Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes.

Recent neuroimaging and postmortem studies have reported abnormalities in white matter of schizophrenic brains, suggesting the involvement of oligodendrocytes in the etiopathology of schizophrenia. This view is being supported by gene microarray studies showing the downregulation of genes related to oligodendrocyte function and myelination in schizophrenic brain compared to control subjects. However, there is currently little information available on the response of oligodendrocytes to antipsychotic drugs (APDs), which could be invaluable for corroborating the oligodendrocyte hypothesis. In this study we found: (1) quetiapine (QUE, an atypical APD) treatment in conjunction with addition of growth factors increased the proliferation of neural progenitors isolated from the cerebral cortex of embryonic rats; (2) QUE directed the differentiation of neural progenitors to oligodendrocyte lineage through extracellular signal-related kinases; (3) addition of QUE increased the synthesis of myelin basic protein and facilitated myelination in rat embryonic cortical aggregate cultures; (4) chronic administration of QUE to C57BL/6 mice prevented cortical demyelination and concomitant spatial working memory impairment induced by cuprizone, a neurotoxin. These findings suggest a new neural mechanism of antipsychotic action of QUE, and help to establish a role for oligodendrocytes in the etiopathology and treatment of schizophrenia.

Inhibition of rat liver microsomal CYP1A2 and CYP2B1 activity by N-(2-heptyl)-N-methyl-propargylamine and by N-(2-heptyl)-propargylamine.

(R)-N-(2-Heptyl)-N-methyl-propargylamine (R-2HMP) and (R)-N-(2-heptyl)-propargylamine (R-2HPA) are analogs of R-deprenyl. R-Deprenyl, a selective monoamine oxidase B inhibitor, is a mechanism-based inactivator of purified CYP2B1. The aim of the present study was to determine whether R-2HMP and R-2HPA behaved like deprenyl with respect to inhibiting cytochrome P450 (CYP450) enzyme activity. The activities of CYP1A2 and CYP1A1 were assessed by measuring the deethylation of 7-ethoxyresorufin by liver microsomes obtained from control and beta-naphthoflavone-treated female Wistar rats, respectively. CYP2B1 activity was assessed by measuring depentylation of 7-pentoxyresorufin by liver microsomes obtained from phenobarbital-treated rats. The activity of CYP1A1 was unaffected by 100 microM concentrations of R-deprenyl, R-2HMP, or R-2HPA. In contrast, the activities of CYP1A2 and CYP2B1 were significantly decreased. In general, the percentage of CYP1A2 activity remaining in the presence of 100 microM of one of these propargylamines ranged from 45 to 56%, whereas 10% or less of CYP2B1 activity remained. No marked differences between the various propargylamines were observed. The IC(50) values for the inhibition of CYP2B1 activity by R-deprenyl, R-2HMP, and R-2HPA were found to be 2.6, 8.5, and 3.6 microM, respectively. The S-enantiomers of deprenyl, 2HMP, and 2HPA also inhibited the activity of microsomal CYP2B1. R-2HMP, R-2HPA, and S-2HPA were found to be mechanism-based inactivators of CYP2B1 activity. The inactivation constants k(inact) and K(I) were found to be as follows: R-deprenyl, 1.3 microM and 0.32 min(-1); R-2HMP, 0.8 microM and 0.08 min(-1); R-2HPA, 0.5 microM and 0.36 min(-1); and S-2HPA, 0.24 microM and 0.18 min(-1).

Metabolism and pharmacokinetics, in the rat, of (R)-N-(2-Heptyl)Methyl-propargylamine (R-2HMP), a new potent monoamine oxidase inhibitor and antiapoptotic agent.

(R)-N-(2-Heptyl)-N-methylpropargylamine (R-2HMP) is a monoamine oxidase inhibitor and putative antiapoptotic agent analogous to (R)-deprenyl. In the rat, the major amine metabolites of R-2HMP have been identified as (R)-N-2-heptylmethylamine (R-2HMA), (R)-N-2-heptylpropargylamine (R-2HPA), and (R)-2-heptylamine (R-2HA). After R-2HMP was administered s.c. to male Wistar rats, it was observed that the greatest concentration was of the original drug followed in decreasing order by R-2HMA, R-2HPA, and R-2HA in brain, liver, and plasma at all times after administration. The greatest concentrations of the three metabolites were found in brain followed by liver and plasma, and the peak concentrations occurred between 15 and 30 min after administration. After oral administration, the liver contained the greatest concentrations of drug and metabolites, and, again, the peak concentrations occurred at about 15 min. In all cases, depropargylation appears to occur at a faster rate than demethylation. After s.c. administration, R-2HMP and its metabolites exhibited biexponential redistribution and elimination losses. Half-lives of the compounds in brain for the redistribution phase were: R-2HMP, 10 min; R-2HMA, 11 min; R-2HPA, 16 min; and R-2HA, 15 min.

Polymorphism of a class 3 aldehyde dehydrogenase present in human saliva and in hair roots.

The types of aldehyde dehydrogenases (ALDH) present in human hair roots and in saliva were investigated. ALDH was detected by activity staining following separation of crude extracts by isoelectric focusing. Hair roots were found to express ALDH1, ALDH2, ALDH3, and ALDH4, whereas saliva expressed ALDH3. Two different patterns of ALDH3 were detected in hair roots collected from 42 donors, 40 expressed one pattern (variant I) and two another pattern (variant II) of activity staining. The variant I pattern of hair root ALDH3 changed with repetitive freezing and thawing of the sample, whereas the variant II pattern was stable. In contrast to hair root ALDH3, all patterns of ALDH3 activity in saliva were stable. The patterns of ALDH3 activity present in human hair roots that had been frozen and thawed twice matched those present in saliva collected from the same individual. Three polymorphisms of ALDH3 (variants I, II, and III) were detected in the 33 saliva samples analyzed. Variants I and II were inherited in each of three generations of a 10-member family.

Absence of the atypical mitochondrial aldehyde dehydrogenase (ALDH2) isozyme in Saskatchewan Cree Indians.

Three methods were employed to assess whether human volunteers (Caucasian, Asian or Cree Indian) possessed the typical or atypical mitochondrial aldehyde dehydrogenase (ALDH2) isozyme. These methods were: (1) questioning individuals about facial flushing responses following alcohol consumption; (2) application of the ethanol skin patch test, and (3) direct analysis using isoelectric focusing and activity staining of ALDH activity in hair root samples. The results from the three methods were in good agreement and revealed that only the typical ALDH2 isozyme was expressed in Saskatchewan Cree Indians. In agreement with previous reports, the typical ALDH2 was expressed in the Caucasian group of subjects, while both the typical and atypical forms were expressed in the Asian subjects.

Effects of monoamine oxidase inhibitors on the acid metabolites of some trace amines and of dopamine in the rat striatum.

The effects of the administration of selective and non-selective inhibitors of monoamine oxidase (MAO) on the concentrations of three trace acid metabolites [phenylacetic acid (PAA); m-hydroxyphenylacetic acid (mHPAA); and p-hydroxyphenylacetic acid (pHPAA)] and of an acid metabolite of dopamine [3,4-dihydroxyphenylacetic acid (DOPAC)] in the rat striatum were determined. Administration of brofaromine (1-100 mg/kg, s.c.) a type AMAO inhibitor, dose-dependently decreased DOPAC and mHPAA levels. pHPAA levels were decreased by 100 mg/kg brofaromine, but PAA levels were unaffected. Doses of deprenyl of less than 100 mg/kg, i.p., had no effect on any of the acids, while 100 mg/kg decreased DOPAC, mHPAA and pHPAA but not PAA levels. Clorgyline, pargyline and tranylcypromine treatment decreased the levels of DOPAC, mHPAA and pHPAA but not PAA. Administration of alpha-monofluoromethyldopa, an inhibitor of aromatic amino acid decarboxylase, decreased the levels of all four acids. It was concluded that deamination of the respective parent amine by type A MAO is primarily responsible for the synthesis of DOPAC and mHPAA, but that another pathway contributes to pHPAA synthesis. It appears that either PAA arises predominantly independently from the actions of MAO or that is removal via transport or further metabolism regulates its concentration.

Conjugation of phenylacetic acid and m- and p-hydroxyphenylacetic acids in the rat striatum.

Two factors that might regulate the levels of the trace acids, phenylacetic acid (PAA), m-hydroxyphenylacetic acid (mHPAA) and p-hydroxyphenylacetic acid (pHPAA) in the rat striatum were investigated: first, formation of conjugates of these acids and second, transport out of the brain by a probenecid-sensitive system. The presence of conjugates of these acids was investigated by subjecting homogenates of rat striatum to hydrolysis. The concentrations of PAA were increased ten-fold by hydrolysis, pHPAA increased two-fold, and mHPAA was unaffected. These findings coupled with the failure of parglyline to decrease free or total PAA levels suggest that conjugation of PAA is an important factor regulating free PAA levels. The transport inhibitor, probenecid, increased the concentrations of free mHPAA, free pHPAA and the total concentrations of all three acids indicating that all three trace acids can be removed from the rat brain by a transport system.

Reversible, amine--selective effects of acute and chronic brofaromine treatment in the rat.

The effects of brofaromine, clorgyline (reversible and irreversible type A MAO inhibitors, respectively) and tranylcypromine (non-selective MAO inhibitor) on rat striatal levels of phenylethylamine, tryptamine, m-tyramine and p-tyramine were determined. Brofaromine and clorgyline increased m- and p-tyramine levels, but not phenylethylamine levels. Brofaromine given at a dose of 100 mg/kg did increase tryptamine levels. Tranylcypromine increased the levels of all four amines greatly. The effects of chronic treatment with brofaromine on amine levels were not different from those following acute treatment. By contrast, chronic treatment with clorgyline caused greater increases in striatal m- and p-tyramine levels than did acute clorgyline. These data show that changes in the rat striatal levels of m-tyramine and p-tyramine may be used as in vivo indicators of the selectivity and reversiblity of inhibition of type A MAO, while tryptamine levels reflect non-selective inhibition of both types of MAO.

Cutaneous vasomotor sensitivity to ethanol and acetaldehyde: subtypes of alcohol-flushing response among Chinese.

A cutaneous test has been applied in examination of the flushing response to ethanol and acetaldehyde in 402 Chinese of Han ethnicity. Using this noninvasive method, five response subtypes have been observed: (A) fast flushing to both ethanol and acetaldehyde; (B) fast flushing only to ethanol but not to acetaldehyde; (C) slow flushing to ethanol only; (D) no response either to ethanol or to acetaldehyde; (E) vasoconstriction to ethanol, or to both ethanol and acetaldehyde. A total of 94% in subtype (A) are reported to be flushers, while only 25% was reported in subtype (D). Other physiological responses, such as tachycardia, dizziness, headache, drowsiness, and nausea are less frequent after alcohol ingestion. The recent history of consumption of alcohol of the subjects in different subtypes was also obtained. Although alcohol-induced flushing is thought to be a deterrent factor to heavy consumption of alcohol, the frequency of drinking of alcoholic beverages was not found to be different between flushers and nonflushers.

Isoenzymes of aldehyde dehydrogenase in human lymphocytes.

The types of isozymes of aldehyde dehydrogenase (ALDH) present in human lymphocytes has been investigated using isoelectric focusing of polyacrylamide gels followed by substrate-specific staining. Lymphocytes obtained from most individuals were found to contain both types I and II ALDH. This group of 'typical' individuals reported that they did not develop marked facial flushing or rapid heart rate after drinking alcohol nor did they develop an erythema to cutaneously applied ethanol. Lymphocytes obtained from 'atypical' individuals who do suffer from alcohol-induced flushing and rapid heart rate and who developed erythema to cutaneous ethanol displayed type II, but not type I, ALDH. Lymphocytes thus appear to be an easily accessible and suitable tissue for determining type I ALDH phenotype.

Effects of dopamine on phosphoinositide hydrolysis in slices of rat striatum and cortex.

Phosphoinositide hydrolysis was studied in slices of rat striatum and frontal cortex which had been incubated with [(3)H]inositol to prelabel the inositol phospholipids. Dopamine (100 ?M to 10 mM) increased phosphoinositide hydrolysis to a maximum of about 200% compared to control in both areas. Noradrenaline (1 ?M to 1 mM) stimulated [(3)H]inositol phosphate formation to about 400% of control. Dopamine-stimulated phosphoinositide hydrolysis was completely blocked by prazosin; while spiperone and SCH 23390 were partial inhibitors. The ability of noradrenaline (5 to 100 ?M) to stimulate phosphoinositide hydrolysis was antagonized by co-incubation with dopamine (1-10 mM). Low concentrations of dopamine (10 nM and 1 ?M) did not affect total [(3)H]inositol phosphate formation, and ion exchange chromatography of the [(3)H]inositol phosphates failed to show any inhibitory effects on the individual fractions (mono-, bis- and tris-phosphates). Ten mM dopamine, on the other hand, increased the production of [(3)H]inositol mono- and bis-phosphates compared to control. It was concluded that dopamine acts as partial ?(1)-agonist in both the rat striatum and frontal cortex. As such, it increased phosphatidylinositol hydrolysis. Dopamine partially inhibited noradrenaline-stimulated phosphatidylinositol hydrolysis, but it did not inhibit basal rates of phosphatidylinositol hydrolysis.

Effects of antidepressant drugs on inositol phospholipid hydrolysis in rat cerebral cortical slices.

The effects of several different types of antidepressant drugs on phosphoinositide hydrolysis by slices of rat cerebral cortex was investigated by prelabeling inositol phospholipids with [3H]inositol and then measuring the formation of [3H]inositol phosphates (a total fraction consisting of the mono- and poly-phosphates was collected) in the presence of 10 mM LiCl. All of the drugs tested (amitriptyline, trimipramine, mianserin, desipramine, tranylcypromine, and citalopram) inhibited NE-stimulated [3H]inositol phosphate formation. This inhibition appeared to be due to antagonism of alpha 1-receptors. In addition to inhibiting the effects of NE, the tricyclic antidepressants themselves were able to stimulate [3H]inositol phosphate formation. This stimulation occurred at drug concentrations higher than that needed to inhibit stimulation by NE. Stimulatory effects of the antidepressants themselves were not blocked by the alpha 1-antagonist, prazosin. An examination of the types of inositol phosphates formed revealed that formation of inositol monophosphate was stimulated, but that inositol biphosphate production was decreased by tricyclic antidepressants compared to control.

Inhibition of polyphosphoinositide turnover in rat cerebral cortex by clonidine.

In the rat brain, a number of receptors are linked to phospholipase C which catalyzes the hydrolysis of membrane inositol phospholipids; stimulation of alpha 1-adrenergic receptors, for example, increases polyphosphoinositide turnover, but stimulation of alpha 2-receptors does not. The hydrolysis of inositol phospholipids in rat cortical slices was investigated using a direct assay involving prelabeling these lipids with 3H-inositol and then measuring the formation of 3H-inositol phosphates in the presence of lithium ions. As expected, clonidine, an alpha 2-agonist, did not stimulate the formation of 3H-inositol phosphates; however, clonidine antagonized the ability of noradrenaline to stimulate 3H-inositol phosphate formation. This effect was not blocked by antagonists of alpha 2, 5HT2, H2, or muscarinic receptors. Clonidine did not affect carbachol-stimulated 3H-inositol phosphate formation.

Effects of beta-phenylethylamine on polyphosphoinositide turnover in rat cerebral cortex.

The effects of the trace amine, beta-phenylethylamine, on the hydrolysis of inositol phospholipids in rat cerebral cortical slices was studied using a direct assay involving prelabeling with [3H]inositol and then examining the production of [3H]inositol phosphates in the presence of lithium. Phenylethylamine exhibited two different effects. Millimolar concentrations of phenylethylamine stimulated the production of [3H]inositol phosphates to about 200% of control, while much smaller concentrations (micromolar) inhibited noradrenaline(NE)-stimulated [3H]inositol phosphate formation dose-dependently. The alpha 1-antagonist, prazosin, inhibited the increases in [3H]polyphosphoinositide turnover stimulated by phenylethylamine and by NE, though it inhibited phenylethylamine to a lesser extent than NE. It appears, therefore, that phenylethylamine affects [3H]inositol phosphate formation by acting as a partial alpha 1-agonist.

Release of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor.

The basal and 50 mM K+-stimulated release of m-tyramine (mTA), p-tyramine (pTA), tryptamine (TR) and phenylethylamine (PE) from striatal slices obtained from rats pretreated with a monoamine oxidase inhibitor (MAOI) was investigated. A K+-stimulated release of mTA and pTA was observed, but K+ did not stimulate either TR or PE release. The latter two amines, therefore, are unlikely to be conventional neurotransmitters in the rat striatum. The release of endogenous striatal pTA from control rats was also investigated. Veratridine stimulated endogenous pTA release, but 50 mM K+ did not. It is possible, therefore, that endogenous pTA can be released in a transmitter-like fashion.

Effect of chronic deuterated and non-deuterated phenelzine on rat brain monoamines and monoamine oxidase.

The effects of phenelzine and 1,1-dideuterophenelzine (0.5 or 2.5 mg/kg/day) administered s.c. via miniosmotic pumps for 13 days were compared. Striatal levels of p-tryrosine and tryptophan were unaffected by either treatment. The concentrations of DOPAC, HVA and 5-HIAA were dose-dependently decreased by phenelzine and deuterated phenelzine; furthermore, the deuterated compound decreased the amounts of these acids more than the same dose of phenelzine. Dopamine levels were increased by a rather small amount by all drug treatments; no effects of drug dose or drug type (deuterated or nondeuterated) were observed. With the exception of phenylethylamine, qualitatively similar effects were found with all other amines measured; their amounts were increased dose-dependently and the effects of deuterated phenelzine were greater than those of phenelzine. Rat cerebral MAO activity was inhibited dose-dependently by phenelzine and by deuterated phenelzine. Type A MAO was inhibited more than type B, and deuterated phenelzine inhibited both types more than did phenelzine. The present study shows that the efficacy of phenelzine was increased about 5-fold by deuteration, that deuterated phenelzine increased tryptamine, m-tyramine and p-tyramine levels much more than it did the other monoamines, that phenylethylamine levels were least affected by the drug treatments, and that deuterated phenelzine inhibited MAO more than did phenelzine.

Involvement of brain trace amines in the behavioural effects of phenelzine.

The MAO inhibitor phenelzine (PLZ) at a dose of 25 mg/kg does not affect the behavior of rats. In contrast, the equivalent dose of a deuterated analog (alpha, alpha, beta, beta-tetradeutero-PLZ, d4PLZ) elicits a biphasic behavioral syndrome in rats. In an attempt to correlate changes in cerebral monoamines with behavior, the concentration of various amines were measured at various times after the administration of either d4PLZ or PLZ (25 mg/kg). In general, PLZ and d4PLZ caused elevations in brain amine levels, particularly in the time period 2-12 hours after drug administration. Furthermore, d4PLZ increased the concentrations of serotonin (5-HT), phenylethylamine (PE), tryptamine (T), meta-tyramine (mTA), and 3-methoxytyramine (3-MT) to a greater extent than PLZ. Since the time course of behavioral excitation closely parallels the elevations in T and PE levels in the brain and since the percentage increases in PE and T levels following d4PLZ compared to PLZ treatment were substantially greater than those of the other amines, it was postulated that PE and T are involved in d4PLZ-induced behaviors.

Effect of decarboxylase inhibitors on brain p-tyrosine levels.

A number of inhibitors of L-aromatic amino acid decarboxylase (AAD) and monoamine oxidase (MAO) were tested to determine whether they also inhibited tyrosine aminotransferase (TAT). The AAD inhibitors carbidopa, NSD-1015, NSD-1034 and Ro4-5127 inhibited liver TAT. Carbidopa inhibited brain AAD and liver TAT equally well. In contrast, other AAD inhibitors (Ro4-4602 and alpha-monofluoromethyldopa) did not inhibit TAT. Phenelzine, an MAO inhibitor, inhibited liver TAT, but other MAO inhibitors (tranylcypromine and isocarboxazid) did not. Systemic administration of those drugs that were found to be inhibitors of TAT in vitro caused significant increases in rat brain p-tyrosine levels.