Serum concentrations of thioridazine, its major metabolites and serum neuroleptic-like activities in schizophrenics with and without tardive dyskinesia.

Two groups of elderly chronic schizophrenic patients, one with and one without tardive dyskinesia (TD), were studied. In addition to estimation of the neuroleptic-like radioreceptor activity (RRA) of the serum, serum concentrations of thioridazine (THD) and its major metabolites, THD-2-sulfoxide, THD-2-sulfone and THD-5-oxide, were measured with high performance liquid chromatography. Blood samples were collected at two different occasions when the patients were considered to be in a pharmacological "steady state".

Increase in dopamine metabolites in rat brain by neurotensin.

Neurotensin (NT), an endogenous tridecapeptide, is heterogeneously distributed in the central nervous system. The present study examined the effects of physiologically and behaviorally active doses of NT (1--100 micrograms intracisternally) on dopamine, serotonin and their primary metabolites as well as accumulation of dopa after inhibition of dopa decarboxylase. NT was shown to increase dopa accumulation when compared with saline treatment, suggesting that dopamine synthesis was increased.

Simultaneous determination of thioridazine and its S-oxidized and N-demethylated metabolites using high-performance liquid-chromatography on radially compressed silica.

A method for simultaneously quantifying thioridazine, northioridazine, thioridazine-2-sulfoxide, thioridazine-2-sulfone and thioridazine-5-oxide in serum and plasma is described. Following solvent extraction these compounds were separated by high-performance liquid chromatography on radially compressed silica gel and detected by UV absorbance at 254 nm. Chromatography time is less than 7 min.

Effects of vagotomy and glossopharyngectomy on respiratory response to dopamine-agonists.

In normal rats lightly anesthetized with halothane apomorphine increased both resting and CO2-dependent minute ventilation (VM) by stimulating respiratory frequency (RF) whereas tidal volume (VT) was slightly decreased. Acute bilateral glossopharyngectomy, which impaired carotid body function, did not change the apomorphine effects in contrast to bilateral vagotomy, which abolished the RF response of the drug, but now increased VT. Intravenous infusion of dopamine increased VM by elevating RF, and this effect was only slightly blunted by bilateral glossopharyngectomy but nearly abolished by vagotomy and totally eliminated by the combined procedures.

Drug alterations of punished responding after chlordiazepoxide: possible screen for agents useful in minimal brain dysfunction.

In the present study, the effect of various stimulant drugs on the action of chlordiazepoxide to increase punished responding was studied. Drugs such as d-amphetamine, methylphenidate and imipramine that are effective in attentional deficit disorder (MBD) were found to reverse this benzodiazepine-induced increase in responding. Phenobarbital which worsens this condition enhanced the benzodiazepine effect.

Simultaneous quantification of dopamine, 5-hydroxytryptamine and four metabolically related compounds by means of reversed-phase high-performance liquid chromatography with electrochemical detection.

A method for simultaneously quantifying dopamine, 5-hydroxytryptamine (5-HT) and four metabolically related compounds has been developed, permitting more efficient neurochemical examination of these often interrelated biogenic amine systems. The method uses high-performance liquid chromatographic separation of these compounds on a C18 reversed-phase column with a buffered mobile phase containing methanol as an organic modifier and heptanesulfonate as an ion-pair reagent. Using 5-hydroxy-N-methyltryptamine as an internal standard and electrochemical detection, chromatography time is less than 12 min.

Synthesis and pharmacology of hydroxylated metabolites of methylphenidate.

threo-dl-p-Hydroxymethylphenidate and erythro-dl-p-hydroxymethylphenidate (5a and 5b) and the deesterified products, threo-dl- and erythro-dl-p-hydroxyritalinic acid (6a and 6b), were synthesized. The effects of the intracerebroventricular administration of these compounds on the locomotor activity of rats was determined and compared to that of the respective racemates of methylphenidate (1a and 1b) and ritalinic acid (2a and 2b) as a relative index of in vivo dopaminergic activity. The maximal locomotor response was significantly greater for 5a than for 5b, 1a, or 1b.

Alteration of aminophylline-induced respiratory stimulation by perturbation of biogenic amine systems.

Aminophylline-induced stimulation of respiration in halothane-anesthetized rats was abolished in rats given 6-hydroxydopamine and desmethylimipramine neonatally to selectively destroy central nervous system dopamine nerve terminals. The respiratory stimulation was also prevented by prior administration of dopamine receptor antagonists haloperidol and cisflupenthixol. The combination of apomorphine and aminophylline produced an additive stimulatory effect on respiration to values greater than those observed with either drug alone.

Aminophylline may stimulate respiration in rats by activation of dopaminergic receptors.

In intact young rats anesthetized with halothane, aminophylline produces an increase in respiratory minute ventilation due primarily to an increase in respiratory frequency. Although the simulation of respiration by inhalation of 10% CO2 is augmented only at high doses of aminophylline, the response to CO2 is increased at doses as low as 3 mg/kg of aminophylline. Division of the ninth cranial nerve together with removal of the carotid body did not alter the response, whereas vagotomy changed the response from one of increased frequency to an increase in tidal volume.

Antagonism of ethanol-induced decrease in LH by para-chlorophenylalanine: lack of correlation with altered serotonergic mechanisms.

Acute administration of ethanol lowers plasma levels of luteinizing hormone (LH) in several species. Since ethanol may interact with central serotonergic (5HT) neurons, and since 5HT systems have been found to play a role in modulating LH release, we examined the possible role of central serotonergic neurons in the ethanol-induced depression of LH. Acute PCPA (400 mg/kg, 20 hr before 2.

Effects of acute and chronic 1,3-butanediol treatment on central nervous system function: a comparison with ethanol.

In the present investigation, the neuropharmacology of 1,3 butanediol (1,3-BD) was compared with that of ethanol. Acute i.p.

An evaluation of the locomotor stimulating action of ethanol in rats and mice.

The locomotor activity of groups of three CD-1 female mice was increased by 1.0 and 2.0 g/kg ethanol, IP, was decreased during the first hour and increased during the second hour by 3.

Differential effects of TRH, amphetamine, naloxone, and fenmetozole on ethanol actions: attenuation of the effects of punishment and impairment of aerial righting reflex.

The effects of four putative ethanol antagonists [thyrotropin releasing hormone (TRH), naloxone, d-amphetamine, and fenmetozole] on two distinct behavioral actions of ethanol were compared. TRH (20-40 mg/kg) reduced ethanol-induced impairment of the aerial righting reflex (ARR) but enhanced the ethanol-induced increase in punished drinking (anticonflict effect). Naloxone antagonized both actions of ethanol but only at high doses (20-60 mg/kg).

Effect of 5,7-dihydroxytryptamine on serotonergic control of prolactin secretion and behavior in rats.

The intracisternal administration of 5,7-dihydroxytryptamine (5,7-DHT) to rats resulted in a potentiated response to 5-hydroxytryptophan (5-HTP) when the animals were tested 30 days later. The 5-HTP-induced changes include elevation of serum prolactin, decrease in operant responding, and the magnitude of the "serotonin behavioral syndrome" observed after 5-HTP administration. The serotonin concentration in brains of 5,7-DHT-treated animals reached maximum earlier and remained elevated longer than that of controls following administration of 5-HTP.

Use of 6-hydroxydopamine to deplete brain catecholamines in the rhesus monkey: effects on urinary catecholamine metabolites and behavior.

The purpose of this study was to determine: 1) whether 6-hydroxydopamine (6-OHDA), previously shown to deplete brain catecholamines (CA) in rodents, depletes brain CA in rhesus monkeys; 2) whether depletion of brain CA produces changes in behavior; and, 3) whether urinary output of 3-methoxy-4-hydroxyphenylglycol (MHPG) reflects brain norepinephrine (NE) depletions. Repeated intracerebroventricular (ICV) injection of 6-OHDA (N = 20; 15.5-73.

Modification of the actions of ethanol by centrally active peptides.

Ethanol (2.0-5.0 g/kg, IP) caused a dose-related impairment of the aerial righting reflex of mice 60 min after injection.

Effects of TRH on central nervous system function.

Evidence has been reviewed which strongly suggests that TRH functions as a neurotransmitter or neuromodulator in the mammalian central nervous system. Both the peptide and its receptor sites are located in the brain. Furthermore, it has protein actions to modify the effects of many neuropharmacological agents and can itself cause alterations in functions mediated by the CNS.

Brain neurotransmitter and high-energy phosphate concentration after combined hypoxia and hypotension.

Previous work by the authors has established decreased brain ATP concentration after a combined hypoxic-hypotensive episode. This study was undertaken to determine what changes, if any, occur in brain norepinephrine (NE), dopamine (DA), and serotonin (5HT) concentration in association with hypoxia and hypotension, and to correlate any observed changes with simultaneously measured ATP concentrations. Rats were subjected to a 30-minute period of hypoxia (F102 = 0.

Behavioral and biochemical studies of the scopolamine-induced reversal of neuroleptic activity.

Scopolamine reversed the reduction in avoidance responding caused by spiperone and antagonized the inhibitory effects of spiperone on the behavioral actions of d-amphetamine or apomorphine. Scopolamine-induced locomotor activity was greater in 6-hydroxydopamine (6-OHDA)-treated animals than in controls. This increase was prevented by administration of alpha-methyltyrosine, but not by inhibition of dopamine-beta-hydroxylase, indicating that this action of scopolamine was associated with presynaptic dopaminergic fibers.

Effects of different monoamine oxidase inhibitors on respiratory activity in rats with chronically impaired central serotonergic function.

Resting and CO2 stimulated respiration were measured by means of a whole-body plethysmograph in rats lightly anaesthetized with halothane. Rats pretreated neonatally with intracisternal 5,7-dihydroxytryptamine (5,7-DHT) to destruct permanently central serotonergic neurones had significantly lower resting and CO2 stimulated respiratory frequency (RF) and minute volume (VM) than naive rats. In the 5,7-DHT pretreated rats, but not in naive rats, the monoamine oxidase inhibitors clorgyline and pargyline further reduced both resting and CO2 stimulated RF and VM, whereas 1-deprenyl stimulated respiration.