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.

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.

Effect of deuterium substitution on the disposition of intraperitoneal tryptamine.

To determine whether alpha,alpha-dideutero substitution in the side chain of the tryptamine molecule can exert primary isotope effects and enhance its bioavailability, equimolar mixtures of tryptamine (T) and either alpha,alpha-dideutero-tryptamine (alpha,alpha-[2H2]T) or beta,beta-dideutero-tryptamine (beta,beta-[2H2]T) were injected i.p. into rats. The amounts of these amines in the brain, liver and plasma were then measured at various times following the injection, and ratios between the deuterated T and T were computed. The ratio remained close to unity in plasma, but exceeded unity in the liver and brain when alpha,alpha-[2H2]T and T were injected; however, when beta,beta-[2H2]T and T were injected, the ratios were unity in all cases at all times. In the presence of a monoamine oxidase inhibitor, the relative enrichment of alpha,alpha-[2H2]T compared to T was reduced. It is concluded that alpha,alpha-dideutero substitution exerts a primary isotope effect during oxidative deamination so that much more of this amine penetrates into, and persists in, the brain.

Formation of beta-phenylethylamine from the antidepressant, beta-phenylethylhydrazine.

To determine whether the monoamine oxidase inhibitor phenelzine was metabolized in vivo to produce beta-phenylethylamine (PE) and p-hydroxy-beta-phenylethylamine [p-tyramine (pTA)], a deuterated analogue, alpha, alpha,, beta, beta-2H-phenelzine (d4-phenelzine) was synthesized and injected i.p. into rats. In the first experiment, rat striata from d4-phenelzine-treated rats were analyzed for the presence of d4-PE and d4-pTA at a time at which phenelzine was known to cause particularly large increases in striatal pTA. While d4-PE was found to be present in these rat striata at a concentration equivalent to the endogenous PE, no d4-pTA was present. The amounts of d4-PE produced at various times after the i.p. injection of 50 mg/kg d4-phenelzine were measured; at 1 hr post-injection, 371 +/- 60, 1295 +/- 682 and 1242 +/- 394 ng/g (mean +/- S.E.M.) d4-PE were present in whole brain, liver and kidney. Rat urine collected for a 24-hr period after this treatment contained (mean +/- S.E.M.) 88.5 +/- 14.0 micrograms d4-PE. These results clearly indicate that the antidepressant phenelzine was metabolized in vivo to produce the trace amine PE.

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.

Potentiation of the biochemical effects of beta-phenylethylhydrazine by deuterium substitution.

The concentrations of dopamine (DA), m-tyramine (mTA), p-tyramine (pTA) and serotonin (5-HT) in the striata of rats 18 hr after the administration of three different doses (5, 50, or 100 mg/kg) of beta-phenylethylhydrazine (phenelzine, PEH) were measured. These concentrations were compared to those following the administration of the same doses of 1,1,2,2-tetradeutero-PEH (d4PEH). In general, PEH and d4PEH caused dose-dependent increases in the levels of mTA, pTA and 5-HT. The lowest dose of d4PEH caused greater increases than PEH in the levels of all four monoamines. The concentration of 5-HT was increased more by d4PEH than PEH at all three doses. The inhibition of mitochondrial MAO obtained from rat striatum by PEH or d4PEH in vitro revealed no differences. However, the inhibition of striatal MAO obtained from rats injected with d4PEH was found to be greater than that from rats injected with PEH. It was concluded that deuteration of PEH potentiates its ability to inhibit MAO following its administration to the rat by slowing its degradation in vivo.

Potentiation of the behavioural effects of the antidepressant phenelzine by deuterium substitution.

Phenelzine in the rat induced biphasic behavioural stimulation, which was profoundly potentiated by deuterium substitution. Doses of 12.5 or 25.0 mg/kg phenelzine had little or no effect on spontaneous activity, whereas the same doses of deuterated phenelzine produced hyperactivity, wet-dog shakes, forepaw padding, splayed hind limbs, backward walking, sniffing and stereotyped grooming 2-12 h after injection. Similarly, the behavioural response induced by 50.0 mg/kg phenelzine was strongly potentiated by deuterium substitution. It appears likely that the increased behavioural response induced by deuterated phenelzine may be due to its greater potency as a monoamine oxidase inhibitor compared to undeuterated phenelzine. Since phenelzine is an antidepressant that is particularly efficacious in the treatment of severe anxiety, a deuterated analogue of the drug seems likely to be clinically useful.

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.

Methylphenidate-like stimulants in vitro release [3H]tyramines but not [14C]dopamine.

The effects of methylphenidate, cocaine, nomifensine and amfonelic acid on the simultaneous uptake and release of [14C]dopamine and [3H]p-tyramine or [3H]m-tyramine were examined in rat striatal slices. While the uptake of each amine was inhibited equally by each drug, only [3H]tyramines were released. The d-amphetamine-induced release of [14C]dopamine and [3H]p-tyramine was antagonized by these drugs. These findings suggest that the tyramines can be transported independently from dopamine.

A comparison of the effects of methylphenidate and amphetamine on the simultaneous release of radiolabelled dopamine and p- or m-tyramine from rat striatal slices.

The release of [14C]dopamine (DA) from slices of rat caudate nucleus was studied simultaneously with the release of either [3H]para-tyramine (pTA) or [3H]meta-tyramine (mTA). Amphetamine (10(-5) M) caused a large concurrent release of [14C]DA and [3H]pTA; similar results were obtained when [14C]DA and [3H]mTA release were studied. The release of all three amines by amphetamine was quantitatively similar. In contrast, methylphenidate caused a release of [3H]pTA similar to that seen with amphetamine, but only a very small simultaneous release of [14C]DA. [3H]mTA was also strongly released by methylphenidate concurrent with a minimal release of [14C]DA. The inclusion of reserpine in the incubation medium had no detectable effect on the release of any of the three amines by amphetamine. Methylphenidate-induced release of tritiated mTA and pTA was also unaffected by reserpine. However, the release of [14C]DA by methylphenidate was potentiated in the presence of reserpine. The uptake of radiolabelled pTA, mTA and DA was inhibited by both amphetamine and methylphenidate, although amphetamine was a stronger inhibitor of the uptake of all three amines. It is suggested that release of endogenous tyramines may be involved in mediating some actions of psychomotor stimulant drugs.

The role of catecholamines, 5-hydroxytryptamine and m-tyramine in the behavioural effects of m-tyrosine in the rat.

The behavioural and neurochemical effects of m-tyrosine and a monoamine oxidase inhibitor in the rat are described. Systemic injections of m-tyrosine (50-150 mg/kg) 30 min after the administration of pargyline (75 mg/kg) produced intense behavioural stimulation which was not evident after injection of either compound alone. The behavioural syndrome induced consisted of forepaw padding, headweaving, backward walking, splayed hindlimbs, wet dog shakes, hyperactivity and hyperreactivity. m-Tyrosine alone or in combination with pargyline caused a significant increase in brain m-tyramine levels and a significant depletion of catecholamines. 5-Hydroxytryptamine (5-HT) levels, however, were unaffected by the administration of m-tyrosine at most of the times studied. The increase in levels of m-tyramine produced by m-tyrosine plus pargyline was 10 times greater than that produced by m-tyrosine alone, whereas the depletion in levels of the more abundant amines was not potentiated by pargyline pretreatment. The biochemical results suggest that an increased formation of m-tyramine may have been responsible for the observed behavioural stimulation and that a threshold level of m-tyramine in the brain appears to be necessary to produce an overt behavioural effect. The behavioural components observed indicate that m-tyramine could act by releasing newly synthesized catecholamines or 5-HT. Alternatively, m-tyrosine may function as a direct agonist at 5-HT or dopamine receptors, although an action on a specific tyraminergic receptor cannot be ruled out at present.

Release of monoamines from striatal slices by phenelzine and beta-phenylethylamine.

Slices of striatum obtained from control rats were incubated with 3H-serotonin (3H-5HT) or 14C-dopamine (14C-DA) in the presence of pargyline; then, they were subjected to a rapid transfer technique during which they were washed either with a normal Krebs buffer or one containing known quantities of phenelzine (PEH) or beta-phenylethylamine (PE). Both PEH and PE were able to stimulate releases of 3H-5HT and 14C-DA that were greater than control. More 14C-DA than 3H-5HT was released by both compounds. Much lower concentrations of PE than of PEH were required to stimulate monoamine release. Other rats were injected intraperitoneally with behaviourally effective doses of either PEH or PE and were killed at various times. The concentrations of PEH or of PE in the striata of these animals were very high 15 min after I.P. injection, but declined rapidly thereafter. These results may be interpreted to suggest that after I.P. injection, sufficient levels of PEH and PE were attained in the rat striatum to stimulate release of endogenous 5HT and DA.

Biphasic behavioural stimulation induced by a monoamine oxidase-inhibiting antidepressant.

1. Male Wistar rats were injected i.p. with phenelzine at doses of 12.5-150 mg/kg and their behaviour monitored for 12 hr. 2. Phenelzine at doses of 50 mg/kg and above induced biphasic behavioural stimulation. During the first hr after injection the rats exhibited stereotyped rearing, sniffing and headbobbing and were hyperactive and hyperreactive. In contrast, 2-12 hr post-injection, the drug treated rats exhibited WDS, forepaw padding, grooming, splayed hindlimbs and backward walking. 3. It seems likely that the initial phase of stimulation is due to DA release whereas the subsequent response may be the result of an accumulation of the indoleamines 5-HT and T due to MAO inhibition.

Changes in brain catecholamine levels following DL-dopa are not potentiated by deuterium substitution.

Adult male Wistar rats were treated with either DL-dopa, D3-DL-dopa or vehicle and sacrificed at various time intervals after treatment. Brain dopamine and noradrenaline concentrations were measured using quantitative mass spectrometric analysis. After treatment with DL-dopa or D3-DL-dopa, total dopamine levels increased above control values; however, no differences were observed between the two drug treatments. Total noradrenaline levels were not significantly altered by treatment with either DL-dopa or D3-DL-dopa. Deuterium substitution did not appear to affect catecholamine deamination or beta-hydroxylation in vivo.

The behavioural effects of phenelzine and phenylethylamine may be due to amine release.

Intraperitoneal administration of phenelzine (PLZ) or of beta-phenylethylamine (PE) quickly leads to short periods of behavioural activation, which are primarily dopaminergic and serotonergic in nature, respectively. In order to determine whether these behavioural effects are due to PLZ- or PE-induced displacement of dopamine (DA) or serotonin (5HT), the ability of these compounds to stimulate release of radiolabelled DA and 5HT from slices of rat striatum was assessed. Additionally, at various times following IP administration of behaviourally active doses of PLZ or PE to rats, the striatal levels of the drugs were measured. Both PLZ and PE were able to stimulate a greater release of radiolabelled DA than of 5HT. Lower concentrations of PE (0.8, 8.0 microM) than of PLZ (100 microM, 1 mM) stimulated release. The striatal levels (approximately 200 microM) of PLZ, as well as of PE, attained at times corresponding to behavioural activation seemed sufficient to cause release of both DA and 5HT. It was concluded, therefore, that the mode of action of these compounds may involve displacement, or release, of these biogenic amines, though it is not clear how such release ultimately leads to the behaviours observed.

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.

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.

Effect of monofluoromethyldopa (MFMD) on trace amine levels.

The concentrations of the trace amines, m-tyramine, p-tyramine, phenylethylamine and tryptamine, were measured in the striatum of the brain and in the kidney of adult rats treated with alpha-monofluoromethyldopa (MFMD), an inhibitor of aromatic amino acid decarboxylase. While MFMD decreased the levels of all four amines in the kidney, only phenylethylamine and tryptamine levels were decreased in the striatum compared to control. Striatal p-tyramine levels were not affected, while striatal m-tyramine levels were increased by MFMD. When the rats were injected with a monoamine oxidase (MAO) inhibitor before MFMD administration, similar changes in striatal and kidney trace amine levels were observed compared to MFMD alone.

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.

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.