Changes in the metabolic profile of human male postmortem frontal cortex and cerebrospinal fluid samples associated with heavy alcohol use.

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry-based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2-piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2-piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use.

Screening approach for identifying candidate drugs and drug-drug interactions related to hip fracture risk in persons with Alzheimer disease.

PURPOSE: To assess whether a "drugome-wide" screen with case-crossover design is a feasible approach for identifying candidate drugs and drug-drug interactions. METHODS: All community-dwelling residents of Finland who received a clinically verified Alzheimer disease diagnosis in 2005 to 2011 and experienced incident hip fracture (HF) afterwards (N = 4851). Three scenarios were used to test the sensitivity of this approach (1) hazard period 0 to 30 and control period 31 to 61 days before HF, (2) hazard period 0 to 30 and control period 336 to 366 days before HF, and (3) hazard period 0 to 14 and control period 16 to 30 days before HF. RESULTS: Nine, 44, and 5 drugs were associated with increased HF risk and 8, 23, and 4 with decreased risk in scenarios 1, 2, and 3, respectively. Six drugs were identified with scenario 1 only and 54 and 1 with scenarios 2 and 3, respectively. Only six drugs (metoprolol, simvastatin, trimethoprim, codeine combinations, fentanyl, and paracetamol) were associated with HF in all scenarios, four with 1 and 2 (cefalexin, buprenorphine, olanzapine, and memantine), and one with 1 and 3 (enalapril) or 2 and 3 (ciprofloxacin). The direction of associations was the same in all/both scenarios. The interaction results were equally versatile, with hydroxocobalamin*oxazepam being the only interaction observed in all scenarios. CONCLUSIONS: Case-crossover analysis is a potential approach for identifying candidate drugs and drug-drug interactions associated with adverse events as it implicitly controls for fixed confounders. The results are highly dependent on applied hazard and control periods, but the choice of periods can help in targeting the analyses to different phases of drug use.

Sociodemographic characteristics and drug abuse patterns of treatment-seeking illicit drug abusers in Finland, 1997-2008: the Huuti study.

The epidemiological part of the Huume tietokanta (HUUTI) consortium research project is the first large-scale longitudinal study of treatment-seeking illicit drug abusers in Finland. The objective of this report was to describe the sociodemographic characteristics and drug abuse patterns of treatment-seeking clients at their first visit. This study analysed baseline data of 4817 clients (3365 men and 1452 women) aged 11-65 years who sought treatment for drug abuse between 1997 and 2008 at Helsinki Deaconess Institute. Data were collected using a structured questionnaire. The majority (56%) of clients were between 15 and 24 years, educated at elementary school level (75%), and unemployed (57%). Opiates (30%) were the primary drugs of abuse. The primary drugs were mostly injected (45%) and were abused daily during the past month (44%). Cannabis was the most common secondary drug of abuse (34%). The secondary drugs were predominantly smoked (39%) or taken orally (38%) and were abused once per week or less frequently during the past month (33%). Age at initiation of illicit drug abuse ranged from 5 to 49 years. Polydrug abuse was common, with a mean consumption of 3.5 concurrent polydrug use, which were combined from 3 or more drug classes. The prevalence of lifetime/ever intravenous drug abuse was 64% and past month intravenous drug abuse was 64%, respectively, and 13% reported sharing injecting equipment during the past month. Early initiation, polydrug abuse, and risky consumption of illicit drugs were major areas of concern among the study population. Injecting drug use could place considerable burden on health services in view of complications and transmission of infectious diseases.

Correlation between the SERT binding densities in hypothalamus and amygdala in Cloninger type 1 and 2 alcoholics.

UNLABELLED: Serotonin plays a role in the regulation of emotional states in amygdala which in turn affect the function of hypothalamus. The physiological effects of emotions are mediated to autonomic nervous system by the hypothalamus, also innervated by the serotonergic Raphe nuclei. AIMS: We evaluated the putative alterations of the serotonin transporter (SERT) density in the paraventricular nucleus (PVN) of hypothalamus of Cloninger type 1 and 2 (early onset, anti-social) alcoholics and controls. METHODS: The study was performed by human whole-hemisphere auto-radiography with [3H]citalopram. RESULTS: Substantially sparser SERT density (-26%) with a moderate effect size (0.53) was observed in the hypothalamus of alcoholic subjects in relation to non-alcoholic comparison subjects, although the result failed to reach statistical significance. In type 2 alcoholics, there was a trend towards decreased SERT binding with large effect size (0.88), and no correlation between the SERT binding and the age at the time of death. There was a strong positive correlation between the SERT binding in amygdala and in PVN in type 2 alcoholics (P = 0.001), and negative correlation in type 1 alcoholics (P = 0.05), and no correlation in the control subjects. The difference between the groups was significant (chi2 = 16.75, P = 0.0002). CONCLUSIONS: Taken together, these preliminary results support the hypothesis that the serotonergic regulation in the hypothalamus and amygdala are defected especially in type 2 alcoholics.

Midbrain dopamine D2/3 receptor binding in schizophrenia.

Several studies suggest that dysregulation of dopaminergic transmission in the midbrain and thalamus may contribute to the symptomatology of schizophrenia. The objective of this study was to examine the putative alteration of dopamine D(2/3 )receptor densities in the thalamus and midbrain of drug-naïve schizophrenic patients. We used the high-affinity single-photon emission tomography ligand [(123)I]epidepride for imaging D(2/3 )receptor binding sites in six neuroleptic-naïve schizophrenic patients, and seven healthy controls. Schizophrenic symptoms were evaluated by the Positive and Negative Syndrome Scale. Significantly lower D(2/3 )values were observed in the midbrain of patients with schizophrenia compared to controls (P = 0.02). No statistically significant difference was observed in the thalamus between two groups. Negative correlations were found between thalamic D(2/3 )receptor binding and general psychopathological schizophrenic symptoms (r from -0.78 to -0.92). These observations implicate altered dopaminergic activity in the midbrain of schizophrenic patients.

Reduced brain serotonin transporter binding in patients with panic disorder.

There is strong evidence for the importance of the serotonin (5-HT) system in the neurobiology of panic disorder (PD); however, the exact role of this system remains unclear. The 5-HT transporter (5-HTT) is a key element in 5-HT neurotransmission. The current study aimed to investigate the binding of 5-HTT in the brain of patients with PD. We used single-photon emission computed tomography with a radioligand that specifically labels the 5-HTT, [(123)I]nor-beta-CIT. Subjects comprised eight patients with current PD, eight patients with PD in remission, and eight healthy control subjects. The patients with current PD showed a significant decrease in 5-HTT binding in the midbrain, in the temporal lobes and in the thalamus in comparison to the controls. The binding of 5-HTT in patients with PD in remission was similar to findings in the control group in the midbrain and in the temporal lobes, but lower in the thalamus. Regional 5-HTT binding significantly and negatively correlated with the severity of panic symptoms. These findings point to a dysregulation of the 5-HT system in PD patients. Altered function of 5-HTT appears to be related to the clinical status of patients. Clinical improvement in the patients in remission is associated with normalization of 5-HTT binding.

SPECT imaging of serotonin transporter binding in patients with generalized anxiety disorder.

The purpose of this study was to characterize the binding properties of serotonin transporter (5-HTT) in the brain of the patients with generalized anxiety disorder (GAD) in comparison to healthy subjects using single photon emission computer tomography (SPECT) with the radioligand [123I]nor-beta-CIT. The subjects were 7 patients with GAD and 7 matched healthy volunteers. The regions of interest (ROI) were the midbrain and the thalamus. The comparison of the volumes of distribution did not show significant differences between the patients and controls in the binding of nor-beta-CIT to 5-HTT in the ROI. Binding of 5-HTT in the midbrain of patients was significantly and negatively correlated with their anxiety levels measured by the visual analogue scale immediately before the first scan (r=-0.79, p=0.035). This study failed to demonstrate an altered functional activity of 5-HTT in patients with GAD when compared with controls.