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Decreased Benzodiazepine Receptor Binding in Cingulate Cortex of Alcoholics
Examined by I-123 Iomazenil SPECT
Running head: Benzodiazepine Receptor in Alcoholics
Hiroaki Harai, M.D. 1
Masaru Murakami, M.D. 1
Masatoshi Ishibashi, M.D. Ph.D. 2
1 Hizen National Mental Hospital
Kanzaki, Saga, JAPAN 842-01
2 Department of Radiology and Division of Nuclear Medicine,
Kurume University School of Medicine
Kurume, Fukuoka, JAPAN 830
Address for correspondence to: Hiroaki Harai, M.D.
Hizen National Mental Hospital
Kanzaki, Saga, JAPAN 842-01
Benzodiazepine receptor imaging with I -123 iomazenil was performed to assess brain function on three alcohol-dependent males. A decrease in benzodiazepine receptor binding in the cingulate cortex was observed of all subjects. This finding suggests that benzodiazepine receptor imaging with I-123 iomazenil is valuable in detecting abnormal brain function in alcohol-dependent patients. To our knowledge, this is the first study to use I -123 iomazenil single-photon emission computed tomography (SPECT) for assessing benzodiazepine receptor function in alcoholics.
Alcohol dependence; benzodiazepine receptor; SPECT; I-123-iomazenil; cingulate cortex
Method of 123 iomazenil
Iomazenil (Ro 16-0154), an iodinated ligand for central-type benzodiazepine (BDZ) receptors, is an analog of flumazenil, which has been used in positron-emission tomography (PET) studies to investigate BDZ receptors. This agent is a partial inverse agonist of BDZ with a high affinity for the central type BDZ receptors. Its characteristics are favorable for use in the in vivo assessment of BDZ receptors by SPECT (1)#Sybirska#(2)#Onishi#.
Ethanol and GABA
Clinical evidence of cross-tolerance between ethanol and BDZs and the preventive effect of benzodiazepine administration on the development of alcohol withdrawal syndrome has been demonstrated. Recent studies have shown that BDZ receptors are structurally combined with gamma-aminobutyric acid A-type (GABAA) receptors, acute ethanol administration enhances certain types of GABAA receptors in the cerebellum, spinal cord, and cortex. As a contrast, chronic ethanol intake enhances inverse agonists on BDZ receptors (3)#Sanna#(4)#Korpi#. Whether the chronic use of ethanol decreases the function of GABAA/BDZ receptors in humans remains a subject of debate.
We predicted decreased BDZ receptor binding with 123-I iomazenil SPECT in patients with chronic heavy alcohol consumption and the recurrent withdrawal syndrome.
Materials and Methods
We studied three Japanese male inpatients who had been admitted to the alcohol unit of Hizen National Mental Hospital who met the DSM III R diagnostic criteria for alcohol dependence. Their history of alcohol consumption and related disorders is shown in the Table. Findings on neurological examination and EEG were normal. The subjects had not consumed alcohol for two months or received psychotropic medication for more than 2 weeks. No systemic diseases were noted at the time of examination. We explained the experimental procedure to each subject and obtained written informed consent prior to the study.
Data acquisition and SPECT
I-123 Iomazenil was obtained from Nihon Medi-Physics Co., Ltd. (Nishinomiya, Japan). A dose of 167 MBq was injected intravenously as a bolus. SPECT scan was performed at 20 min. and again at 3 hours after injection of the tracer. Continuous transaxial tomograms were reconstructed, and coronal and sagittal images were derived from the transaxial images.
Brain perfusion SPECT
Images of cerebral blood flow (CBF) were obtained 20 minutes after the intravenous injection of 222 MBq of I-123 N-isopropyl-p-iodoamphetamine (IMP) using the same equipment and data processing as for I-123 iomazenil SPECT.
Each patient underwent MR imaging within one month after I-123 iomazenil SPECT by means of a 1.5 T unit (Magnex 150, Shimadzu, Kyoto, Japan). The following imaging parameters were used: spin-echo sequences with a repetition time (msec) / echo time (msec) ratio of 500/20 for T1-weighted images; 2500/90 for T2-weighted images and 2500/20 for proton-density images; 8-mm section thickness with a 2-mm interslice gap, and a 256×256 acquisition matrix.
Results are depicted in the Table. A decrease in BDZ receptor binding was seen in the cingulate cortex of the three subjects with preservation of CBF. The brain images in Case 2, a 46 years old man, exhibited a marked decrease in BDZ receptor binding in the cingulate cortex, shown in the Figure.
The decrease in GABAA/BDZ receptor binding and the preservation of CBF in the cingulate cortex may be explained by changes in the composition of GABAA/BDZ receptor subunits induced by biological mechanisms of alcohol dependence or by chronic ethanol exposure. Abnormality of the cingulate cortex has been demonstrated in patients with obsessive-compulsive disorder (OCD)(5)#Insel#. The obsessive behavior exhibited in OCD and the binge drinking characteristic of alcohol dependence are similar manifestations of a loss of control. Thus the cingulate cortex may play an important role in controlling impulsive behavior. The hypothesis that an abnormal function of the cingulate cortex is a biological indicator of alcohol dependence merits further investigation.
The decrease in GABAA/BDZ receptor binding and the preservation of CBF in the cingulate cortex might be interpreted as follows; 1) one of the biological abnormalities that cause alcohol dependence or 2) chronic ethanol exposure caused so that the affinity for BDZ decreased. Various studies suggest that there is an abnormality of the cingulate cortex in Obsessive-Compulsive Disorders(OCD)(6)#Insel#. It is possible that the cingulate cortex plays an important role in controlling impulsive behaviors. The obsessive behavior of OCD and the binge drinking of alcohol dependence share the same characteristics in terms of loss of control. The hypothesis that abnormal function of the cingulate cortex is one of the biological indicators of alcohol dependence is of interest.
Compare with other researches
Various methods have been used by researchers to demonstrate abnormal changes in BDZ receptors in alcohol-dependent patients. However, none of those methods have been successful to detect the existence of BDZ receptors in the living human brain, and findings of BDZ receptor function have been inconsistent. Since I-123 iomazenil SPECT directly reveals the presence of BDZ receptors and produced consistent findings in our three subjects, it appeared to be more reliable than other methods for studying BDZ receptors.
The strong point of the paper
To our knowledge, this is the first report of I-123 iomazenil SPECT analysis of alcohol dependence. A decrease in BDZ receptor binding was observed in the cingulate cortex in all three subjects. Further study is required to confirm these findings.
- Sybirska E, Al-Tikriti MS, Zoghbi SS, Baldwin RM, Johnson EW, Innis RB. SPECT imaging of the benzodiazepine receptor: autoradiographic comparison of receptor density and radioligand distribution. Synapse 1992:12:119-28.
- Onishi Y, Yonekura Y, Mukai T et al. Simple quantification of benzodiazepine receptor binding and ligand transport using iodine-123-iomazenil and two SPECT scans. J Nucl Med 1995:36:1201-10
- Sanna E, Harris RA. Neuronal ion channels. Recent Dev Alcohol 1993 :11:169-86
- Korpi E R. Role of GABAA receptors in the actions of alcohol and in alcoholism: recent advances. Alcohol & Alcoholism 1994:29:115-29
- Insel T R. Toward a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiatry 1992:49:739-44
Table Characteristics of Subjects and Results
|Case 1||Case 2||Case 3|
|Age of onset of daily drinking||20||21||20|
|Age of onset of heavy drinking (over 150 ml of pure ethanol)||40||30||30|
|Yrs of heavy drinking||8||16||7|
|The average consumption of pure ethanol (ml/day) before admission||220||140||270|
|Withdrawal syndrome (age of onset)||Delirium tremens (43)||Epileptic seizure (43)||Delirium tremens (36)|
|Iodoamphetamine-SPECT||No defect||No defect||No defect|
|Early||No defect||No defect||No defect|
|Delayed||Decrease in cingulate cortex||Decrease in cingulate cortex||Decrease in cingulate cortex|
CBF = cerebral blood flow
Figure 1. Typical brain images as observed in Case 2.
(A) MRI (T1 imaging) shows no focal lesion in the cerebral cortex. (B) I-123 iodoamphetamine-SPECT demonstrates normal CBF. (C) Early I-123 iomazenil-SPECT demonstrates normal uptake. (D) Delayed I-123 iomazenil-SPECT shows a marked reduction in benzodiazepine binding in the cingulate cortex.