoids (CBs).

Depression is one of the frequently-observed psychiatric symptoms associated with nicotine (NC) use. In the present study, considering the unique effects of NC (e.g. antidepressant effects have also been reported), the time course of the NC-induced depressive behavioral alterations in a mouse model was compared with a typical depression-inducing stressor. Furthermore, based on the involvement of cannabinoid (CB) receptors in the behavioral effects of NC, the effects of antidepressants including CB ligands (CBs) against the NC-induced behavioral alterations were also investigated. Repeated subcutaneous NC treatments (0.3 mg/kg, 4 days), like repeated immobilization stress (IM) treatments (10 min, 4 days), caused prolonged depressive effects (increased immobility time) at both 2 hr and 1 day time points after the last treatment in the tail suspension test. However, in the NC group, depressive effects (suppressed swimming behaviors) were observed only at the 2 hr time point in the forced swimming test. The antidepressants amitriptyline, clomipramine and fluvoxamine, the endogenous mixed CB agonist/antagonist virodhamine and the anandamide-like cannabimimetic O-2093 provided antagonistic effects against the depressive behaviors in the tail suspension test. However, in the forced swimming test, NC-induced depressive behaviors were antagonized only by the CBs virodhamine and O-2093. The present results demonstrated depressive effects of NC in two typical behavioral tests, which support the risk of repeated NC use. The shortened behavioral alterations in the forced swimming test, as compared to the IM group, seemed to reflect the neuronal modifications peculiar to NC, which are antagonized by some CBs.

Chronologically overlapping occurrences of nicotine-induced anxiety- and depression-related behavioral symptoms: effects of anxiolytic and cannabinoid drugs.

BACKGROUND: Anxiety and depression are among the most frequently-observed psychiatric symptoms associated with nicotine (NC). In addition to the similarity to other addictive drugs, these NC-induced symptoms are characteristic in that the opposite behavioral effects, i.e. anxiolytic and antidepressant effects, which may reinforce the habitual use of NC, have also been reported. In the present study, the time course of anxiety- and depression-related behavioral alterations was examined in mice. Furthermore, based on the reported similarity in the mechanisms responsible for NC-induced anxiety- and depression-related symptoms, as well as the contribution of brain cannabinoid (CB) receptors to these behavioral symptoms, the effects of anxiolytics and CB receptor ligands (CBs) against these behavioral symptoms were investigated. RESULTS: Repeated subcutaneous NC treatments (0.3 mg/kg, 4 days), compared with a single treatment (0.5 mg/kg), caused both prolonged anxiogenic effects in the elevated plus-maze test, and prolonged depressive effects in the forced swimming test, even at 120 min time point after the last NC treatment. A transient anxiolytic preference for open arms was also observed in the elevated plus-maze test. Among the anxiolytics and CBs, the serotonin 1A (5-HT1A) antagonist WAY 100135 and the endogenous mixed CB agonist/antagonist virodhamine (VD), when administered intraperitoneally before each NC treatment, provided the strongest antagonistic effects against the anxiety-related symptoms. However, against the depression-related symptoms, only VD provided significant antagonistic effects in both single and repeated treatment groups. CONCLUSION: The present results support the presence of a chronological overlap of NC-induced anxiety- and depression-related behavioral symptoms, and the contribution of brain CB receptors to these behavioral symptoms. The repeated NC-induced prolongation of these behavioral symptoms and the early transient anxiolytic behavioral alterations support an increased possibility of the habitual use of NC. Furthermore, based on the antagonistic effects of VD, one can predict that the characteristic effects on brain CB receptors as a mixed CB agonist/antagonist contributed to its therapeutic effects as both an anxiolytic and an antidepressant.

Microarray profile analysis of toxic cocaine-induced alterations in the expression of mouse brain gene sequences: a possible 'protective' effect of buprenorphine.

Using a mouse brain cDNA microarray consisting of 2688 gene sequences, which include unknown sequences with the empirical possibility of expression in the brain, the effects of repeated toxic doses of intraperitoneal (i.p.) cocaine (40 mg x kg(-1), 4 days) on the expression pro fi le of the cerebral genes were investigated. The modifications in this pro file caused by buprenorphine (BUP) (0.25 mg x kg(-1) i.p., 4 days), a protective drug against cocaine, were also examined. In the cocaine group, the expression levels reached the recommended increased levels (>or=2 times the control value in the saline-treated control group) in 24.0% of the genes but were equal to or less than the recommended attenuation levels (0.5 and <2 times the control value). Although statistically significant modifications in the expression of cocaine- or BUP-related brain-region-specific genes were not proved using whole cerebrums, including many unknown genes, our results suggest that the expression of genes related to neuronal cell damage, including non-peculiar genes related to the damage accompanying convulsive seizures and malignant tumors, were normalized and the genes related to the protection of neural cells were induced by BUP.

Increased immunoreactivity of POMC-derived neuropeptides and immediate-early gene-derived proteins (c-Fos and Egr-1 proteins) as an early step of acute cocaine-induced stressor effects: comparison with the effects of immobilization stress.

The effects of an acute toxic dose of cocaine (COC) (60 mg/kg, i.p.) as a stressor were examined in rats both neuroendocrinally and behaviorally. The time course (5 min, 5, 12, and 24 h) of the alterations in the immunoreactivity of POMC (preopiomelanocortin)-derived neuropeptides [ACTH (adrenocorticotropin), beta-endorphin, and alpha-MSH (melanocyte stimulating hormone)] and immediate-early gene-derived proteins (c-fos and egr-1 proteins) was examined in the hypothalamus, including the regions reported to be neuroendocrinally sensitive to stressor effects, along with the accompanying alterations in the spontaneous behaviors in the cage and the forced swimming behaviors. Similar to the observations in rats treated with a 30 min immobilization stress (IM), an increase in the number of immunoreactive nerve cells for each neuroendocrinal product and a delayed depression in the swimming behaviors as compared to the alterations in the spontaneous activity, which seemed to be correlated with some intermediate steps, were characteristically caused by a toxic dose of COC. However, the early enhancement (at 5 h) of the swimming behaviors and the brain ACTH level might also be the characteristic acute COC effects, which could be differentiated from the effects of other non-psychostimulant stressors.