Schizophrenia

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Cannabinoid CB₁ receptor antagonism markedly increases dopamine receptor-mediated stereotypies

Belen Ferrer^a^,^b, Miguel Angel Gorriti^b, Ana Palomino^a, Isolde Gornemann^a, Yolanda de Diego^a, Francisco Javier Bermudez-Silva^a, Ainhoa Bilbao^a^,^b, Emilio Fernandez-Espejo^c, Rosario Moratalla^d, Miguel Navarro^b and Fernando Rodríguez de Fonseca^a^,^b^,^,
^aFundación IMABIS, Hospital Carlos Haya, Málaga 29010, Spain
^bDepartamento de Psicobiología, Facultad de Psicología, Universidad Complutense, Madrid 28223, Spain
^cDepartamento de Fisiologia, Facultad de Medicina, Universidad de Sevilla, Spain
^dInstituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain
Received 31 August 2006; revised 18 December 2006; accepted 8 January 2007. Available online 19 January 2007.

Abstract

The contribution of the endocannabinoid system to dopamine-mediated disorganized behavior in schizophrenia is discussed. We used a model of concurrent stimulation of dopamine D₁ and D₂receptors to evaluate the role of this system in dopamine-mediated stereotypies measured in a hole-board test. Pretreatment with the cannabinoid CB₁ receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1 mg/kg) potentiated stereotyped behavior induced by coadministration of the dopamine D₁receptor agonist SKF 38393 (0.05, 0.1 and 1 mg/kg) and the dopamine D₂ receptor agonist quinpirole (0.25 mg/kg). Thus, the endocannabinoid system acts as a brake for abnormal behavior associated with dopaminergic overactivation.

Keywords: Endocannabinoids; Cannabinoid receptors; Dopamine receptors; Schizophrenia; Stereotypies

Schizophrenia Research
Volume 97, Issues 1-3, December 2007, Pages 109-117

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doi:10.1016/j.schres.2007.08.015

Acute effects of Δ⁹-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity

Georg Juckel^a^,^b^,^,, Patrik Roser^b, Thomas Nadulski^c, Andreas M. Stadelmann^a^,¹ and Jürgen Gallinat^a^,¹
^aDepartment of Psychiatry, University Hospital Charité, Berlin, Germany
^bDepartment of Psychiatry, Ruhr-University, Bochum, Germany
^cInstitute of Legal Medicine, University Hospital Charité, Berlin, Germany
Received 25 February 2007; revised 12 August 2007; accepted 15 August 2007. Available online 19 September 2007.

Abstract

Reduced amplitudes of auditory evoked mismatch negativity (MMN) have often been found in schizophrenic patients, indicating deficient auditory information processing and working memory. Cannabis-induced psychotic states may resemble schizophrenia. Currently, there are discussions focusing on the close relationship between cannabis, the endocannabinoid and dopaminergic system, and the onset of schizophrenic psychosis. This study investigated the effects of cannabis on MMN amplitude in 22 healthy volunteers (age 28 ± 6 years, 11 male) by comparing Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and standardized cannabis extract containing Δ⁹-THC and cannabidiol (CBD) in a prospective, double-blind, placebo-controlled cross-over design. The MMNs resulting from 1000 auditory stimuli were recorded by 32 channel EEG. The standard stimuli were 1000 Hz, 80 dB SPL, and 100 ms duration. The deviant stimuli differed in frequency (1500 Hz). Significantly greater MMN amplitude values at central electrodes were found under cannabis extract, but not under Δ⁹-THC. There were no significant differences between MMN amplitudes at frontal electrodes. MMN amplitudes at central electrodes were significantly correlated with 11-OH-THC concentration, the most important psychoactive metabolite of Δ⁹-THC. Since the main difference between Δ⁹-THC and standardized cannabis extract is CBD, which seems to have neuroprotective and anti-psychotic properties, it can be speculated whether the greater MMN amplitude that may imply higher cortical activation and cognitive performance is related to the positive effects of CBD. This effect may be relevant for auditory cortex activity in particular because only MMN amplitudes at the central, but not at the frontal electrodes were enhanced under cannabis.

Keywords: Cannabis; Mismatch negativity; Schizophrenia

Schizophrenia Research
Volume 94, Issues 1-3, August 2007, Pages 29-36

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doi:10.1016/j.schres.2007.04.025

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

F. Markus Leweke^a^,^,¹^,, Andrea Giuffrida^b^,¹, Dagmar Koethe^a, Daniela Schreiber^a^,^c, Brit M. Nolden^a, Laura Kranaster^a, Miriam A. Neatby^a, Miriam Schneider^a, Christoph W. Gerth^a, Martin Hellmich^d, Joachim Klosterkötter^a and Daniele Piomelli^c
^aDepartment of Psychiatry and Psychotherapy, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany
^bDepartment of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA
^cDepartments of Pharmacology and Biological Chemistry, University of California, Irvine, CA, USA
^dInstitute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany
Received 17 February 2007; revised 6 April 2007; accepted 25 April 2007. Available online 13 June 2007.

Abstract

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 first-episode, antipsychotic-naïve schizophrenics (n = 47) and healthy volunteers (n = 81). Based on reported patterns of cannabis use and urine Δ⁹-tetrahydrocannabinol (Δ⁹-THC) tests, each subject group was further divided into two subgroups: ‘low-frequency’ and ‘high-frequency’ cannabis users (lifetime use ≤ 5 times and > 20 times, respectively). Serum Δ⁹-THC was investigated to determine acute use and three patients were excluded from the analysis due to detectable Δ⁹-THC levels in serum.

Results

Schizophrenic low-frequency cannabis users (n = 25) exhibited > 10-fold higher CSF anandamide levels than did schizophrenic high-frequency users (n = 19, p = 0.008), healthy low-frequency (n = 55, p < 0.001) or high-frequency users (n = 26, p < 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.

Keywords: Anandamide; Cannabis; Endocannabinoids; First episode; Schizophrenia

Corresponding author. Tel.: +49 221 478 7250; fax: +49 221 478 4876.
¹ These authors contributed equally to this work.

Schizophrenia Research
Volume 94, Issues 1-3, August 2007, Pages 29-36

1: Psychiatry Res. 2007 Sep 25 [Epub ahead of print]Links

Affect processing and positive syndrome schizotypy in cannabis users.

Skosnik PD, Park S, Dobbs L, Gardner WL.

Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA.

While cannabis is associated with positive syndrome schizophrenia (SZ), it is unclear whether cannabinoids are also related to negative symptoms such as affective blunting. We examined whether cannabis use is associated with schizotypy and utilized event-related potentials (ERPs) to assess affect processing. Cannabis users demonstrated increased P300 amplitudes for unpleasant trait words, and demonstrated higher positive syndrome schizotypy which correlated with levels of cannabis use. The cannabis group also exhibited lower negative syndrome schizotypy. The lack of blunted responses during the affect ERP and decreased negative subscale schizotypy scores provide evidence that the endocannabinoid theory of schizophrenia may be primarily relevant in relation to positive syndrome SZ.

PMID: 17897720 [PubMed - as supplied by publisher]

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Abstract

Abstract

Abstract

Background

Methods

Results

Conclusions

Affect processing and positive syndrome schizotypy in cannabis users.