| 1 | Neuropsychopharmacology 2006 Apr 31: 795-803 |
|---|---|
| PMID | 16052245 |
| Title | Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. |
| Abstract | Cannabidiol, a nonpsychoactive constituent of the Cannabis sativa plant, has been reported to act as an agonist of the vanilloid 1 channel in the transient receptor potential family (TRPV1) and also to inhibit the hydrolysis and cellular uptake of the endogenous cannabinoid anandamide. Cannabidiol has also been reported to have potential as an antipsychotic. We investigated the effect of cannabidiol on sensorimotor gating deficits in mice induced by the noncompetitive NMDA receptor antagonist, MK-801. Sensorimotor gating is deficient in psychotic disorders such as schizophrenia and may be reliably measured by prepulse inhibition (PPI) of the startle response in rodents and humans. MK-801 (0.3-1 mg/kg i.p.) dose dependently disrupted PPI while cannabidiol (1-15 mg/kg i.p.), when administered with vehicle, had no effect on PPI. Cannabidiol (5 mg/kg i.p.) successfully reversed disruptions in PPI induced by MK-801 (1 mg/kg i.p.), as did the atypical antipsychotic clozapine (4 mg/kg i.p.). Pretreatment with capsazepine (20 mg/kg i.p.) prevented the reversal of MK-801-induced disruption of PPI by cannabidiol, providing preliminary evidence that TRPV1 receptors are involved in the reversal of MK-801-induced sensorimotor gating deficits by cannabidiol. |
| SCZ Keywords | schizophrenia |
| 2 | Biol. Psychiatry 2006 Mar 59: 508-15 |
| PMID | 16199010 |
| Title | Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. |
| Abstract | Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD). Because of continuously increasing evidence for a neuromodulatory role of endocannabinoids in dopamine-related pathophysiological responses, we assessed endocannabinoid signaling in DAT KO mice and evaluated the ability of endocannabinoid ligands to normalize behavioral deficits, namely spontaneous hyperlocomotion in these mice. In DAT KO mice, we found markedly reduced anandamide levels, specifically in striatum, the dopamine nerve terminal region. Furthermore, three distinct indirect endocannabinoid agonists, the selective anandamide reuptake inhibitors AM404 and VDM11 and the fatty acid amidohydrolase inhibitor AA5HT, attenuated spontaneous hyperlocomotion in DAT KO mice. The hypolocomotor effects of AM404, VDM11, and AA5HT were significantly attenuated by co-administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine but not the selective cannabinoid type 1 (CB1)receptor antagonist AM251. Interestingly, TRPV1 binding was increased in the striatum of DAT KO mice, while CB1 receptor binding was unaffected. These data indicate a dysregulated striatal endocannabinoid neurotransmission associated with hyperdopaminergic state. Restoring endocannabinoid homeostasis in active synapses might constitute an alternative therapeutic strategy for disorders associated with hyperdopaminergia. In this process, TRPV1 receptors seem to play a key role and represent a novel promising pharmacological target. |
| SCZ Keywords | schizophrenia |
| 3 | Adv. Exp. Med. Biol. 2011 -1 704: 987-1009 |
| PMID | 21290337 |
| Title | TRP channels and psychiatric disorders. |
| Abstract | Depression and schizophrenia are major psychiatric disorders that cause much human suffering. Current treatments have major limitations and new drug targets are eagerly sought. Study of transient receptor potential (TRP) channels in these disorders is at an early stage and the potential of agents that activate or inhibit these channels remains speculative. The findings that TRPC6 channels promote dendritic growth and are selectively activated by hyperforin, the key constitutent of St John's wort, suggest that TRPC6 channels might prove to be a new target for antidepressant drug development. There is now considerable evidence that TRPV1 antagonists have anxiolytic activity but there is no direct evidence that they have antidepressant activity. There is also no direct evidence that TRP channels play a role in schizophrenia. However, the findings that TRPC channels are involved in neuronal development and fundamental synaptic mechanisms, and that TRPV1 channels play a role in central dopaminergic and cannabinoid mechanisms is suggestive of potential roles of these channels in schizophrenia. Investigation of TRP channels in psychiatric disorders holds the promise of yielding further understanding of the aetiology of psychiatric disorders and the development of new drug treatments. |
| SCZ Keywords | schizophrenia |
| 4 | Inflamm. Res. 2012 Nov 61: 1283-91 |
| PMID | 22820944 |
| Title | Overdose of the histamine H? inverse agonist pitolisant increases thermal pain thresholds. |
| Abstract | Pitolisant (BF2.649) is a selective inverse agonist for the histamine H(3) receptor and was developed for the treatment of excessive daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since H(3)-ligands can decrease inflammatory pain, we tested Pitolisant in inflammatory and neuropathic pain models. MATERIALS AND TREATMENTS: Behavioral effects of pitolisant and the structural different H(3) receptor inverse agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and the spared nerve injury model for neuropathic pain. Responses to mechanical and thermal stimuli were determined. Calcium imaging was performed with primary neuronal cultures of dorsal root ganglions. Clinically relevant doses of pitolisant (10 mg/kg) had no relevant effect on mechanical or thermal pain thresholds in all animal models. Higher doses (50 mg/kg) dramatically increased thermal but not mechanical pain thresholds. Neither ciproxifan nor ST-889 altered thermal pain thresholds. In peripheral sensory neurons high concentrations of pitolisant (30-500 ?M), but not ciproxifan, partially inhibited calcium increases induced by capsaicin, a selective activator of transient receptor potential vanilloid receptor 1 (TRPV1). High doses of pitolisant induced a strong hypothermia. The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H(3) receptor-independent. |
| SCZ Keywords | schizophrenia |
| 5 | Behav. Brain Res. 2014 Oct 272: 55-65 |
| PMID | 24975423 |
| Title | Effects of neonatal treatment with the TRPV1 agonist, capsaicin, on adult rat brain and behaviour. |
| Abstract | Treatment of neonatal rats with the transient receptor potential vanilloid 1 (TRPV1) channel agonist, capsaicin, produces life-long loss of sensory neurons expressing TRPV1 channels. Previously it was shown that rats treated on day 2 of life with capsaicin had behavioural hyperactivity in a novel environment at 5-7 weeks of age and brain changes reminiscent of those found in subjects with schizophrenia. The objective of the present study was to investigate brain and behavioural responses of adult rats treated as neonates with capsaicin. It was found that the brain changes found at 5-7 weeks in rats treated as neonates with capsaicin persisted into adulthood (12 weeks) but were less in older rats (16-18 weeks). Increased prepulse inhibition (PPI) of acoustic startle was found in these rats at 8 and 12 weeks of age rather than the deficit commonly found in animal models of schizophrenia. Subjects with schizophrenia also have reduced flare responses to niacin and methylnicotinate proposed to be mediated by prostaglandin D2 (PGD2). Flare responses are accompanied by cutaneous plasma extravasation. It was found that the cutaneous plasma extravasation responses to methylnicotinate and PGD2 were reduced in capsaicin-treated rats. In conclusion, several neuroanatomical changes observed in capsaicin-treated rats, as well as the reduced cutaneous plasma extravasation responses, indicate that the role of TRPV1 channels in schizophrenia is worthy of investigation. |
| SCZ Keywords | schizophrenia |
| 6 | Schizophr. Res. 2014 Mar 153: 150-9 |
| PMID | 24556469 |
| Title | Effects of cannabinoid and vanilloid drugs on positive and negative-like symptoms on an animal model of schizophrenia: the SHR strain. |
| Abstract | Studies have suggested that the endocannabinoid system is implicated in the pathophysiology of schizophrenia. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. In addition, SHRs display hyperlocomotion - reverted by atypical and typical antipsychotics. These results suggest that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia and the effects of potential drugs with an antipsychotic profile. The aim of this study was to investigate the effects of WIN55-212,2 (CB1/CB2 agonist), ACEA (CB1 agonist), rimonabant (CB1 inverse agonist), AM404 (anandamide uptake/metabolism inhibitor), capsaicin (agonist TRPV1) and capsazepine (antagonist TRPV1) on the social interaction and locomotion of control animals (Wistar rats) and SHRs. The treatment with rimonabant was not able to alter either the social interaction or the locomotion presented by Wistar rats (WR) and SHR at any dose tested. The treatment with WIN55-212,2 decreased locomotion (1mg/kg) and social interaction (0.1 and 0.3mg/kg) of WR, while the dose of 1mg/kg increased social interaction of SHR. The treatment with ACEA increased (0.3mg/kg) and decreased (1mg/kg) locomotion of both strain. The administration of AM404 increased social interaction and decreased locomotion of SHR (5mg/kg), and decreased social interaction and increased locomotion in WR (1mg/kg). The treatment with capsaicin (2.5mg/kg) increased social interaction of both strain and decreased locomotion of SHR (2.5mg/kg) and WR (0.5mg/kg and 2.5mg/kg). In addition, capsazepine (5mg/kg) decreased locomotion of both strains and increased (5mg/kg) and decreased (10mg/kg) social interaction of WR. Our results indicate that the schizophrenia-like behaviors displayed by SHR are differently altered by cannabinoid and vanilloid drugs when compared to control animals and suggest the endocannabinoid and the vanilloid systems as a potential target for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 7 | Physiol. Behav. 2014 Feb 125: 38-44 |
| PMID | 24291382 |
| Title | The effects of juvenile capsaicin desensitization in rats: behavioral impairments. |
| Abstract | Capsaicin desensitization leads to behavioral changes, some of which are related to schizophrenia, but investigations into these effects have been scarce. The goal of this study was to characterize the consequences of juvenile capsaicin desensitization on different functions: acute and inflammation-induced thermal and mechanical sensitivity, urinary bladder capacity and thermoregulation, and also on the potentially schizophrenia-related impairments in sensory-motor gating, motor activity and cognitive functioning. Male Wistar rats desensitized with increasing doses of subcutaneous capsaicin after weaning were investigated. Heat and mechanical pain sensitivity did not change significantly; however, morphine produced a prolonged decrease in the nociceptive response to inflammation in desensitized animals. Ultrasound examination of the bladder revealed enhanced bladder volume in treated animals. Capsaicin-treated animals had higher body temperature at 22 °C in both dark and light periods, and they also showed prolonged hyperthermia in new environmental circumstances. Warm environment induced a profound impairment of thermoregulation in desensitized animals. The treated animals also showed higher levels of activity during the active phase and at both cool and warm temperatures. The amplitude of the responses to auditory stimuli and prepulse inhibition did not differ between the two groups, but the desensitized animals showed learning impairments in the novel object recognition test. These results suggest that juvenile capsaicin desensitization leads to sustained changes in several functions that may be related to schizophrenia. We propose that capsaicin desensitization, together with other interventions, may lead to an improved chronic animal model of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 8 | Mod Trends Pharmacopsychiatri 2015 -1 30: 80-93 |
| PMID | 26436415 |
| Title | Supraspinal Transient Receptor Potential Subfamily V Member 1 (TRPV1) in Pain and Psychiatric Disorders. |
| Abstract | The transient receptor potential subfamily V member 1 (TRPV1) belongs to the diverse transient receptor potential (TRP) family of cation channels. It was first characterized in primary afferent fibres as a receptor for capsaicin. Peripheral TRPV1 has a very well-described role in nociception. However, TRPV1 is now recognized to have a broader distribution and function, with supraspinal/brain TRPV1 known to modulate pain processing. Recently, studies employing histological, genetic and pharmacological approaches have provided evidence that supraspinal TRPV1 also modulates brain neurobiology and behaviours related to anxiety, depression and schizophrenia. Key brain regions involved in TRPV1-mediated modulation of pain and affect include the periaqueductal grey, hippocampus and medial prefrontal cortex. Thus, TRPV1 in the brain is emerging as an important molecular substrate which is dually implicated in both pain and psychiatric disorders, and represents a novel therapeutic target for these conditions and their comorbidity. |
| SCZ Keywords | schizophrenia |
| 9 | Neurosci. Lett. 2016 Mar 616: 170-6 |
| PMID | 26836139 |
| Title | Slow synaptic transmission mediated by TRPV1 channels in CA3 interneurons of the hippocampus. |
| Abstract | Metabotropic glutamate receptors (mGluRs) modulate various neuronal functions in the central nervous system. Many studies reported that mGluRs have linkages to neuronal disorders such as schizophrenia and autism related disorders, indicating that mGluRs are involved in critical functions of the neuronal circuits. To study this possibility further, we recorded mGluR-induced synaptic responses in the interneurons of the CA3 stratum radiatum using rat hippocampal organotypic slice cultures. Electrical stimulation in the CA3 pyramidal cell layer evoked a slow inward current in the interneurons at a holding potential of -70mV in the presence of antagonists for AMPA/kainate receptors, NMDA receptors, GABAA receptors and GABAB receptors. The slow inward current was blocked in the absence of extracellular calcium, suggesting that this was a synaptic response. The slow excitatory postsynaptic current (EPSC) reversed near 0mV, reflecting an increase in a non-selective cationic conductance. The slow EPSC is mediated by group I mGluRs, as it was blocked by AP3, a group I mGluR antagonist. Neither a calcium chelator BAPTA nor a phospholipase C (PLC) inhibitor U73122 affected the slow EPSC. La(3+), a general TRP channel blocker or capsazepine, a selective TRPV1 channel antagonist significantly suppressed the slow EPSC. DHPG, a selective group I mGluRs agonist induced an inward current, which was suppressed by capsazepine. These results indicate that in the interneurons of the hippocampal CA3 stratum radiatum group I mGluRs activate TRPV1 channels independently of PLC and intracellular Ca(2+), resulting in the slow EPSC in the interneurons. |
| SCZ Keywords | schizophrenia |
| 10 | Chin J Physiol 2016 Feb 59: 21-32 |
| PMID | 26875559 |
| Title | Involvement of TRPV1 in the Olfactory Bulb in Rimonabant-Induced Olfactory Discrimination Deficit. |
| Abstract | Rimonabant is well recognized as a cannabinoid CB? receptor antagonist/inverse agonist. Rimonabant not only antagonizes the effects induced by exogenous cannabinoids and endocannabinoids at CB? receptors, it also exerts several pharmacological and behavioral effects independent of CB? receptor inactivation. For example, rimonabant can function as a low-potency mixed agonist/antagonist of the transient receptor potential vanilloid receptor 1 (TRPV1). Hence, it is important to explain the underlying mechanisms of the diverse physiological effects induced by rimonabant with caution. Interestingly, CB? receptor has recently been suggested to play a role in olfactory functions. Olfaction not only is involved in food intake, visual perception and social interaction, but also is proposed as a putative marker for schizophrenia and autism. Therefore, the present study aimed to investigate whether CB? receptor and TRPV1 played a role in olfactory functions. We first used the genetic disruption approach to examine the role of CB? receptor in olfactory functions and found that CB? knockout mice exhibited olfactory discrimination deficit. However, it is important to point out that these CB? knockout mice, despite their normal locomotivity, displayed deficiencies in the olfactory foraging and novel object exploration tasks. These results imply that general exploratory behaviors toward odorant and odorless objects are compromised in CB? knockout mice. We next turned to the pharmacological approach to examine the role of CB? receptor and TRPV1 in olfactory functions. We found that the short-term administration of rimonabant, injected systemically or directly into the olfactory bulb (OB), impaired olfactory discrimination that was rescued by the TRPV1 antagonist capsazepine (CPZ), via the same route of rimonabant, in wild-type mice. These results suggest that TRPV1 in the OB is involved in rimonabant-induced olfactory discrimination deficit. However, the rimonabant and/or CPZ treatments neither affected locomotivity nor general exploratory behaviors in wild-type mice. Finally, the acute systemic administration of rimonabant, unlike the short-term administration regimen, did not affect olfactory discrimination. Taken together, this study not only is the first one, to the best of our knowledge, suggests that the olfactory TRPV1 plays a role in olfactory functions, but also provides a possible mechanism for the olfactory discrimination deficit induced by rimonabant. |
| SCZ Keywords | schizophrenia |