Effect of alcohol abuse on human brain histamine and tele-methylhistamine

Inflammation Research -     

Specific binding and laterality of human extrastriatal dopamine D2/D3 receptors in late onset type 1 alcoholic patients

Late onset type 1 alcoholism has been suggested to be associated with decreased dopaminergic transmission. Our hypothesis was that late onset type 1 alcoholics have also abnormal extrastriatal dopamine D(2)/D(3) receptor distribution. We performed binding, heterogeneity and laterality analysis of extrastriatal and striatal dopamine D(2)/D(3) receptors in nine late onset male alcoholics and in 12 age-matched healthy males. A radioligand, [(123)I]epidepride was used in high resolution single-photon emission tomography (SPET). Specific binding of epidepride in the left temporal pole was significantly (P<0.05) lower in type 1 alcoholics (0.74+/-0.14 ml/ml) than in controls (0.89+/-0.14 ml/ml). In alcoholics, there was no normal left-to-right asymmetry of the temporal cortical heterogeneity of epidepride distribution observed in control males (0.89+/-0.19 vs. 1.10+/-0.19; P<0.05). The results suggest that the specific binding of dopamine D(2)/D(3) receptors in late type 1 alcoholics is decreased and its laterality in the temporal brain is altered from normal.     

Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial

OBJECTIVE: We tested the hypothesis that topiramate is more effective than placebo in reducing symptoms in patients with treatment-resistant schizophrenia when combined with ongoing antipsychotic medication. METHOD: Twenty-six hospitalized treatment-resistant patients with chronic DSM-IV-diagnosed schizophrenia participated in a randomized, double-blind, placebo-controlled trial in which 300 mg/day of topiramate was gradually added to their ongoing treatment (clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods. Data were collected from April 2003 to November 2003. RESULTS: In intention-to-treat analysis, topiramate was more effective than placebo in reducing Positive and Negative Syndrome Scale general psychopathologic symptoms (effect size = 0.7, p = .021), whereas no significant improvement was observed in positive or negative symptoms. CONCLUSION: Glutamate antagonist topiramate may be an effective adjuvant treatment in reducing general psychopathologic symptoms in patients with schizophrenia resistant to treatment with second-generation antipsychotics.     

Dopamine receptors and transporters in the brain reward circuits of type 1 and 2 alcoholics measured with human whole hemisphere autoradiography

The role of the dopamine system in brain reward mechanisms and development of substance abuse is well-established with nucleus accumbens as a key structure in mediating these effects. Several studies on alcoholism have indicated defects in dopaminergic neurotransmission and alterations in dopamine receptor densities. However, it has remained unclear if the substance abuse-related dopaminergic defect is specifically associated with a certain receptor subtype. The aim of this study was to compare putative alterations of dopamine D(1,) D(2), and D(3) receptors in nucleus accumbens, amygdala, and substantia nigra among alcoholics and controls. We studied the densities of dopamine D(1) and D(3) receptors in brains of 9 type 1 alcoholics, 8 type 2 alcoholics, and 10 healthy controls by using postmortem human whole hemisphere autoradiography. The mean densities of dopamine D(1) and D(3) receptors were at the same level in all study groups. Combining these with our previous results, our data suggest that among type 1 alcoholics dopamine transporters are lower in nucleus accumbens and dopamine D(2), but not D(1) or D(3) receptors in nucleus accumbens and amygdala. Further, the densities of all these dopamine-binding sites among type 2 alcoholics are at the level of healthy controls. The results suggest that lower dopamine receptor density is specific for D(2) receptor and for type 1 alcoholism, which supports Cloninger's neurogenetic model of two alcoholic subtypes, and indicates the importance of classifying these subgroups separately when issues related to dopaminergic activity are studied.     

Amygdala serotonin transporters in alcoholics measured by whole hemisphere autoradiography

BACKGROUND: A dysfunction in brain serotonin turnover is a well-established factor associated with the impulsive and sociopathic behavior in alcoholics. The conjuncted alterations in functioning of serotonin transporter (SERT) may play a role in the regulation of emotional balance, judgement, and the adverse behavioral effects of ethanol misuse. These traits may be related to serotonergic regulation in the amygdala and prefrontal cortex. METHODS: The binding of [(3)H]citalopram to SERT was evaluated in the amygdala of Cloninger type 1 and 2 alcoholics (n = 17), and nonalcoholic control subjects (n = 10) by postmortem whole-hemisphere autoradiography. RESULTS: The SERT binding was substantially lower in the dorsal amygdala in alcoholic subjects when compared with the controls (-28%, effect size 1.26, P = 0.016). In secondary analysis, this reduction was observed in both alcoholic subgroups (-26% in type 1 alcoholics, and -33% in type 2 alcoholics). In ventral amygdala, no alteration was observed. There were significant correlations between the SERT binding in dorsal amygdala and in previous results from frontal cortical areas in alcoholics, depending on the type of alcoholic. CONCLUSIONS: These results suggest that SERT binding in the amygdala, as well as the differential regulation of the SERT in amygdala and frontal cortex in alcoholics may help to explain the dysfunctional regulation of emotions in alcoholics.     

Iodine-123 labelled PE2I for dopamine transporter imaging: influence of age in healthy subjects.

The iodine-123 labelled selective ligand N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4-methylphe nyl)nortr opane ([(123)I]PE2I) has been developed and has been shown to be suitable for single-photon emission tomography imaging of the dopamine transporter. In this study the influence of age on ligand binding was investigated in 16 healthy males with an age range of 23- 75 years. Single-photon emission tomography (SPET) imaging was performed with a triple-headed gamma camera. A simplified reference region model, in which the input function was derived from the non-displaceable cerebellar compartment, was used to calculate the volume of distribution in the striatum. The volume of distribution was shown to decline with age (-0.4%/year; P<0.005). The results were in agreement with in vivo and in vitro findings of a decline in dopamine transporter binding with age. The findings confirm the suitability of [(123)I]PE2I for SPET imaging in clinical routine but emphasize the necessity of using age-matched controls in patient studies.     

Striatal dopaminergic terminals in type 1 and type 2 alcoholics measured with [H]dihydrotetrabenazine and human whole hemisphere autoradiography

A number of studies have pointed to the importance of dopamine system in the context of alcoholism. Previous studies have shown lower dopamine transporter levels on late-onset Cloninger type 1 alcoholics. However, whether this lower level is due to a lower level of dopamine transporter protein or a lower level of dopaminergic nerve terminals remains unclear. The aim of this study was to compare putative alterations of dopaminergic terminals in caudate, putamen and nucleus accumbens of type 1 and type 2 alcoholics and healthy controls by using [³H]dihydrotetrabenazine as a radioligand in postmortem human whole hemisphere autoradiography. We compared the present results with the findings of our earlier studies on the dopamine transporter in these same subjects, demonstrating that alcoholics do not differ significantly from controls in striatal [³H]dihydrotetrabenazine binding. Although type 1 alcoholics have been reported to have up to 36% lower striatal dopamine transporter levels than controls, the results suggest that the density of their dopaminergic nerve terminals is not altered.     

Different effect of age on dopamine transporters in the dorsal and ventral striatum of controls and alcoholics

It is generally agreed that there is a deterioration in brain dopamine (DA) system with aging. The role of the mesolimbic DA in brain ethanol reinforcement is well established, with nucleus accumbens (NAC) serving as a major terminal area of this system, whereas dorsal striatum is more associated with motor control. The aim of this study was to compare putative age-related alterations of dopamine transporters (DAT) in dorsal and ventral striatum of healthy controls and alcoholics. We studied the effect of age on DAT in caudate (NC), putamen (Pu), and nucleus accumbens (NAC) of eight type 1 and 2 alcoholics and 10 healthy controls by using [(125)I]PE2I as a radioligand for postmortem human whole hemisphere autoradiography. In the type 1 alcoholic group age and DAT density did not correlate significantly with any of the structures studied. The mean densities of DAT declined significantly with age in controls and type 2 alcoholics in dorsal striatum (NC, Pu) (range of correlation coefficient from -0.49 to -0.94), but not statistically significantly in NAC. In type 1 alcoholics the lack of correlation between DAT density and age may indicate a preexisting dopaminergic deficit in this patient group, whereas age-related decline among type 2 alcoholics resembled that of healthy controls. Furthermore, dorsal striatal DAT may be more vulnerable to age-related decline than DAT in NAC. This is supported by the notion that DAT in NAC and dorsal striatum have different molecular weights.     

Striatal dopamine D1 receptors in type 1 and 2 alcoholics measured with human whole hemisphere autoradiography

A considerable number of human and animal studies have implied the importance of dopamine system and alterations in dopamine receptors in the context of alcoholism. However, it has remained unclear if the alcohol-abuse related dopaminergic deficit is specifically associated with certain receptor subtype. The aim of this study was to compare putative alterations of dopamine D(1) receptors in caudate and putamen of nine type 1 alcoholics, eight type 2 alcoholics and 10 healthy controls by using [(3)H]SCH 23390 as a radioligand in postmortem human whole hemisphere autoradiography. In addition, we compared the present results to our earlier studies on dopamine transporters and dopamine D(2) receptors in these same subjects and evaluated the putative correlations of dopamine D(1) receptor densities between the nucleus accumbens and the above-mentioned structures. Our results show that alcoholics do not have significantly different striatal dopamine D(1) receptor densities compared to controls. Neither were there any significant correlations between the dopamine D(1) receptors and the two other dopamine binding sites. However, the correlations of the dopamine D(1) receptors between nucleus accumbens and dorsal striatal structures were consistently and mostly statistically significantly positive in alcoholics, but not in controls, which may suggest some pathology related to addiction. In addition, considering the facts that dopamine D(1) receptors were more abundant in the mesolimbic nucleus accumbens than in the caudate or putamen and that there was a strong tendency towards lower binding among type 1 alcoholics may suggest the importance of dopamine D(1) receptors in reward and/or alcoholism.     

Nucleus accumbens serotonin transporters in alcoholics measured by whole-hemisphere autoradiography

Nucleus accumbens (NAC) is regulated by the dopaminergic and serotonergic pathways, and it is a brain area with a crucial role in the rewarding effects of ethanol. In this preliminary study, possible alterations of [³H]citalopram binding to serotonin transporter (SERT) were evaluated in the NAC of Cloninger type 1 and 2 alcoholics (nine and seven subjects, respectively), and nonalcoholic controls (10 subjects) by human postmortem whole-hemisphere autoradiography.

The [³H]citalopram binding in the NAC was 35% higher in the alcoholics than in the controls; in the type 1 alcoholics, the binding was 54% and in the type 2 alcoholics it was 17% higher. Although the effect size showed medium effects (0.49–0.60), the results did not reach statistical significance due to large standard deviations. The [³H]citalopram binding declined significantly with age in the controls, but not in the alcoholics. In the controls, there was a significant positive correlation between the [³H]citalopram binding in the NAC and in the anterior cingulate gyrus, an area in which the [³H]citalopram binding has been shown to be lower among alcoholics. On the contrary, a significant negative correlation was observed in the type 2 alcoholics and no correlation in the type 1 alcoholics. In addition, there was a strong tendency toward a positive correlation between the SERT and dopamine transporter binding in the type 2 alcoholics, but not in the other groups. These preliminary results suggest a differential monoaminergic imbalance in type 1 and 2 alcoholism in brain areas important for the regulation of motivation, reward, and reinforcement.