Hiroyuki Umegaki

Overexpression of dopamine D2 receptors reduces alcohol self-administration

The mechanism(s) underlying predisposition to alcohol abuse are poorly understood but may involve brain dopamine system(s). Here we used an adenoviral vector to deliver the dopamine D2 receptor (DRD2) gene into the nucleus accumbens of rats, previously trained to self‐administer alcohol, and to assess if DRD2 levels regulated alcohol preference and intake. We show that increases in DRD2 (52%) were associated with marked reductions in alcohol preference (43%), and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. In addition, this DRD2 overexpression similarly produced significant reductions in ethanol non‐preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This is the first evidence that overexpression of DRD2 reduces alcohol intake and suggests that high levels of DRD2 may be protective against alcohol abuse.

Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J‐EDIT)

Type 2 diabetes is associated with cognitive dysfunction and increases the risk of dementia in the elderly. The aim of this study was to explore, by means of magnetic resonance (MR) imaging, possible relationships among clinical profiles of diabetes, cognitive function, white matter hyperintensities (WMHs) and subcortical brain atrophy.

DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking

BACKGROUND Transient overexpression of the dopamine D2 receptor (DRD2) gene in the nucleus accumbens (NAc) using an adenoviral vector has been associated with a significant decrease in alcohol intake in Sprague Dawley rats. This overexpression of DRD2 reduced alcohol consumption in a two-bottle-choice paradigm and supported the view that high levels of DRD2 may be protective against alcohol abuse. METHODS Using a limited access (1 hr) two-bottle-choice (water versus 10% ethanol) drinking paradigm, we examined the effects of the DRD2 vector in alcohol intake in the genetically inbred alcohol-preferring (P) and -nonpreferring (NP) rats. In addition, micro-positron emission tomography imaging was used at the completion of the study to assess in vivo the chronic (7 weeks) effects of ethanol exposure on DRD2 levels between the two groups. RESULTS P rats that were treated with the DRD2 vector (in the NAc) significantly attenuated their alcohol preference (37% decrease) and intake (48% decrease), and these measures returned to pretreatment levels by day 20. A similar pattern of behavior (attenuation of ethanol drinking) was observed in NP rats. Analysis of the [C]raclopride micro-positron emission tomography data after chronic (7 weeks) exposure to ethanol revealed clear DRD2 binding differences between the P and NP rats. P rats showed 16% lower [C]raclopride specific binding in striatum than the NP rats. CONCLUSIONS These findings further support our hypothesis that high levels of DRD2 are causally associated with a reduction in alcohol consumption and may serve as a protective factor against alcoholism. That this effect was seen in P rats, which are predisposed to alcohol intake, suggests that they are protective even in those who are genetically predisposed to high alcohol intake. It is noteworthy that increasing DRD2 significantly decreased alcohol intake but did not abolish it, suggesting that high DRD2 levels may specifically interfere with the administration of large quantities of alcohol. The significantly higher DRD2 concentration in NP than P rats after 7 weeks of ethanol therefore could account for low alcohol intake.

D2R DNA Transfer Into the Nucleus Accumbens Attenuates Cocaine Self-Administration in Rats

Dopamine (DA) D2 receptor (D2R) agonists and antagonists can modulate self‐administration behavior, conditioned place preference, and locomotor responses to cocaine. Low levels of D2R have also been observed in cocaine addicted subjects and in non human primates after chronic cocaine exposures. Prior studies had shown that D2R upregulation in the nucleus accumbens (NAc) in rodents trained to self‐administer alcohol markedly attenuated alcohol preference and intake. Here we assess the effects of D2R upregulation in the NAc on cocaine intake in rats trained to self‐administer cocaine. Following 2 weeks of i.v. cocaine self‐administration (CSA), rats were stereotaxically treated with an adenovirus that carried the D2R gene to upregulate D2R in the NAc. D2R vector treatment resulted in a significant decrease (75%) in cocaine infusions and lever presses (70%) for cocaine. This effect lasted 6 days before cocaine consumption returned to baseline levels, which corresponds roughly to the time it takes D2R to return to baseline levels. These findings show that CSA and D2R in the NAc are negatively correlated and suggest that cocaine intake is modulated in part by D2R levels in NAc. Thus strategies aimed at increasing D2R expression in NAc may be beneficial in treating cocaine abuse and addiction. Synapse 62:481–486, 2008. Published 2008 Wiley‐Liss, Inc.

Involvement of dopamine D2 receptors in complex maze learning and acetylcholine release in ventral hippocampus of rats

In the current study we focus on the involvement of dopamine D(2) receptors in the ventral hippocampus in memory performance and acetylcholine release. Using the aversively motivated 14-unit T-maze (Stone maze) the injection of raclopride, a D(2) receptor antagonist, into the ventral hippocampus (8 microg/kg) was found to impair memory performance. Co-injection of quinpirole, a D(2) receptor agonist (8 microg/kg), overcame the impairment in performance. Microdialysis study revealed that quinpirole infusion (10-500 microM) into the ventral hippocampus stimulated acetylcholine release in a dose-dependent manner, and systemic injection of quinpirole (0.5 mg/kg, i.p.) also stimulated acetylcholine release in the ventral hippocampus. Infusion of eticlopride, another D(2) receptor antagonist, into the ventral hippocampus suppressed acetylcholine release in the hippocampus induced by systemic injection of quinpirole. Taken together, we suggest that D(2) receptors in the ventral hippocampus are involved in memory performance, possibly through the regulation of acetylcholine.

The Clock Drawing Test as a Valid Screening Method for Mild Cognitive Impairment

To validate the Clock Drawing Test (CDT) as a screening method for detecting mild cognitive impairment (MCI) and to find the appropriate scoring protocol and its cutoff point, we compared the sensitivity and specificity of three CDT protocols. Subjects included 219 outpatients with memory complaints, who were attending the geriatric memory clinic. Cahn’s protocol, with a cutoff point of 7, was more successful at differentiating clinically diagnosed MCI subjects from normal elderly individuals, with higher sensitivity (74.7%) and specificity (75.6%), than were the other protocols. The CDT, as a handy screening method, may be useful for clinicians to reliably identify subjects with MCI, and it may contribute to early detection of dementia.

Decreased interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia

We examined IL-6 levels in the cerebrospinal fluid (CSF) of patients clinically diagnosed with Alzheimer-type dementia (ATD) and with vascular dementia (VD) and of age-matched normal subjects. The IL-6 levels in the CSF of ATD, but not VD patients, were significantly decreased. In the early onset ATD patients (disease onset < 65 years), IL-6 levels were reduced to 21% of the control level. The IL-6 levels in the CSF were not associated with the severity of the dementia or the duration of the disease since the identification of the first symptoms.

Plasma cortisol levels in elderly female subjects with Alzheimer’s disease: a cross-sectional and longitudinal study

We investigated the plasma cortisol levels at a fasting state in elderly female Alzheimers disease (AD), vascular dementia (VD), and non-demented subjects (n=66, 28 and 21, respectively). Twenty-eight AD subjects were followed for 40 months. The plasma cortisol levels in AD and VD subjects were significantly higher than those of non-demented subjects at baseline. In AD subjects in relatively early stages of the disease [Mini-Mental State Examination (MMSE)], at baseline, high plasma cortisol led to rapid declines in MMSE scores over a 40-month period.

Age-Associated Increase in Abdominal Obesity and Insulin Resistance, and Usefulness of AHA/NHLBI Definition of Metabolic Syndrome for Predicting Cardiovascular Disease in Japanese Elderly with Type 2 Diabetes Mellitus

Background: Management of metabolic syndrome (MetS) seems to constitute an efficient strategy to attain successful ageing. Although the clinical entity of MetS in patients with diabetes mellitus has been discussed, there is very little information on MetS-type cardiometabolic risk factor clustering in diabetic elderly. Objective: To determine the relationship among age-associated changes in obesity, insulin resistance, and clustering of MetS-type risk factors, in association with vascular complications, in Japanese elderly with type 2 diabetes. Methods: A cross-sectional study was conducted of 812 diabetic elderly enrolled in the Japanese Elderly Diabetes Intervention Trial. Information on diabetes, blood examinations and complications was obtained. Abdominal obesity, insulin resistance and prevalence of MetS risk factor clustering, defined by three sets of criteria from the International Diabetes Federation (IDF), the Japanese Society of Internal Medicine (JSIM), and the American Heart Association and the National Heart, Lung, and Blood Institute (AHA/NHLBI), were analyzed. Results: Waist circumference and insulin resistance estimated by homeostasis model assessment insulin resistance (HOMA-IR) increased with age, followed by a partial decrease at age 80 and over. Prevalence of IDF-MetS and JSIM-MetS also increased with age at least until the age of 80, whereas the incidence of AHA/NHLBI-MetS did not show any apparent age changes. There was a significant crude linear association between waist circumference and HOMA-IR, which was highly elevated in IDF and AHA/NHLBI overlapping with MetS, and also elevated in AHA/NHLBI without abdominal obesity. Although IDF-MetS and JSIM-MetS, which specify abdominal obesity, did not always appear to be associated with cardiovascular diseases, AHA/NHLBI-MetS, comprising both abdominal obesity and non-abdominal obesity, independently correlated with coronary heart disease and stroke after adjustment for other risk factors of atherosclerotic diseases. Conclusion: There was an age-associated increase in the prevalence of abdominal obesity and insulin resistance in elderly diabetic Japanese subjects, with a clear relationship between waist circumference and insulin resistance. However, insulin resistance was elevated not only in cases with but also in those without abdominal obesity if accompanied by clustering of metabolic disorders. The AHA/NHLBI definition of MetS proved to be the most useful to predict cardiovascular disease in the diabetic elderly.

Type 2 diabetes as a risk factor for cognitive impairment: current insights

Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction and dementia in the elderly. T2DM has been thought to be associated with vascular diseases, eventually leading to vascular dementia, but recent studies have established that T2DM is also associated with Alzheimer’s disease (AD). With the increase in the number of elderly individuals with T2DM, the number of diabetic patients with cognitive dysfunction has been increasing. T2DM may accelerate AD-associated pathologies through insulin resistance. Vascular pathologies may also be associated with cognitive dysfunction and dementia in T2DM subjects. Several other mechanisms also seem to be involved in T2DM-related cognitive dysfunction. More investigations to clarify the association of T2DM with cognitive impairment are warranted. These investigations may help to increase our understanding of AD and open a new door to the development of therapeutics. Recent pharmaceutical advancement in T2DM treatment has resulted in the availability of a wide range of antidiabetics. Some evidence has suggested that antidiabetic therapies help to prevent cognitive dysfunction. At present, however, the optimal level of blood glucose control and the best combination of medications to achieve it in terms of cognitive preservation have not been established. More investigation is warranted. Cognitive dysfunction is an emerging new complication of T2DM that requires further study.