Increased [³H]quisqualic acid binding density in the dorsal striatum and anterior insula of alcoholics: A post-mortem whole-hemisphere autoradiography study.

The function of group I metabotropic glutamate receptors mGluR1 and mGluR5 is involved in the hyperglutamatergic state caused by chronic alcohol. Preclinical studies suggest that group I mGluR modulation could serve as a novel treatment of alcoholism. Considering the wide role of glutamatergic neurochemistry in addiction, group I mGluR binding was studied in brain areas involved in decision-making, learning and memory. Post-mortem whole hemisphere autoradiography was used to study the binding density of [³H]quisqualic acid, a potent group I mGluR agonist, in 9 Cloninger type 1 alcoholics, 8 Cloninger type 2 alcoholics and 10 controls. Binding was studied in the dorsal striatum, hippocampus and cortex. Alcoholics displayed a trend towards increased [³H]quisqualic acid binding in all brain areas. The most robust findings were in the putamen (p = 0.006) and anterior insula (p = 0.005), where both alcoholic subtypes displayed increased binding compared to the controls. These findings suggest altered group I mGluR function in alcoholic subjects in the dorsal striatum, which is involved in habitual learning, and in the anterior insula, which has a pivotal role in the perception of bodily sensations. Increased [³H]quisqualic acid binding might suggest a beneficial impact of mGluR1/5 modulators in the treatment of alcoholism.

Decreased [3H]naloxone Binding in the Dentate Gyrus of Cloninger Type 1 Anxiety-Prone Alcoholics: A Postmortem Whole-Hemisphere Autoradiography Study.

BACKGROUND: The opioid system of the central nervous system plays an essential role in the regulation of the rewarding effects of alcohol. Alcohol affects mu-opioid receptor (MOR) function. Enhanced MOR function inhibits the GABAergic inhibition of the nucleus accumbens (Nac), which leads to a release of dopamine in the Nac. Of the few pharmaceutical treatments for alcoholism, the MOR antagonists naltrexone and nalmefene benefit most a subset of alcoholics who are characterized with early onset and impulsivity. Our aim was to investigate possible differences in the binding density of [³H]naloxone, a MOR competitive antagonist, between Cloninger type 1 anxiety-prone and harm-avoidant alcoholics, Cloninger type 2 impulsive and antisocial alcoholics, and healthy controls in brain areas that are essential for reward, learning, impulse-control, and mood regulation. METHODS: We used postmortem whole-hemisphere autoradiography with [³H]naloxone, as a binding ligand. A subsequent autoradiography was performed with [³H]DAMGO, a selective MOR agonist. RESULTS: Cloninger type 1 alcoholics displayed decreased [³H]naloxone binding density in all studied brain areas. This trend reached statistical significance in the dentate gyrus, where type 1 alcoholics' [³H]naloxone binding density was significantly decreased (p = 0.019) when compared to controls. A similar trend of decreased binding in type 1 alcoholics was observed in the [³H]DAMGO study. CONCLUSIONS: Our finding suggest that Cloninger type 1 anxiety-prone alcoholics may have an altered [³H]naloxone binding in brain areas related to reward, impulse-control, mood, and learning. The finding lends support to the idea of Cloninger type 1 anxiety-prone alcoholics responding weaker to the opioidergic pharmaceuticals of the treatment of alcoholism than Cloninger type 2 impulsive alcoholics.

[³H]Ifenprodil binding in post-mortem brains of Cloninger type 1 and 2 alcoholics: a whole-hemisphere autoradiography study.

The glutamate N-methyl-d-aspartate (NMDA) receptor NR2B subunits are sensitive to ethanol and are found in brain areas related to ethanol addiction, dependence, development of alcohol tolerance, and alcohol withdrawal syndrome. Previous studies indicate that early-onset Cloninger type 2 alcoholics have an intact, responsive, dopaminergic system in the nucleus accumbens (NAC), whereas type 1 alcoholics have dopaminergic defects. NR2B-containing NMDA receptors in the NAC are involved in both non-opioid and opioid receptor-mediated reward. Our aim was to evaluate the putative [(3)H]ifenprodil binding alterations of NR2B receptors in limbic, hippocampal, and cortical brain areas of type 1 alcoholics (n=8), type 2 alcoholics (n=8), and control subjects (n=10) by postmortem whole hemisphere autoradiography. We found significantly different binding levels among these three subject groups, and the main difference was localized in the decreased binding in type 2 alcoholics and controls in the nucleus accumbens. Although preliminary and from relatively small diagnostic groups, these results suggest pathological alterations in the NR2B-mediated reward system of type 2 alcoholics.

Increased metabotropic glutamate 2/3 receptor binding in the perigenual anterior cingulate cortex of Cloninger type 2 alcoholics: a whole-hemisphere autoradiography study.

AIMS: Metabotropic glutamate receptors 2 and 3 (mGluR2/3) contribute to control the level of glutamate in the synapse. In rodents, mGluR2/3 agonists attenuate the reinstatement of alcohol-seeking behavior. Linking possible alterations of the mGluR2/3 system to the etiology and type of alcoholism could provide valuable information for the development of novel mGluR2/3 function modulating therapies in addiction treatment. To date, mGluR2/3 binding density has not been studied in human alcoholics. We aimed to investigate the possible differences in mGluR2/3 binding between Cloninger type 1 anxiety-prone and type 2 impulsive alcoholics and controls. METHODS: We performed a post-mortem whole-hemisphere autoradiography to study the mGluR2/3 binding density of 9 type 1 alcoholics, 8 type 2 alcoholics and 10 controls. [(3)H]LY341495, a potent group II metabotropic glutamate receptor antagonist, was used as the radio-ligand with l-glutamate as a displacer. RESULTS: [(3)H]LY341495 binding density was statistically significantly increased (P = 0.046) in the perigenual anterior cingulate cortex (pACC) of type 2 alcoholics when compared with controls. In other brain areas, no significant difference between the groups was found. CONCLUSION: This preliminary study suggests that impulsive type 2 alcoholics might have alterations in the mGluR2/3 function in the pACC, a brain area presumed to be involved in the control of drug-seeking behaviors and self-control.

Lower [3H]Citalopram binding in brain areas related to social cognition in alcoholics.

AIMS: In the present study, putative alterations in the serotonin transporter density were evaluated in anterior and posterior insula, posterior cingulate cortex, dorsolateral and dorsomedial prefrontal cortex, hippocampus, parahippocampal gyrus and dorsal raphe nucleus in Cloninger type 1 (n = 9) and type 2 (n = 8) alcoholics and non-alcoholic controls (n = 10). METHODS: Human whole-hemisphere autoradiography was used to measure [3H]citalopram binding to serotonin transporters in eight brain areas in all post-mortem brains. RESULTS: Significant differences were observed in the mean [3H]citalopram binding between the study groups, with antisocial type 2 alcoholics showing the lowest binding. Differences between the study groups were prominent in the posterior insula and posterior cingulate cortex, where both alcoholic groups had low [3H]citalopram binding, and in the parahippocampal gyrus where only antisocial type 2 alcoholics had low [3H]citalopram binding when compared with non-alcoholic controls. CONCLUSION: Although these data are preliminary, and from relatively small diagnostic groups, these results show that alcoholics may have lower serotonergic tone in the brain, thus decreasing social cognition and increasing alcohol-cue reactivity.

AMPA receptors in post-mortem brains of Cloninger type 1 and 2 alcoholics: a whole-hemisphere autoradiography study.

Dysfunction of the brain glutamate system has been associated with alcoholism. Ionotropic glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) play an important role in both neurotransmission and post-synaptic plasticity. Alterations in AMPAR densities may also play a role in the neurobiological changes associated with alcoholism. In the present study, [(3)H] AMPA binding density was evaluated in the nucleus accumbens (NAc), frontal cortex, anterior cingulate cortex (ACC), dentate gyrus and hippocampus of Cloninger type 1 (n=9) and 2 (n=8) alcoholics, and compared with non-alcoholic control subjects (n=10) by post-mortem whole-hemisphere autoradiography. The [(3)H] AMPA binding density was significantly higher in the ACC of early onset type 2 alcoholics when compared with controls (p=0.011). There was also a significant negative correlation between [(3)H] AMPA binding and previously published results of dopamine transporter (DAT) density in the ACC in these same brain samples (R=-0.95, p=0.001). Although preliminary, and from a relatively small diagnostic group, the present results help to further explain the pathology of alcohol dependence and impulsive behaviour in type 2 alcoholics.

Endogenous cannabinoids in amygdala and hippocampus in post-mortem brains of Cloninger type 1 and 2 alcoholics.

Accumulating evidence continues to link certain aspects of the endogenous cannabinoid (EC) system with alcohol dependence, negative-reinforcement learning, and the modulation of stress responses. Specific alterations in brain regions that are related to stress and negative-reinforcement learning have been reported to exist in Cloninger type 1 and type 2 alcoholics. To study possible differences in profiles of EC systems between Cloninger type 1 (n = 9) and type 2 (n = 8) alcoholics and non-alcoholic control subjects (n = 10), we analyzed post-mortem amygdala and hippocampus brain samples for several ECs by quantitative liquid chromatography with triple quadrupole mass-spectrometric detection. A significant difference was found between these 3 groups in terms of EC profiles in the amygdala (p = 0.037). In particular, this difference was prominent for variations in docosahexaenoylethanolamide levels, which were significantly higher in type 1 alcoholics (p = 0.022) when compared to controls. There was also a large negative correlation between anandamide concentration and mGlu1/5 receptor density in the hippocampi of Cloninger type 1 alcoholics (R = -0.88, p = 0.002), which was not seen in Cloninger type 2 alcoholics or in controls. Although preliminary, and from relatively small diagnostic groups, these results suggest that the EC system profile may be altered in the hippocampus and amygdala of Cloninger type 1 alcoholics.

Decreased GABA(A) benzodiazepine binding site densities in postmortem brains of Cloninger type 1 and 2 alcoholics.

Ethanol modulates the GABA(A) receptor to cause sedative, anxiolytic and hypnotic effects that are qualitatively similar to benzodiazepines and barbiturates. The aim of this study was to explore if GABA(A) receptor density is altered in post-mortem brains of anxiety-prone Cloninger type 1 and socially hostile type 2 alcoholic subtypes when compared to controls. The GABA(A) binding site density was measured by whole-hemisphere autoradiography with tritium labeled flunitrazepam ([(3)H]flunitrazepam) from 17 alcoholic (nine type 1, eight type 2) and 10 non-alcoholic post-mortem brains, using cold flumazepam as a competitive ligand. A total of eight specific brain areas were examined. Alcoholics displayed a significantly (p < 0.001, bootstrap type generalizing estimating equations model) reduced [(3)H]flunitrazepam binding site density when compared to controls. When localized, type 2 alcoholics displayed a significantly (p ≤ 0.05) reduced [(3)H]flunitrazepam binding site density in the internal globus pallidus, the gyrus dentatus and the hippocampus, whereas type 1 alcoholics differed from controls in the internal globus pallidus and the hippocampus. While previous reports have demonstrated significant alterations in dopaminergic and serotonergic receptors between type 1 and type 2 alcoholics among these same subjects, we observed no statistically significant difference in [(3)H]flunitrazepam binding site densities between the Cloninger type 1 and type 2 alcoholics.

mGluR1/5 receptor densities in the brains of alcoholic subjects: a whole-hemisphere autoradiography study.

Increased glutamatergic neurotransmission and hyper-excitability during alcoholic withdrawal and abstinence are associated with increased risk for relapse, in addition to compensatory changes in the glutamatergic system during chronic alcohol intake. Type 5 metabotropic glutamate receptor (mGlur5) is abundant in brain regions known to be involved in drug reinforcement, yet very little has been published on mGluR1/5 expression in alcoholics. We evaluated the densities of mGluR1/5 binding in the hippocampus and striatum of post-mortem human brains by using [(3)H]Quisqualic acid as a radioligand in whole hemispheric autoradiography of Cloninger type 1 (n=9) and 2 (n=8) alcoholics and healthy controls (n=10). We observed a 30-40% higher mGluR1/5 binding density in the CA2 area of hippocampus in type 1 alcoholics when compared with either type 2 alcoholics or healthy subjects. Although preliminary, and from a relatively small number of subjects from these diagnostic groups, these results suggest that the mGluR1/5 receptors may be increased in type 1 alcoholics in certain brain areas.