Pub Date : 2010-07-01DOI: 10.2174/1876523801003010001
A. Etiévant
The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks such as delayed onset of action and a high percentage of non-responders. Despite significant advancements in the devel- opment of new drugs with more acceptable side-effect profiles, patients with schizophrenia or major depression experi- ence substantial disability and burden of disease. The present review discusses the usefulness of partial dopamine D2/serotonin 5-HT1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinson's disease. Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial ago- nist depends on the target receptor population and the local concentrations of the natural neurotransmitter. Thus, these drugs may restore adequate neurotransmission while inducing less side effects. In schizophrenia, partial DA D2/5-HT1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA re- lease, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT1A receptors. Aripipra- zole appears also as a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders aripiprazole may have only a benefit effect in the treatment of manic episodes. Conversely, treatment of Parkinson's disease with partial DA D2/5-HT1A receptor agonists remains still experi- mental. However several studies suggest that these drugs decrease usually observed side effects (dyskinesia, psychotic- like symptoms) in Parkinson's disease treatment. Hence, these relatively recent researches provide an exciting future in the discovery of novel stabilizators agents for the management of the latter diseases.
{"title":"Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents~!2009-12-17~!2010-04-07~!2010-07-20~!","authors":"A. Etiévant","doi":"10.2174/1876523801003010001","DOIUrl":"https://doi.org/10.2174/1876523801003010001","url":null,"abstract":"The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks such as delayed onset of action and a high percentage of non-responders. Despite significant advancements in the devel- opment of new drugs with more acceptable side-effect profiles, patients with schizophrenia or major depression experi- ence substantial disability and burden of disease. The present review discusses the usefulness of partial dopamine D2/serotonin 5-HT1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinson's disease. Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial ago- nist depends on the target receptor population and the local concentrations of the natural neurotransmitter. Thus, these drugs may restore adequate neurotransmission while inducing less side effects. In schizophrenia, partial DA D2/5-HT1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA re- lease, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT1A receptors. Aripipra- zole appears also as a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders aripiprazole may have only a benefit effect in the treatment of manic episodes. Conversely, treatment of Parkinson's disease with partial DA D2/5-HT1A receptor agonists remains still experi- mental. However several studies suggest that these drugs decrease usually observed side effects (dyskinesia, psychotic- like symptoms) in Parkinson's disease treatment. Hence, these relatively recent researches provide an exciting future in the discovery of novel stabilizators agents for the management of the latter diseases.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"3 1","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2010-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68143991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-09-08DOI: 10.2174/1876523800902020086
F. Formenti, Viviana Sonntag, F. Congestrì, F. Crespi
SB-277011A is a compound entering the brain with high affinity and selectivity for the dopamine (DA) D3 receptor. Recent electrophysiological study has shown that acute oral administration of SB-277011A significantly alters the spontaneous activity of DA neurons in the ventral tegmental area (VTA) but that intravenous administration has no effects. In that electrophysiological study hypotheses to explain this discrepancy involved either administration route- dependent timing for the compound to reach its active site or the formation of an active metabolite following oral administration that would sustain the activity of SB-277011A on DA cell firing. In an attempt to assess whether formation of a metabolite may account for the activity of the parent compound we conducted electrophysiological multi-unit field recordings of DA neurons in the VTA of anaesthetised rats following treatment with SB-277011A either systemically or locally in the VTA. The local dose (2.5� g) was selected based on brain exposure achieved following systemic i.p. administration of 10mg/kg. Results show that both administrations increased VTA neurons firing compared to vehicle administration. However, local injection of SB-277011A in the VTA induced a more rapid and higher increase of neuronal activity than systemic treatment. These results suggest that the increased VTA cell firing occurring following systemic administration of SB-277011A is likely due to the compound itself and not to a putative metabolite. Finally, since the growing evidence that cannabinoids (CBs) modulate DA release in the brain and in view of the fact that CB1 receptors are widely distributed over DA neurons, the interplay between these two systems in the context of the current findings is discussed.
{"title":"Dopamine D3 Receptor Antagonist SB-277011A Influences Cell Firing in the Rat Ventral Tegmental Area, Parallel Role with the Cannabinoid System in Addiction and Neuropsychiatry Disorders?","authors":"F. Formenti, Viviana Sonntag, F. Congestrì, F. Crespi","doi":"10.2174/1876523800902020086","DOIUrl":"https://doi.org/10.2174/1876523800902020086","url":null,"abstract":"SB-277011A is a compound entering the brain with high affinity and selectivity for the dopamine (DA) D3 receptor. Recent electrophysiological study has shown that acute oral administration of SB-277011A significantly alters the spontaneous activity of DA neurons in the ventral tegmental area (VTA) but that intravenous administration has no effects. In that electrophysiological study hypotheses to explain this discrepancy involved either administration route- dependent timing for the compound to reach its active site or the formation of an active metabolite following oral administration that would sustain the activity of SB-277011A on DA cell firing. In an attempt to assess whether formation of a metabolite may account for the activity of the parent compound we conducted electrophysiological multi-unit field recordings of DA neurons in the VTA of anaesthetised rats following treatment with SB-277011A either systemically or locally in the VTA. The local dose (2.5� g) was selected based on brain exposure achieved following systemic i.p. administration of 10mg/kg. Results show that both administrations increased VTA neurons firing compared to vehicle administration. However, local injection of SB-277011A in the VTA induced a more rapid and higher increase of neuronal activity than systemic treatment. These results suggest that the increased VTA cell firing occurring following systemic administration of SB-277011A is likely due to the compound itself and not to a putative metabolite. Finally, since the growing evidence that cannabinoids (CBs) modulate DA release in the brain and in view of the fact that CB1 receptors are widely distributed over DA neurons, the interplay between these two systems in the context of the current findings is discussed.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"124 1","pages":"86-92"},"PeriodicalIF":0.0,"publicationDate":"2009-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68143913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-09-08DOI: 10.2174/1876523800902020064
Delphine Psychoyos, B. Hungund, R. Finnell
Marijuana is the most commonly abused illicit drug by pregnant women in the world. Its psychoactive cannabinoid, 9 -tetrahydrocannabinol, crosses the placenta and accumulates in the fetus, potentially harming its development. In humans, marijuana use in early pregnancy is associated with an increased risk for miscarriage, anencephaly, as well as subtle neurodevelopmental defects in the offspring, including ADHD, psychiatric disorders, learning disabilities and memory impairment. Little is known about the mechanisms by which marijuana exert its detrimental effects on the developing embryo, although recent evidence points to the possibility that 9 tetrahydrocannabinol might interfere with an endogenous endocannabinoid system present in the embryo during early stages of pregnancy. Here we review our current knowledge on evidence for an endocannabinoid system in early embryonic development and discuss a possible mechanism of action for 9 -tetrahydrocannabinol in early pregnancy.
{"title":"Endocannabinoid Signaling in Early Neurodevelopment: Effect of Gestational Δ9-THC Exposure","authors":"Delphine Psychoyos, B. Hungund, R. Finnell","doi":"10.2174/1876523800902020064","DOIUrl":"https://doi.org/10.2174/1876523800902020064","url":null,"abstract":"Marijuana is the most commonly abused illicit drug by pregnant women in the world. Its psychoactive cannabinoid, 9 -tetrahydrocannabinol, crosses the placenta and accumulates in the fetus, potentially harming its development. In humans, marijuana use in early pregnancy is associated with an increased risk for miscarriage, anencephaly, as well as subtle neurodevelopmental defects in the offspring, including ADHD, psychiatric disorders, learning disabilities and memory impairment. Little is known about the mechanisms by which marijuana exert its detrimental effects on the developing embryo, although recent evidence points to the possibility that 9 tetrahydrocannabinol might interfere with an endogenous endocannabinoid system present in the embryo during early stages of pregnancy. Here we review our current knowledge on evidence for an endocannabinoid system in early embryonic development and discuss a possible mechanism of action for 9 -tetrahydrocannabinol in early pregnancy.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"64-76"},"PeriodicalIF":0.0,"publicationDate":"2009-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68144232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-09-08DOI: 10.2174/1876523800902020053
T. Femenía, Pablo Portillo, J. M. Pérez‐Ortiz, A. Aracil-Fernández, G. Rubio, J. Manzanares
The development of alcohol dependence is the result of a combination of various factors. Psychosocial and psychiatric conditions, together with functional alterations of the brain or genetic traits, contribute to the development of problems related to alcohol use or alcohol dependence. Clinical studies using neuroimaging techniques (PET, fMRI) and preclinical studies using different animal models of problems related to ethanol consumption have improved our knowledge of the neurochemical mechanisms involved in alcohol dependence. These studies have served to identify peptides or receptors modified by ethanol consumption, which are functionally altered in strains of rats or mice highly vulnerable to ethanol consumption. Such peptides or receptors may be interesting targets for the treatment of alcoholism. Among the different targets studied in recent years, the opioid and cannabinoid systems meet a number of conditions for eligibility as candidates for the treatment of alcohol dependence. The � -opioid receptor and cannabinoid CB1 receptor, in particular, are affected by ethanol consumption. In clinical studies, genetic polymorphisms of the � -opioid and CB1 receptors have been associated with increased vulnerability to alcohol consumption. Similarly, functional alterations in � - opioid and cannabinoid receptors have been identified in specific strains of rats or mice with high preference to ethanol consumption. Furthermore, several studies have shown that the manipulation of these receptors using agonists or antagonists may increase or decrease ethanol consumption, which confirms the validity of these receptors as targets for the treatment of alcohol dependence. In this review, we analyzed the genetic traits and psychiatric and/or psychosocial conditions that affect vulnerability to and the pharmacologic treatment of alcohol dependence, with special emphasis on the role of opioid and cannabinoid receptors. The use of animal models as important tools for identifying neurochemical mechanisms relevant to understanding and treating alcohol use problems was evaluated.
{"title":"Opioid and cannabinoid systems as therapeutic targets for the treatment of alcohol dependence: From animal models to clinical practice","authors":"T. Femenía, Pablo Portillo, J. M. Pérez‐Ortiz, A. Aracil-Fernández, G. Rubio, J. Manzanares","doi":"10.2174/1876523800902020053","DOIUrl":"https://doi.org/10.2174/1876523800902020053","url":null,"abstract":"The development of alcohol dependence is the result of a combination of various factors. Psychosocial and psychiatric conditions, together with functional alterations of the brain or genetic traits, contribute to the development of problems related to alcohol use or alcohol dependence. Clinical studies using neuroimaging techniques (PET, fMRI) and preclinical studies using different animal models of problems related to ethanol consumption have improved our knowledge of the neurochemical mechanisms involved in alcohol dependence. These studies have served to identify peptides or receptors modified by ethanol consumption, which are functionally altered in strains of rats or mice highly vulnerable to ethanol consumption. Such peptides or receptors may be interesting targets for the treatment of alcoholism. Among the different targets studied in recent years, the opioid and cannabinoid systems meet a number of conditions for eligibility as candidates for the treatment of alcohol dependence. The � -opioid receptor and cannabinoid CB1 receptor, in particular, are affected by ethanol consumption. In clinical studies, genetic polymorphisms of the � -opioid and CB1 receptors have been associated with increased vulnerability to alcohol consumption. Similarly, functional alterations in � - opioid and cannabinoid receptors have been identified in specific strains of rats or mice with high preference to ethanol consumption. Furthermore, several studies have shown that the manipulation of these receptors using agonists or antagonists may increase or decrease ethanol consumption, which confirms the validity of these receptors as targets for the treatment of alcohol dependence. In this review, we analyzed the genetic traits and psychiatric and/or psychosocial conditions that affect vulnerability to and the pharmacologic treatment of alcohol dependence, with special emphasis on the role of opioid and cannabinoid receptors. The use of animal models as important tools for identifying neurochemical mechanisms relevant to understanding and treating alcohol use problems was evaluated.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"53-63"},"PeriodicalIF":0.0,"publicationDate":"2009-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68144220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-09-08DOI: 10.2174/1876523800902020040
P. Maccioni, Noemi Fantini, M. Carai, G. Gessa, G. Colombo
Administration of the cannabinoid CB1 receptor antagonist, rimonabant (also known as SR 141716), has been reported to reduce alcohol intake (measured under the homecage 2-bottle "alcohol vs water" choice regimen) in selectively bred, Sardinian alcohol-preferring (sP) rats. The present study investigated whether rimonabant also had the capacity to decrease, in this rat line, alcohol's reinforcing properties. To this end, male sP rats were initially trained to lever-press (on a fixed ratio 4 schedule of reinforcement) to orally self-administer alcohol (15%, v/v) in daily 30-min sessions. Once lever-pressing and self-administration behaviors reached stable levels (150-200 responses/session and 0.8- 1 g/kg alcohol per session, respectively), the effect of rimonabant (0, 0.3, 1, and 3 mg/kg, i.p.) on responding for alcohol and amount of self-administered alcohol was determined. Pretreatment with rimonabant resulted in a significant, dose- dependent reduction in both variables; specifically, the total number of lever responses for alcohol and amount of self- administered alcohol in the rat groups treated with 0.3, 1, and 3 mg/kg rimonabant were approximately 20%, 35%, and 60% lower than those recorded in vehicle-treated rats. Pretreatment with 3 mg/kg rimonabant also resulted in a significant increase in the latency to the first response on the "alcohol" lever. These results demonstrate the capacity of rimonabant to suppress alcohol's reinforcing properties in alcohol-preferring sP rats. These data constitute a further piece of experimental evidence in support of the hypothesized role for the CB1 receptor in the control of alcohol drinking and reinforcement.
{"title":"Suppressing Effect of the Cannabinoid CB1 Receptor Antagonist, Rimonabant, on Alcohol Self-Administration in Alcohol-Preferring Rats","authors":"P. Maccioni, Noemi Fantini, M. Carai, G. Gessa, G. Colombo","doi":"10.2174/1876523800902020040","DOIUrl":"https://doi.org/10.2174/1876523800902020040","url":null,"abstract":"Administration of the cannabinoid CB1 receptor antagonist, rimonabant (also known as SR 141716), has been reported to reduce alcohol intake (measured under the homecage 2-bottle \"alcohol vs water\" choice regimen) in selectively bred, Sardinian alcohol-preferring (sP) rats. The present study investigated whether rimonabant also had the capacity to decrease, in this rat line, alcohol's reinforcing properties. To this end, male sP rats were initially trained to lever-press (on a fixed ratio 4 schedule of reinforcement) to orally self-administer alcohol (15%, v/v) in daily 30-min sessions. Once lever-pressing and self-administration behaviors reached stable levels (150-200 responses/session and 0.8- 1 g/kg alcohol per session, respectively), the effect of rimonabant (0, 0.3, 1, and 3 mg/kg, i.p.) on responding for alcohol and amount of self-administered alcohol was determined. Pretreatment with rimonabant resulted in a significant, dose- dependent reduction in both variables; specifically, the total number of lever responses for alcohol and amount of self- administered alcohol in the rat groups treated with 0.3, 1, and 3 mg/kg rimonabant were approximately 20%, 35%, and 60% lower than those recorded in vehicle-treated rats. Pretreatment with 3 mg/kg rimonabant also resulted in a significant increase in the latency to the first response on the \"alcohol\" lever. These results demonstrate the capacity of rimonabant to suppress alcohol's reinforcing properties in alcohol-preferring sP rats. These data constitute a further piece of experimental evidence in support of the hypothesized role for the CB1 receptor in the control of alcohol drinking and reinforcement.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"40-44"},"PeriodicalIF":0.0,"publicationDate":"2009-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68143861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-09-08DOI: 10.2174/1876523800902010031
B. Hungund, K. V. Yaragudri
Alcoholism is a psychiatric disorder characterized by impaired control over drinking, leading to tolerance, physical dependence, uncontrollable craving and relapse. The mechanism/s underlying this disorder is poorly understood at present. Ethanol (alcohol) effects are mediated through several signal transduction pathways involving many neurotransmitters and ion channels in various brain regions. There is a growing body of evidence now suggesting a critical role for the endocannabinoid (EC) system in alcohol-related behaviors. The EC system is comprised of endogenous cannabimimetic substances (endocannabinoids) and their receptors (cannabinoid (CB)) and the enzymes involved in the synthesis and degradation of the ECs. Recent studies have demonstrated that both the genetic and pharmacological manipulation of the EC system modulate the development of tolerance to and dependence on alcohol. The present article provides a review of the existing literature on the role of the EC system, and possible mechanisms and the therapeutic potential of the drugs targeted against this system in preventing alcohol addiction.
{"title":"Role of the Endocannabinoid System in Alcohol-Related Behaviors","authors":"B. Hungund, K. V. Yaragudri","doi":"10.2174/1876523800902010031","DOIUrl":"https://doi.org/10.2174/1876523800902010031","url":null,"abstract":"Alcoholism is a psychiatric disorder characterized by impaired control over drinking, leading to tolerance, physical dependence, uncontrollable craving and relapse. The mechanism/s underlying this disorder is poorly understood at present. Ethanol (alcohol) effects are mediated through several signal transduction pathways involving many neurotransmitters and ion channels in various brain regions. There is a growing body of evidence now suggesting a critical role for the endocannabinoid (EC) system in alcohol-related behaviors. The EC system is comprised of endogenous cannabimimetic substances (endocannabinoids) and their receptors (cannabinoid (CB)) and the enzymes involved in the synthesis and degradation of the ECs. Recent studies have demonstrated that both the genetic and pharmacological manipulation of the EC system modulate the development of tolerance to and dependence on alcohol. The present article provides a review of the existing literature on the role of the EC system, and possible mechanisms and the therapeutic potential of the drugs targeted against this system in preventing alcohol addiction.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"31-39"},"PeriodicalIF":0.0,"publicationDate":"2009-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68143850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-09-08DOI: 10.2174/1876523800902020045
E. Onaivi, H. Ishiguro, Qing-Rong Liu, J. Gong, P. Tagliaferro, A. Brusco, T. Arinami, G. Uhl
Cannabinoids, endocannabinoids and marijuana use activates two well characterized cannabinoid receptors (CBRs), CB1-Rs and CB2-Rs. The expression of CB1-Rs in the brain and periphery has been well studied, but CB2-Rs have received much less attention than CB1-Rs. CB2-Rs were previously thought to be predominantly expressed in immune cells in the periphery and were traditionally referred to as peripheral CB-Rs. We and others have now demonstrated the presence of CB2-Rs in neuronal, glial and endothelial cells in the brain, and this warrants a re-evaluation of the central nervous system (CNS) effects of CB2-Rs. However, many features of CB2-R gene structure, variants and regulation remain poorly characterized compared to the CB1-R. To further improve understanding of the role of CB2-Rs in the brain, we hypothesized that genetic variants of CB2-R (CNR2) gene might be associated with depression in a human population and that alteration in CNR2 gene expression may be involved in the effects of abused substances in rodents. In this review we show that our data and those of others reveal that CB2-Rs are expressed in neurons in the brain and play a role in depression and substance abuse beyond neuro-immuno-cannabinoid activity.
{"title":"CNS Effects of CB2 Cannabinoid Receptors","authors":"E. Onaivi, H. Ishiguro, Qing-Rong Liu, J. Gong, P. Tagliaferro, A. Brusco, T. Arinami, G. Uhl","doi":"10.2174/1876523800902020045","DOIUrl":"https://doi.org/10.2174/1876523800902020045","url":null,"abstract":"Cannabinoids, endocannabinoids and marijuana use activates two well characterized cannabinoid receptors (CBRs), CB1-Rs and CB2-Rs. The expression of CB1-Rs in the brain and periphery has been well studied, but CB2-Rs have received much less attention than CB1-Rs. CB2-Rs were previously thought to be predominantly expressed in immune cells in the periphery and were traditionally referred to as peripheral CB-Rs. We and others have now demonstrated the presence of CB2-Rs in neuronal, glial and endothelial cells in the brain, and this warrants a re-evaluation of the central nervous system (CNS) effects of CB2-Rs. However, many features of CB2-R gene structure, variants and regulation remain poorly characterized compared to the CB1-R. To further improve understanding of the role of CB2-Rs in the brain, we hypothesized that genetic variants of CB2-R (CNR2) gene might be associated with depression in a human population and that alteration in CNR2 gene expression may be involved in the effects of abused substances in rodents. In this review we show that our data and those of others reveal that CB2-Rs are expressed in neurons in the brain and play a role in depression and substance abuse beyond neuro-immuno-cannabinoid activity.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"45-52"},"PeriodicalIF":0.0,"publicationDate":"2009-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68143874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-07-28DOI: 10.2174/1876523800902010022
W. Adriani, O. Granstrem, E. Romano, S. Koroleva, G. Laviola
Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attention, and brain cortical processes. A synthetic analog of one Cortexin fraction, Cortagen (i.e. Ala-Glu-Asp-Pro peptide), was developed. Both agents stimulate neural growth in vitro, presumably in association with neurotrophic factors. We assessed the psychoactive effects of Cortexin and cortagen, using elevated plus maze (EPM) and locomotor activity habituation (LAH) paradigms in CD-1 mice. In Exp. I, mice were injected with Cortexin (0, 0.25, 0.50, or 1.00 mg/kg i.p.) and tested in the EPM (acute) and the LAH (sub-chronic response). In Exp. II, separate mice were injected with cortagen (0, 0.01, 0.03, or 0.10 mg/kg i.p.) or a reference dose of Cortexin, and tested in the LAH (acute and sub-chronic) and the EPM (sub-chronic response). Results: Evidence of anxyolitic effects was found in the EPM for acute Cortexin treatment at the 0.25 and 1.00 mg/kg dosages. The Cortexin 0.25 mg/kg was selected as reference dose for Exp. II, since it had no locomotor effects over 4 days, whilst the 1.00 mg/kg dose led to the development of hyperactivity. When comparing to Cortexin reference, the 0.03 mg/kg dose of cortagen enhanced locomotion both upon acute and after sub-chronic treatment, also having few effects on anxiety-related behavior. Conversely, following a sub-chronic regimen (5 days), the Cortexin reference and the other doses of cortagen turned out to produce anxiogenic effects. Conclusion: Cortexin has anxiolytic-like effects when given acutely, and anxiogenic-like arousal emerges following repeated treatment. Conversely, acute and sub-chronic cortagen leads to motor stimulation with no side effects on emotional-affective profiles. Such behavioral stimulation may find beneficial employment in the treatment of affective / depressive symptoms in humans. Peptides are active in very low dosages with no side effects, and deserve deeper investigation for their promising role in therapy.
{"title":"Modulatory Effects of Cortexin and Cortagen on Locomotor Activity and Anxiety-Related Behavior in Mice","authors":"W. Adriani, O. Granstrem, E. Romano, S. Koroleva, G. Laviola","doi":"10.2174/1876523800902010022","DOIUrl":"https://doi.org/10.2174/1876523800902010022","url":null,"abstract":"Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attention, and brain cortical processes. A synthetic analog of one Cortexin fraction, Cortagen (i.e. Ala-Glu-Asp-Pro peptide), was developed. Both agents stimulate neural growth in vitro, presumably in association with neurotrophic factors. We assessed the psychoactive effects of Cortexin and cortagen, using elevated plus maze (EPM) and locomotor activity habituation (LAH) paradigms in CD-1 mice. In Exp. I, mice were injected with Cortexin (0, 0.25, 0.50, or 1.00 mg/kg i.p.) and tested in the EPM (acute) and the LAH (sub-chronic response). In Exp. II, separate mice were injected with cortagen (0, 0.01, 0.03, or 0.10 mg/kg i.p.) or a reference dose of Cortexin, and tested in the LAH (acute and sub-chronic) and the EPM (sub-chronic response). Results: Evidence of anxyolitic effects was found in the EPM for acute Cortexin treatment at the 0.25 and 1.00 mg/kg dosages. The Cortexin 0.25 mg/kg was selected as reference dose for Exp. II, since it had no locomotor effects over 4 days, whilst the 1.00 mg/kg dose led to the development of hyperactivity. When comparing to Cortexin reference, the 0.03 mg/kg dose of cortagen enhanced locomotion both upon acute and after sub-chronic treatment, also having few effects on anxiety-related behavior. Conversely, following a sub-chronic regimen (5 days), the Cortexin reference and the other doses of cortagen turned out to produce anxiogenic effects. Conclusion: Cortexin has anxiolytic-like effects when given acutely, and anxiogenic-like arousal emerges following repeated treatment. Conversely, acute and sub-chronic cortagen leads to motor stimulation with no side effects on emotional-affective profiles. Such behavioral stimulation may find beneficial employment in the treatment of affective / depressive symptoms in humans. Peptides are active in very low dosages with no side effects, and deserve deeper investigation for their promising role in therapy.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"22-29"},"PeriodicalIF":0.0,"publicationDate":"2009-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68144341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-03-19DOI: 10.2174/1876523800902010011
S. El-Badri, H. Ashton, I. Ferrier, P. B. Moore
The study examined the relationship between obstetric complications, genetic risk and age of illness onset in bipolar disorder. Thirty DSM-IV bipolar I patients in remission (ages 21-39yr, mean 30.7 + 6.1yr.) and twenty seven healthy controls (ages 19-39yr, mean 27.7 + 7.0yr.) were investigated using structured interview, life chart and pregnancy and birth complica- tions questionnaire. Family history, pregnancy and birth complications and age of illness onset were collected. Compari- sons were made between patients and controls and also between patient groups with age of illness onset before and after the age of 21 years. Obstetric complications were more common in patients (effect size= 0.48) than controls but this was not significant statis- tically (Fisher's exact test, p=0.13). There was a non-significant excess in early onset patients. Family histories of mood disorder were found in 22 out of 30 bipolar subjects, but rates in early and late onset groups did not differ (p=0.35). The study failed to find evidence of either increased rates of obstetric complications in bipolar disorder patients or of a link between age of illness onset and a family history of mood disorders. The power of the study was limited by a sample size and difficulties in obtaining unequivocal obstetric data. The finding is in agreement with a recent metanalysis. The large effect size indicates that larger study of obstetric complications in bipolar disorder subjects is justified, looking par- ticularly for subgroups for which there may be an association between complications and clinical variables.
{"title":"Family Illness History, Obstetric Complications and Age of Onset in Bipolar Patients","authors":"S. El-Badri, H. Ashton, I. Ferrier, P. B. Moore","doi":"10.2174/1876523800902010011","DOIUrl":"https://doi.org/10.2174/1876523800902010011","url":null,"abstract":"The study examined the relationship between obstetric complications, genetic risk and age of illness onset in bipolar disorder. Thirty DSM-IV bipolar I patients in remission (ages 21-39yr, mean 30.7 + 6.1yr.) and twenty seven healthy controls (ages 19-39yr, mean 27.7 + 7.0yr.) were investigated using structured interview, life chart and pregnancy and birth complica- tions questionnaire. Family history, pregnancy and birth complications and age of illness onset were collected. Compari- sons were made between patients and controls and also between patient groups with age of illness onset before and after the age of 21 years. Obstetric complications were more common in patients (effect size= 0.48) than controls but this was not significant statis- tically (Fisher's exact test, p=0.13). There was a non-significant excess in early onset patients. Family histories of mood disorder were found in 22 out of 30 bipolar subjects, but rates in early and late onset groups did not differ (p=0.35). The study failed to find evidence of either increased rates of obstetric complications in bipolar disorder patients or of a link between age of illness onset and a family history of mood disorders. The power of the study was limited by a sample size and difficulties in obtaining unequivocal obstetric data. The finding is in agreement with a recent metanalysis. The large effect size indicates that larger study of obstetric complications in bipolar disorder subjects is justified, looking par- ticularly for subgroups for which there may be an association between complications and clinical variables.","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"11-15"},"PeriodicalIF":0.0,"publicationDate":"2009-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68144331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-01-01DOI: 10.2174/1876523800902020077
Lily Alvarez-Jaimes, Ilham Polis, Loren H Parsons
Substantial evidence suggests a facilitatory influence of cannabinoid CB1 receptors in the modulation of ethanol consumption by rodents. Studies performed in rats selectively bred for high alcohol preference point to an involvement of CB1 receptors in the nucleus accumbens (NAC), ventral tegmental area (VTA) and medial prefrontal cortex (mPFC) in the modulation ethanol self-administration. However, the neural mechanisms through which CB1 receptors regulate ethanol intake in out-bred Wistar rats have not been investigated. The present study evaluated alterations in ethanol self-administration induced by localized infusions of the CB1 receptor antagonist SR141716A (0, 1 and 3 μg/side) into the NAC, anterior and posterior VTA and mPFC. Separate groups of Wistar rats were trained to operantly respond for an oral ethanol solution and prepared with bilateral injection cannulae aimed at each brain region. Results revealed significant decreases in ethanol intake following intra-NAC SR141716A administration, consistent with our prior observation of ethanol-induced increases extracellular 2-arachidonoyl glycerol (2-AG) in this brain region. We also observed a significant dose-dependent reduction in ethanol intake following SR141716A administration into the posterior, but not anterior VTA, consistent with evidence of a specific involvement of the posterior VTA in the regulation of ethanol intake. Ethanol consumption was unaltered following intra-mPFC SR141716A administration and ethanol self-administration did not induce robust changes in anandamide or 2-AG levels in mPFC microdialysates. These findings implicate an involvement of CB1 receptors in the NAC and posterior VTA, but not anterior VTA and mPFC in the regulation of ethanol self-administration behavior by outbred Wistar rats.
{"title":"Regional Influence of Cannabinoid CB<sub>1</sub> Receptors in the Regulation of Ethanol Self-Administration by Wistar Rats.","authors":"Lily Alvarez-Jaimes, Ilham Polis, Loren H Parsons","doi":"10.2174/1876523800902020077","DOIUrl":"10.2174/1876523800902020077","url":null,"abstract":"<p><p>Substantial evidence suggests a facilitatory influence of cannabinoid CB<sub>1</sub> receptors in the modulation of ethanol consumption by rodents. Studies performed in rats selectively bred for high alcohol preference point to an involvement of CB<sub>1</sub> receptors in the nucleus accumbens (NAC), ventral tegmental area (VTA) and medial prefrontal cortex (mPFC) in the modulation ethanol self-administration. However, the neural mechanisms through which CB<sub>1</sub> receptors regulate ethanol intake in out-bred Wistar rats have not been investigated. The present study evaluated alterations in ethanol self-administration induced by localized infusions of the CB<sub>1</sub> receptor antagonist SR141716A (0, 1 and 3 μg/side) into the NAC, anterior and posterior VTA and mPFC. Separate groups of Wistar rats were trained to operantly respond for an oral ethanol solution and prepared with bilateral injection cannulae aimed at each brain region. Results revealed significant decreases in ethanol intake following intra-NAC SR141716A administration, consistent with our prior observation of ethanol-induced increases extracellular 2-arachidonoyl glycerol (2-AG) in this brain region. We also observed a significant dose-dependent reduction in ethanol intake following SR141716A administration into the posterior, but not anterior VTA, consistent with evidence of a specific involvement of the posterior VTA in the regulation of ethanol intake. Ethanol consumption was unaltered following intra-mPFC SR141716A administration and ethanol self-administration did not induce robust changes in anandamide or 2-AG levels in mPFC microdialysates. These findings implicate an involvement of CB<sub>1</sub> receptors in the NAC and posterior VTA, but not anterior VTA and mPFC in the regulation of ethanol self-administration behavior by outbred Wistar rats.</p>","PeriodicalId":88752,"journal":{"name":"The open neuropsychopharmacology journal","volume":"2 1","pages":"77-85"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68143905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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