Interaction of psychotropic drugs with brain muscarinic cholinoceptors: similarities of biperiden with pirenzepine in receptor binding properties

It is generally accepted that there are at least three different subtypes of muscarinic cholinoceptors, pirenzepine being considered a selective M1 antagonist. In the present study, a number of different types of psychotropic drugs have been compared with pirenzepine and atropine as reference antimuscarinic drugs regarding their affinities for rat brain muscarinic cholinoceptors with the help of in vitro receptor binding studies. The most potent drugs, inhibiting 3H-1-quinuclidinyl benzilate (3H-QNB) binding at subnanomolar concentrations, were the antimuscarinic drugs scopolamine and atropine. Biperiden, promethazine, pirenzepine and some tricyclic antidepressants (amitriptyline, doxepin) were the next potent drugs, with IC50-values between 8.4 nM and 190 nM. The inhibition curves were steep and parallel giving Hill coefficients close to unity in all but two drugs studied. These exceptions were biperiden and pirenzepine both with Hill coefficients about 0.55. Thus, in addition to pirenzepine also biperiden seems to bind to the M1 receptor selectively. Additional receptor and functional studies are warranted to further elucidate the possible similarities of these two drugs.     

Serotonin 5-HT2C receptor-mediated phosphoinositide hydrolysis in rat choroid plexus after fluoxetine and citalopram treatments.

Selective serotonin reuptake inhibitors (SSRIs) bind directly to various neurotransmitter receptors. The clinical effects of SSRIs appear gradually during weeks of treatment, suggesting a role for adaptive changes in neurotransmitter receptors. Most clinically used antidepressants, e.g. fluoxetine, bind to 5-HT2C receptors. When administered chronically, many antidepressants elicit adaptive regulation of 5-HT2C receptors. The present study was conducted in order to determine the effects of acute and chronic fluoxetine and citalopram treatments on the density and function of 5-HT2C receptors in the rat choroid plexus. Acute and chronic treatments followed by phosphoinositide (PI) hydrolysis assays and quantitative receptor autoradiography were performed. Acute (single-dose) treatment with neither drug significantly affected basal or 5-HT-stimulated PI hydrolysis, but acute citalopram (20 mg/kg) treatment increased both agonist and antagonist binding to 5-HT(2C) receptors. Chronic (14 days) citalopram treatment (20 mg/kg) increased the maximal PI hydrolysis response by 40%, but fluoxetine lacked this effect. The present data suggest that sensitisation of 5-HT2C receptor-mediated intracellular signal transduction may play a role in the effects of citalopram. In contrast, fluoxetine treatment does not functionally sensitise 5-HT2C receptors. Thus, functional 5-HT2C receptor sensitisation is not a common effect of antidepressants, but the differential effects may explain some of the pharmacodynamic differences seen with these drugs, especially upon repeated administration.     

Metabolism of nomifensine after oral and intravenous administration

The metabolism of nomifensine was studied after single oral and intravenous administration and after 2 weeks of oral dosing. The three principal metabolites reached maximum plasma concentrations rapidly (in 1 to 1.5 hours) after nomifensine administration. Less than 10% was detected as a free, unconjugated form. All three metabolites were eliminated rapidly (elimination t1/2 values between 6.8 and 9.0 hours). Only very low concentrations of free metabolites were found in plasma after 24 hours of nomifensine administration. AUC values for free metabolites were between 0.27 to 0.46 hr X mumol/L after all nomifensine schedules. Two weeks of dosing had no significant influence on the elimination t1/2 or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions. In addition, there were no changes in the conjugation reactions during prolonged nomifensine dosing. Nomifensine has a very short t1/2 and no tendency for accumulation after repeated doses. We conclude that nomifensine's clinical pharmacokinetic profile is not significantly changed by the kinetic behavior of its three main metabolites after the usual maintenance doses.     

Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior

Addictive drugs, including ethanol, increase the brain's dopaminergic transmission, and catechol-o-methyltransferase (COMT) enzyme has a crucial role in dopamine inactivation. A common functional polymorphism in the COMT gene results in a three- to four-fold variation in enzyme activity. In a previous study, we found an association between type 1 (with late-onset but without prominent antisocial behavior) alcoholism and the low activity allele of the COMT gene. In this work we analyzed whether the COMT polymorphism has any effect on the development of type 2 (with early-onset and habitual impulsive violent behavior) alcoholism. The COMT genotype was determined in 62 impulsive violent recidivist offenders with early-onset (type 2) alcoholism, 123 late-onset nonviolent (type 1) alcoholics, and 267 race and gender-matched controls. The allele and genotype frequencies of these groups were compared with each other and also with previously published data from 3,140 Finnish blood donors. The type 2 alcoholics did not differ from either the blood donors or the controls. The low activity (L) allele frequency was higher among type 1 alcoholics (chi(2) = 4.98, P = 0.026) when compared with type 2 cases. The odds ratio for type 1 alcoholism as compared with type 2 alcoholism for those subjects with the LL genotype versus the HH genotype was 3.0 (95% confidence interval 1.1-8.4, P = 0.017). The results suggest that COMT genotype has no major role in the development of early-onset alcoholism with severe antisocial behavior.     

Up-regulation of β1-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments

Quantitative receptor autoradiography was used to study the effects of the selective serotonin reuptake inhibitors citalopram and fluoxetine and the tricyclic antidepressant imipramine on the regulation of ₁-adrenergic receptors in the rat brain. Rats were treated with saline, citalopram (10 mg kg^–1), fluoxetine (10 mg kg^–1), or imipramine (15 mg kg^–1) SC once daily for 14 days. [¹²⁵I]Iodocyanopindolol binding to ₁-adrenergic receptors was found to increase significantly in the caudate-putamen and the somatosensory areas of the frontal cortex after both citalopram and fluoxetine treatments. Imipramine treatment elicited a marked decrease in ₁ binding in the outer laminae of the cingulate cortex, as well as in the motor and somatosensory areas of the frontal cortex. In a separate experiment, rats were treated with saline, citalopram (2.5, 10 and 20 mg kg^–1) or fluoxetine (2.5, 10 and 20 mg kg^–1) SC once daily for 14 days. The effects of citalopram and fluoxetine on ₁ receptors in the somatosensory cortex and caudate-putamen were replicated. These results demonstrate that chronic administration of selective serotonin reuptake inhibitors, in contrast to imipramine, can cause a regional up-regulation of ₁-adrenergic receptors in the rat brain.     

Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography

OBJECTIVE: Recent in vivo imaging studies indicate a dysregulated presynaptic function of the striatal dopaminergic system in patients with schizophrenia. To further explore the basis of this phenomenon, the authors studied brain dopamine transporter binding in vivo in patients with first-episode, never-medicated schizophrenia. METHOD: Nine patients with schizophrenia and nine healthy matched comparison subjects were recruited. Striatal dopamine transporter binding was measured with positron emission tomography and a specific dopamine transporter ligand, [(18)F]CFT, a radiolabeled form of 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane. RESULTS: Average caudate and putamen dopamine transporter binding potentials were almost identical in the patients and comparison subjects, but the patients lacked the right-left asymmetry of the caudate dopamine transporter binding seen in the comparison group. CONCLUSIONS: Average striatal dopamine transporter density is unaltered in neuroleptic-naive patients with schizophrenia. However, patients lack asymmetry in caudate dopamine transporter binding, which conforms with disrupted brain lateralization in this disorder.     

Assessing hematopoietic chimerism after allogeneic stem cell transplantation by multiplexed SNP genotyping using microarrays and quantitative analysis of SNP alleles.

Single-nucleotide polymorphisms (SNPs) have the potential to be particularly useful as markers for monitoring of chimerism after stem cell transplantation (SCT) because they can be analyzed by accurate and robust methods. We used a two-phased minisequencing strategy for monitoring chimerism after SCT. First, informative SNPs with alleles differing between donor and recipient were identified using a multiplex microarray-based minisequencing system screening 51 SNPs to ensure that multiple informative SNPs were detected in each donor-recipient pair. Secondly, the development of chimerism was followed up after SCT by sensitive, quantitative analysis of individual informative SNPs by applying the minisequencing method in a microtiter plate format. Using this panel of SNPs, we identified multiple informative SNPs in nine unrelated and in 16 related donor-recipient pairs. Samples from nine of the donor-recipient pairs taken at time points ranging from 1 month to 8 years after transplantation were available for analysis. In these samples, we monitored the allelic ratios of two or three informative SNPs in individual minisequencing reactions. The results agreed well with the data obtained by microsatellite analysis. Thus, we conclude that the two-phased minisequencing strategy is a useful approach in the following up of patients after SCT.     

Carotid artery intima-media thickness in Finnish families with familial combined hyperlipidemia

BACKGROUND: Familial combined hyperlipidemia (FCHL) is the most common hereditary lipid disorder that predisposes the patients to premature coronary heart disease. Members of FCHL families are categorised as affected or unaffected according to serum lipid levels. This study is aimed to evaluate whether there is a difference in carotid artery wall thickness between asymptomatic FCHL family members who are affected and those who are unaffected according to the currently used lipid criteria. METHODS AND RESULTS: Carotid artery ultrasonography with intima-media thickness (IMT) measurements was performed for 148 members of 39 Finnish FCHL families. Study subjects who had no history of coronary heart disease or stroke were divided into two groups according to their serum total cholesterol and/or triglyceride levels. The average carotid IMT of the affected subjects (0.75+/-0.15 mm) was not significantly different from that of their unaffected relatives (0.73+/-0.13 mm), P=0.90. In multivariate analysis, age, gender, and pulse pressure, but no lipid variables, contributed significantly to the variation of carotid IMT. CONCLUSIONS: The IMT findings in FCHL family members indicate that the current lipid criteria alone are of limited value in predicting long-term risk of cardiovascular disease in asymptomatic members of FCHL families.