Selective alterations of the CB1 receptors and the fatty acid amide hydrolase in the ventral striatum of alcoholics and suicides

Abstract

Recent studies in rodents have suggested a role for the central endocannabinoid system in the regulation of mood and alcohol related behaviors. Alcohol use disorder is often associated with suicidal behavior. In the present study, we examined whether abnormalities in the endocannabinoid system in the ventral striatum are associated with alcohol dependence and suicide. The levels of CB1 receptors, receptor-mediated G-protein signaling, and activity and level of the fatty acid amide hydrolase (FAAH) were analyzed postmortem in the ventral striatum of alcohol-dependent nonsuicides (CA, n=9), alcohol-dependent suicides (AS, n=9) and nonpsychiatric controls (C, n=9). All subjects underwent a psychological autopsy, and toxicological and neuropathological examinations. The levels of the CB1 receptors and the CB1 receptor-mediated G-protein signaling were significantly lower in the ventral striatum of CA compared to the control group. However, these parameters were elevated in AS when compared to CA group. The activity of FAAH enzyme was lower in CA compared to the control group while it was found to be significantly higher in AS compared with CA group. These findings suggest that alcohol dependence is associated with the downregulation of the CB1 receptors, while suicide is linked to the upregulation of these receptors in the ventral striatum. Alteration in the activity of FAAH enzyme that regulates the anandamide (AEA) content might in turn explain differences in the CB1 receptor function in alcohol dependence and suicide. These findings may have etiological and therapeutic implications for the treatment of alcohol addiction and suicidal behavior.

Figure 1

The autoradiogram of [³H]Cyanoimipramine shows the distribution of serotonin transporters in the human postmortem brain. The serotonin transporters are highly expressed in the ventral striatum compared to dorsal striatum. This assisted in delineating the ventral striatum from the dorsal striatum.

Figure 2

The CB1 receptor levels were found to be lower in the ventral striatum of CA (74, p<0.0001) and AS (48%, p<0.001) compared to normal controls (Figure 1). However, a marked increase in level of the CB1 receptors was evident in the AS (98%, p<0.05) compared with CA. A representative immunoblot of the CB1 receptor is provided in the upper panel.

Figure 3

The CB1 receptor-mediated [³⁵S]GTP S binding was significantly lower in the membranes isolated from the ventral striatum of CA (35%, p<0.01) compared to normal controls. However, G-protein activation was higher in AS (32%, p<0.001) compared to CA group. Data is presented as percentage of stimulation over the basal binding.

Figure 4

The activity of FAAH was markedly reduced in the ventral striatum of CA (50%, p<0.0001) and AS (23%, p<0.01) compared to normal controls. However, there was a significant higher activity of the FAAH in AS (56%, p<0.01) compared to CA group.

Figure 5

A marked reduction in the level of FAAH was observed in CA (68%, p<0.001) compared to normal controls, whereas the FAAH immunoreactivity was found to be higher in AS (51%, p<0.05) than CA group. A representative immunoblot of the FAAH is shown in the upper panel.