Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia

Zavitsanou, Katerina; Garrick, Thomas; Huang, Xu‐Feng

doi:10.1016/j.pnpbp.2003.11.005

Cited by 241 publications

(148 citation statements)

References 21 publications

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“…A number of studies showed high CB1R binding and elevated levels of endogenous cannabinoids in schizophrenia (Zavitsanou et al 2004) in the ACC and in alcohol dependence (Neumeister et al 2012) in the ACC and OFC, disorders in which executive function and decision making have been compromised which implicates cannabinoid system abnormalities in the pathology of these disorders. Future work should determine further characteristics, including but not limited to dose-response profile, of endocannabinoid regulation of decision-making processes with possible clinical implications, and therapeutic potential of manipulating cannabinoid system function in a range of psychiatric disorders with impairments in decision making.…”

Section: Discussionmentioning

confidence: 99%

Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making

et al. 2014

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Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during costbenefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions.

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Section: Discussionmentioning

confidence: 99%

Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making

et al. 2014

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“…Using [ 3 H]CP-55940 binding, a lack of change in the caudate putamen and an increase in CB 1 receptor expression was reported in the prefrontal cortex of schizophrenic patients when compared with control subjects (Dean et al, 2001). Another study reported an increase in CB 1 receptors in the cingulate cortex of humans with schizophrenia (Zavitsanou et al, 2004). This may reflect the fact that it is not possible to model all aspects of psychosis in animals due to the subjective nature of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…However, other studies have not shown cannabinoid-induced disruption of sensorimotor gating (Stanley-Cary et al, 2002;Bortolato et al, 2005). Also, increases in CB 1 receptor density in frontal cortex subregions have been identified in post-mortem schizophrenic brains (Dean et al, 2001;Zavitsanou et al, 2004), and elevated levels of AEA were detected in cerebrospinal fluid (Leweke et al, 1999;Giuffrida et al, 2004;Leweke et al, 2007) and blood (De Marchi et al, 2003) of anti-psychotic naïve schizophrenics.…”

Section: Introductionmentioning

confidence: 99%

Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats

et al. 2008

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Rearing rats in isolation has been shown to produce behavioral and neurochemical alterations similar to those observed in psychoses such as schizophrenia. Also, a dysregulation in both the endocannabinoid and dopaminergic systems has been implicated in schizophrenia. The aim of this study was to determine if there are differences in CB 1 receptor and fatty acid amide hydrolase (FAAH) protein expression, as well as D 2 dopamine receptor expression in different brain regions in rats reared in different environmental conditions. Twenty-one day old male Sprague-Dawley rats were either reared in individual cages (isolated rats) or in group cages of 6 per cage (group housed rats) for 8 weeks. Quantitative fluorescence immunohistochemistry was performed on brain slices using antibodies specific to the CB 1 or D 2 receptor, or the enzyme FAAH. Raising rats in isolation led to a significant decrease in CB 1 receptor expression in the caudate putamen and the amygdala, a significant increase in FAAH expression in the caudate putamen and the nucleus accumbens core and shell, and no significant change in D 2 receptor expression in any region studied. These results indicate that the endocannabinoid system is altered in an animal model of aspects of psychosis. This implies that rearing rats under different housing conditions may provide new insight into the role of the endocannabinoid system in the development of psychoses.

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“…Secondly, neuroanatomical studies have sought to identify alterations in the properties of brain CB 1 cannabinoid receptors, the molecular target of Δ 9 -THC (Glass et al, 1997;Herkenham et al, 1990;Matsuda et al, 1993;Piomelli, 2003), associated with schizophrenia. These efforts have led to reveal a significant association between disorganized (hebephrenic) schizophrenia and a cannabinoid CB 1 receptor polymorphism (Ujike et al, 2002) as well as increases in CB 1 receptor densities in the dorsolateral prefrontal cortex (Dean et al, 2001) in post mortem brains from schizophrenic patients, while respective findings in anterior cingulate cortex are controversial (Koethe et al, 2007;Zavitsanou et al, 2004). Finally, biochemical analyses have focused on the impact of schizophrenia on serum and CSF levels of endocannabinoid mediators such as anandamide (De Marchi et al, 2003;Giuffrida et al, 2004;Leweke et al, 1999a).…”

Section: Introductionmentioning

confidence: 99%

Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: Impact of cannabis use

Leweke

Giuffrida

Koethe

et al. 2007

Schizophrenia Research

214

168

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Background: Previous studies have shown that cerebrospinal fluid (CSF) from schizophrenic patients contains significantly higher levels of the endogenous cannabinoid anandamide than does CSF from healthy volunteers. Moreover, CSF anandamide levels correlated inversely with psychotic symptoms, suggesting that anandamide release in the central nervous system (CNS) may serve as an adaptive mechanism countering neurotransmitter abnormalities in acute psychoses. In the present study we examined whether cannabis use may alter such a mechanism. Methods: We used liquid chromatography/mass spectrometry (LC/MS) to measure anandamide levels in serum and CSF from firstepisode, antipsychotic-naïve schizophrenics (n = 47) and healthy volunteers (n = 81). Based on reported patterns of cannabis use and urine Δ 9 -tetrahydrocannabinol (Δ 9 -THC) tests, each subject group was further divided into two subgroups: 'low-frequency' and 'high-frequency' cannabis users (lifetime use ≤5 times and N20 times, respectively). Serum Δ 9 -THC was investigated to determine acute use and three patients were excluded from the analysis due to detectable Δ 9 -THC levels in serum. Results: Schizophrenic low-frequency cannabis users (n = 25) exhibited N 10-fold higher CSF anandamide levels than did schizophrenic high-frequency users (n = 19, p = 0.008), healthy low-frequency (n = 55, p b 0.001) or high-frequency users (n = 26, p b 0.001). In contrast, no significant differences in serum anandamide levels were found among the four subgroups. CSF anandamide levels and disease symptoms were negatively correlated in both user groups. Conclusions:The results indicate that frequent cannabis exposure may down-regulate anandamide signaling in the CNS of schizophrenic patients, but not of healthy individuals. Thus, our findings suggest that alterations in endocannabinoid signaling might be an important component of the mechanism through which cannabis impacts mental health.

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Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia

Cited by 241 publications

References 21 publications

Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making

Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making

Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats

Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: Impact of cannabis use

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