Reduced cannabinoid CB1 receptor binding in alcohol dependence measured with positron emission tomography

Abstract

Brain cannabinoid CB1 receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB1 receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography (PET) and [18F]FMPEP-d2, a radioligand for CB1 receptors. We scanned 18 male inpatients with alcohol dependence twice, within 3–7 days of admission from ongoing drinking, and after 2–4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB1 receptor gene (CNR1) that may moderate CB1 receptor density. On the first scan, CB1 receptor binding was 20–30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2–4 weeks of abstinence, CB1 receptor binding remained similarly reduced in these patients. Irrespective of diagnostic status, C allele carriers at rs2023239 had higher CB1 receptor binding compared to non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain and this reduction persists at least 2–4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence in humans.

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

“…The maximum effect of the agonist (E max ) (air = 314 ±14, CIE = 208 ± 4, t test: t (16) = 3.79, P < 0.01), but not the negative logarithm of the half-maximal effective concentration (pEC 50 ) (air = 6.8 ±0.2, CIE = 7.1 ±0.1), values were significantly decreased after CIE. These data are in line with the decreased CB1R binding and signaling previously reported in the DLS of rats chronically exposed to EtOH (42)(43)(44), and in the DS of alcoholdependent patients (45,46). Decreases in CB1R functional binding after chronic EtOH exposure are associated with elevated levels of the ECB 2-arachidonoylglycerol (2-AG) and, in some studies, anandamide (AEA) (18,19).…”

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study

“…Also for CB1R expression, density and functionality, inconsistent results have been found in other studies, which have shown that CB1R is either downregulated and reduced in the hippocampus and caudate-putamen of rodents chronically exposed to ethanol [10,13], or unchanged [14]. In alcoholic patients, a profound cortical and subcortical loss of CB1R availability in vivo is found that is irreversible after several weeks of imposed alcohol abstinence [15,16], while acute ethanol administration in healthy volunteers results in a whole-brain increase in CB1R binding [17].…”

“…Although in the present study we did not quantify AEA levels in these regions, it seems from the above findings as if CB1R signalling specifically in the hippocampus and caudate-putamen of all brain regions plays a key role in ethanol addiction. Also in alcoholdependent patients, chronic alcohol consumption has been shown to result in a reduction in CB1R availability affecting the whole brain, although this reduction remained unaltered after 4 weeks of supervised abstinence from alcohol [15,16]. Nevertheless, recovery to normal levels has also been found to occur in chronic cannabis users upon cannabis abstinence using [ 18 F]FMPEP-d 2 [38].…”

Blocking of Fatty Acid Amide Hydrolase Activity with PF-04457845 in Human Brain: A Positron Emission Tomography Study with the Novel Radioligand [11C]CURB

“…All met the following criteria: (1) No past or present significant medical conditions and/ or neurologic illnesses or head trauma; (2) Normal physical exam, 12-lead electrocardiogram, complete blood count/blood chemistry, electrolytes, renal and liver function tests; (3) No past or present Axis I psychiatric diagnoses as per Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV); (4) No presence of metal objects in the body or implanted electronic devices that preclude safe MR scanning; (5) No claustrophobia; (6) No current pregnancy (as per serum β-HCG) or breastfeeding; (7) No current use or use during the previous month of medication that may affect the central nervous system or positive drug screening for drugs of abuse (as per dip stick urine toxicology screen (10-drug test panel from BTNX Inc., Markham, ON, Canada; at screening visit and at each visit afterwards) and broad-spectrum screen); (8) No exposure to radiation in the last 12 months exceeding permissible limit for subjects participating in research. (9) No abnormal body mass index (19 to 30). All subjects were also reminded not to consume grapefruit/pomelo containing products 7 days before the scan.…”

“…5 Considerable efforts have been invested in the development of imaging tools to investigate the role, if any, of components of the endocannabinoid system in the pathophysiology of these disorders. [6][7][8][9][10] Fatty acid amide hydrolase (FAAH; EC3.5.1.99) 11,12 is a serine hydrolase, prominently expressed in central nervous system and in the periphery. Its main function is to degrade a wide range of fatty acid amides and esters, with preference for primary amides and arachidonoyl and oleoyl substrates, including the major endocannabinoid anandamide (N-arachidonoylethanolamide) but also more abundant oleoylethanolamide and palmitoylethanolamide.…”