Effect of a butyrophenone derivative, U-32,802A, on brain biogenic amines

U-32,802A, a new butyrophenone derivative, was found to block the uptake of and to cause a release of ³H-norepinephrine from the mouse heart. The releasing effect of U-32,802A was not blocked by pretreatment with protriptyline at 10 mg/kg. U-32,802A caused a severe and long-lasting depletion of mouse brain norepinephrine and dopamine with little effect on serotonin at a dose of 5 mg/kg i.p. U-32,802A also caused an increase in homovanillic acid in mouse striatum, a property common to a variety of antipsychotic agents. The spectrum of activity of U-32,802A is different from that of either haloperidol or reserpine and may represent a new class of amine-depleting agents.     

Further observations on trifluperidol: a butyrophenone derivative

Summary The experimental butyrophenone compound, trifluperidol, was compared with trifluoperazine and phenobarbital under double-blind conditions in a group of 60 hospitalized chronic schizophrenic patients. Therapeutic response was evaluated by means of 15 quantitative psychiatric, psychologic, and ward behavior measures. Both trifluperidol and trifluoperazine were clearly superior to phenobarbital, which failed to effect notable improvement in any of the 20 treated subjects. Trifluperidol had a greater and more rapid therapeutic effect than trifluoperazine as measured in the global ratings of improvement, and there was also suggestion in the psychologic data of greater improvement in immediate memory and greater reduction of symptoms reflecting chronicity and deterioration. The results of this study, as well as a review of three recent controlled comparative studies of trifluperidol, suggest that trifluperidol may well be the drug of choice for schizophrenic patients.This study was supported by Public Health Service Grant 5 Tl-MH-03701-04 (Psychopharmacology Service Center, National Institute of Mental Health).     

Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants

The peripheral administration of tetrabenazine (TBZ) induces rapid depletion of brain regional concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). With respect to both dosage and time, striatal DA was most sensitive to the effects of TBZ while hypothalamic NE was least affected. Pretreatment with the monoamine oxidase (MAO)-inhibitor, clorgyline (1-6 mg/kg) dose-dependently prevented the reduction of all three monoamines for up to 60 min after TBZ (3 mg/kg). The TBZ-induced depletion of cortical NE was also significantly antagonized by desmethylimipramine (DMI) but was of shorter duration (up to 30 min after TBZ). DMI, however, did not influence the effect of TBZ on striatal DA or hypothalamic 5-HT. The protective effects of both clorgyline and DMI were also evident under the conditions of the behavioral TBZ test utilizing high doses of TBZ (20 mg/kg).     

Effect of cysteine on the persistent depletion of brain monoamines by amphetamine, p-chloroamphetamine and MPTP

The administration of L-cysteine (500 mg/kg i.p.) 30 min before and 5 h after the administration of (+)-amphetamine sulfate markedly attenuated the persistent decreases in striatal dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rats one week after the administration of a single dose of amphetamine (9.2 mg/kg i.p.) to iprindole-treated animals and in mice one week after the last of four daily injections of amphetamine (30 mg/kg i.p.). Cysteine prevented the persistent decreases in striatal serotonin (5HT) and 5-hydroxyindoleacetic acid (5HIAA) one week after the administration of p-chloroamphetamine to rats, but failed to alter the persistent decreases in striatal DA, DOPAC and HVA in mice one week after the last of four daily doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 30 mg/kg s.c.). The results suggest that the mechanisms by which amphetamine and p-chloroamphetamine, but not MPTP, produce persistent depletions of striatal monoamines involve the generation of neurotoxic electrophilic intermediates which can be inactivated by the administration of cysteine.     

Possible explanations for the antagonism by nicotine against reserpine-induced depletion of monoamines in mouse brain

Summary The inhibitory effect of nicotine pretreatment on reserpine-induced depletion of monoamines in mouse brain was investigated. The depletion of brain monoamines by 24 h after intraperitoneal injection of reserpine (2 mg/kg) was dose-dependently inhibited by nicotine (0.3 – 10 mg/kg, s.c.) pretreatment 20 min before reserpine injection. This effect of nicotine was more marked on dopamine depletion than on noradrenaline or 5-hydroxytryptamine depletion. The nicotine pretreatment also inhibited the reserpine-induced hypothermia and decrease in the locomotor activity. When reserpine (2 mg/kg) was injected intraperitoneally, the inhibitory effect of nicotine (3 mg/kg, s.c.) on the reserpine-induced depletion of brain monoamines and heart noradrenaline was not antagonized by hexamethonium (8 mg/kg, s.c.) but rather potentiated by mecamylamine (2 mg/kg, s.c.). However, when reserpine (0.5 mg/kg) was injected intravenously, pretreatment with nicotine (3 mg/kg, s.c.) inhibited the reserpine-induced dopamine depletion only, and this effect of nicotine was completely blocked by mecamylamine but not by hexamethonium. These results suggest that inhibitory effect of nicotine on the intraperitoneal reserpine-induced depletion of brain monoamines is due to an inhibition of absorption of reserpine, and that central nicotinic action is also involved in the antagonism by nicotine of reserpine-induced dopamine depletion. Correspondence to R. Oishi at the above address     

Cocaine and regional brain monoamines in mice.

Cocaine HCl (0, 10, or 50 mg/kg) was injected into adult male ICR mice IP. Thirty minutes later, brains were removed and nine regions were isolated: olfactory bulbs (OB), olfactory tubercles (OT), prefrontal cortex (PC), septum (SP), striatum (ST), amygdala (AMY), hypothalamus (HT), hippocampus (HC), and thalamus (TH). Using high-performance liquid chromatography, concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their major metabolites were determined. At 10 mg/kg cocaine, NE levels were increased in the AMY and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), was decreased in the PC, AMY, and HT. DA levels were also increased in the AMY, while its intracellular metabolite, dihydroxyphenylacetic acid (DOPAC), was decreased in the ST and its extracellular metabolite, homovanillic acid (HVA), was decreased in the PC. 3-Methoxytyramine (3-MT) levels were not altered in any tissue. 5-HT levels were increased in the AMY, HT, and TH, while its metabolite 5-hydroxyindoleacetic acid (5-HIAA) was decreased in the OB and ST. MHPG/NE ratios were decreased in the PC, AMY, and HT as were those for HVA/DA. DOPAC/DA ratios were decreased in the ST and AMY and increased in the SP while those for 3-MT/DA were decreased in the TH and increased in the PC. 5-HIAA/5-HT ratios were decreased in the AMY, HC and TH. At 50 mg/kg cocaine, there was an increase in DA in the TH. There was a decrease in DOPAC, HVA, and 3-MT, as well as the DOPAC/DA ratio in the ST. In the OT, there was a decrease in DOPAC, the DOPAC/DA ratio, 3-MT, and the 3-MT/DA ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses.

1. The concentration of tacrine (tetrahydroaminoacridine or THA) in plasma, regions of brain and cerebral extracellular fluid has been studied in the rat at various times following injection of a dose of 5 mg kg-1, i.p. 2. The peak plasma THA concentration was 2.46 nmol ml-1, and occurred 30 min post injection and clearance was first order (t1/2 = 90 min). The concentration in the brain peaked between 30-60 min, and was around 30 times plasma concentration (striatum peak concentration = 65 +/- 3 nmol g-1). Extracellular cerebral concentration measured by in vivo microdialysis was similar to plasma concentration with the peak occurring 100 min post-injection. 3. No evidence was obtained by in vivo dialysis for THA inducing dopamine release from striatum or 5-hydroxytryptamine (5-HT) release from the frontal cortex. Enhanced release of dopamine did occur after (+)-amphetamine (5 mg kg-1, i.p.) injection, while KCl (100 mM) in the probe released both dopamine and 5-HT. 4. Since the minimum plasma THA concentration achieved in this study was at least twice that found in the plasma of patients given THA for the treatment of dementia, these results suggest that monoamine release in the brain does not occur during therapy.     

Effect of depletion of cerebral monoamines on the concentration of glycogen and on amphetamine-induced glycogenolysis in the brain

1. An increase in the concentration of glycogen occurs in the mouse brain after depletion of cerebral catecholamines by alpha methyl-p-tyrosine methylester (H44/68), diethyldithiocarbamate, or reserpine.2. Depletion of cerebral 5-hydroxytryptamine with parachlorophenylalanine (PCPA) does not result in a change in the concentration of brain glycogen.3. When H44/68 is administered together with reserpine to inhibit the synthesis and storage of cerebral catecholamines, and thus bring about their total depletion from the brain, the cerebral glycogenolytic effect of amphetamine is abolished.4. Amphetamine-inducing glycogenolysis is only partially antagonized if only one of the catecholamine-depleting agents H44/68, diethyldithiocarbamate, or reserpine is injected prior to the amphetamine. The persistence of this glycogenolytic effect of amphetamine is possibly due to the presence of residual stores of catecholamines available for release by the stimulant drug.5. Depletion of cerebral 5-hydroxytryptamine by PCPA does not result in any antagonism of amphetamine-induced glycogenolysis.6. The results suggest that amphetamine depletes brain glycogen by the release of central catecholamines rather than by a direct action at receptors.     

Quantitation of rodent catalepsy by a computer-imaging technique.

Catalepsy is usually defined as a behavioral state in which an animal maintains an unnatural posture for an extended period of time. While numerous laboratory models have been developed for assessing catalepsy, a common problem encountered with most procedures is the difficulty in quantitating immobility. Measurement of catalepsy is still frequently subjective in nature. To eliminate this subjectivity, a computer-based technique was developed for quantitating catalepsy in mice and rats as measured on the elevated ring. The system consisted of a video camera that was focused on either three mice or two rats. Their behavior was recorded during a 5-min session on videotape that was subsequently transmitted to a Macintosh II microcomputer via a Scion Image-Capture 2 board. A modification of the NIH Image 1.17 public domain program allowed the image of the rat to be transformed to a purely black or white image by assigning pixel values of either 0 or 256. The subsequent captured image was preprocessed in an identical manner and each pixel was subtracted from its corresponding pixel in the previous frame. Thus, changes in animal posture between the two frames can be quantitated. One subtraction cycle (acquisition, bilevel processing, and subtraction) was repeated at an average rate of approximately one per second. To quantitate immobility by image analysis, each frame was subtracted from the previous frame during a 5-min session. The resulting data were sorted according to the magnitude of movement (number of changed pixels) and plotted vs. time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of brain norepinephrine in neuroleptic-induced catalepsy in rats.

Bis (4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA 63) and diethyldithiocarbamate enhanced the catalepsy induced by haloperidol in rats. The norepinephrine (NE) content of the diencephalon in rats treated with haloperidol and FLA 63 was less than that in rats treated with haloperidol alone. The dopamine (DA) decrease in the striatum of haloperidol-treated rats was not altered by FLA 63. Intraperitoneally or intraventricularly administered phentolamine enhanced the catalepsy induced by haloperidol, and clonidine counteracted this effect. Propranolol failed to change haloperidol-induced catalepsy. FLA 63 enhanced the catalepsy induced by ID-4708 (a new butyrophenone compound) by an extent greater than that caused by haloperidol. ID-4708 was more potent in increasing the NE turnover than haloperidol. The combined administration of ID-4708 and FLA 63 produced a greater decrease in the NE content than the combination of haloperidol and FLA 63. These results suggest that the neuroleptic-induced catalepsy would be facilitated when the activity of the NE neurons is lowered or when α-receptors are blocked. A decrease in the activity of DA neurons or the blockade of the DA receptors is essential to elicite catalepsy in rats, and the function of NE neurons would play a role in regulating the degree of catalepsy.     

QF2004B, a potential antipsychotic butyrophenone derivative with similar pharmacological properties to clozapine

The aim of the present work was to characterize a lead compound displaying relevant multi-target interactions, and with an in vivo behavioral profile predictive of atypical antipsychotic activity. Synthesis, molecular modeling and in vitro and in vivo pharmacological studies were carried out for 2-[4-(6-fluorobenzisoxazol-3-yl)piperidinyl]methyl-1,2,3,4-tetrahydro-carbazol-4-one (QF2004B), a conformationally constrained butyrophenone analogue. This compound showed a multi-receptor profile with affinities similar to those of clozapine for serotonin (5-HT2A, 5-HT1A, and 5-HT2C), dopamine (D1, D2, D3 and D4), alpha-adrenergic (alpha1, alpha2), muscarinic (M1, M2) and histamine H1 receptors. In addition, QF2004B mirrored the antipsychotic activity and atypical profile of clozapine in a broad battery of in vivo tests including locomotor activity (ED50 = 1.19 mg/kg), apomorphine-induced stereotypies (ED50 = 0.75 mg/kg), catalepsy (ED50 = 2.13 mg/kg), apomorphine- and DOI (2,5-dimethoxy-4-iodoamphetamine)-induced prepulse inhibition (PPI) tests. These results point to QF2004B as a new lead compound with a relevant multi-receptor interaction profile for the discovery and development of new antipsychotics.     

Rat brain monoamines after acute and chronic myo-inositol treatment.

Inositol was reported to have effects in depression, panic disorder and OCD, and in animal models of depression and anxiety. The present study tested whether inositol treatment alters monoamine systems. Brain areas of rats pre-treated with acute or chronic inositol were analysed by HPLC for monoamines and their metabolites and compared to control animals. Inositol treatment had no significant effect on levels of monoamines, their metabolites, or turnover rates compared to controls.     

Ethanol and delta-sleep-inducing peptide: effects on brain monoamines.

The brain content of dopamine (DA) and its metabolites [dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] were the same in rats with different immobilization times in forced swimming test, while the serotonin (5-HT) concentration was higher in high active (HA, immobilization < 2 min) than low active (LA, immobilization > 5 min) animals. Ethanol (2 g/kg, PO) tended to increase the DA level in the striatum and nucleus accumbens in LA rats and decrease the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentration in HA rats. delta-Sleep-inducing peptide (DSIP) injection reduced the level of 5-HT in the medial prefrontal cortex (MFC) in both groups, did not affect the concentration of DA or DOPAC, but increased HVA in the striatum of HA rats. DSIP injected before ethanol administration augmented the ethanol effects on 5-HT in the MFC and attenuated the action of ethanol on 5-HIAA in the nucleus accumbens. A relationship between the different levels of voluntary alcohol consumption and sensitivity to stress among LA and HA rats and the differences in DA and 5-HT concentrations is suggested. The use of LA and HA rats in developing models for testing of stress-shielding compounds is also described.     

Studies on the depletion of brain amines by m-tyrosine.

The biochemical basis of the well-known physiological and pharmacological actions of m-tyrosine was examined by a detailed study of its effect on the brain biogenic amines. m-Tyrosine was injected i.p. and rat brain monoamine levels were measured. Endogenous levels of dopamine, norepinephrine and serotonin all showed approximately 50% reductions 1 h after the administration of L-m-tyrosine at 150 mg/kg. These actions of L-m-tyrosine could be blocked by the inhibition of the central dopa decarboxylase. Depletion of brain monoamines was also observed with the D-isomer of m-tyrosine, although this effect was less pronounced than that of the L-isomer. In vitro experiments with rat brain homogenates showed that L-m-tyrosine, m-tyramine and m-octopamine enhanced in efflux of exogenous labeled monamines from brain particles, whereas D-m-tyrosine was completely ineffective. From these results it is concluded that the observed decreased in brain monamine levels by L-m-tyrosine may be due to a m-tyramine-enhanced release of the amines which are quickly metabolized in vivo.