Behavioral changes induced by the thyrotropin-releasing hormone analogue, RGH 2202

The behavioral activity of the thyrotropin-releasing hormone (TRH) analogue, L-6-ketopiperidine-2-carbonyl-leucyl-L-prolinamide (RGH 2202), has been studied in the rat. The number of errors in a radial maze test was reduced after acute intraperitoneal (IP) injection of RGH 2202 at the dose of 5 or 10 mg/kg. Grooming activity was increased with a lower dose, 1 mg/kg. Hypoxia-induced amnesia, as assessed with active and passive avoidance behavior tests, was reversed in rats treated with 5 or 10 mg/kg of the drug. The loss of learning and memory capacity shown by aged rats in the same behavioral tests was also reduced after injection of RGH 2202. In a test for sexual activity of male rats, the higher dose of the drug induced a facilitation of mounting and ejaculations, while smaller doses were ineffective. The rotorod test revealed a decreased number of falls in animals treated with 5 or 10 mg/kg of RGH 2202. In all behavioral tests, the same doses of natural thyrotropin-releasing hormone (TRH) were less effective, indicating that this analogue may be qualified as a potentially active drug in human pathologies.     

The effects of a hypothalamic peptide factor,MIF and its cyclic analog on tolerance to haloperidol in the rat

The effects of the hypothalamic peptide, ProLeuGlyNH₂ (MIF) and its analog, cyclo (LeuGly) (CLG) on the development of tolerance to haloperidol were investigated in male Sprague-Dawley rats. Chronic oral administration of haloperidol (1.5 mg/kg/day) for 21 days resulted in the development of tolerance to its pharmacological effects. A dose of haloperidol (3 mg/kg ip) exhibited an absence of cataleptic as well as hypothermic response in chronically haloperidol treated rats. Subcutaneous administration of MIF or CLG (2 mg/kg each) daily one hour prior to haloperidol injection blocked the haloperidol-induced tolerance as evidenced by the appearance of both the cataleptic and hypothermic responses. It is concluded that the hypothalamic peptide hormone, MIF may be important in regulating chronic effects of neuroleptic drugs.     

Pro-Leu-glycinamide and its peptidomimetic,PAOPA, attenuate haloperidol induced vacuous chewing movements in rat: A model of human tardive dyskinesia

In the present experimental paradigm, we examine the effect of L-prolyl-L-leucyl-glycinamide (PLG) co-administration with haloperidol on vacuous chewing movements (VCM) in rats-a model of tardive dyskinesia (TD) in humans. We examined the dose dependent induction of VCM through both injected and orally administered PLG (MIF-1). Our results show significant levels of VCM attenuation (P<0.05) in rats treated with 10mg/kg of PLG. Doses of 1 and 100mg/kg were ineffective. Reductions were present in both orally treated and injected rats. We also examined the therapeutic effect of a peptidomimetic of PLG-PAOPA. PAOPA was able to produce similar behavioral effects to PLG at a dose, which was 100-fold lower than the effective dose of PLG. These results suggest that PLG may play a role in D2 receptor expression and function, as well as providing a therapy for neuroleptic induced TD.     

Inhibition of plasma prolactin in the rat by amantadine

A single iv injection of 15 or 30 but not 7.5 mg/kg BW of an antiviral drug, amantadine, significantly (P less than 0.05) decreased plasma prolactin (PRL) concentrations in male rats. This effect was dose-dependent, with the highest dose producing a longer-lasting decrease in plasma PRL. The amantadine-induced decrease was unaffected by a simultaneous injection of 5-hydroxytryptophan (30 mg/kg BW) but was completely blocked by a simultaneous injection of haloperidol (0.05 mg/kg BW). It is concluded that this novel effect of amantadine on PRL is produced by an interaction with the dopaminergic system.     

Role of serotonin2 receptors in regulating aggressive behavior

Quipazine and pirenperone , the drugs interacting with serotonin2 -receptors, more readily displaced 3H-spiroperidol from its binding sites in the frontal cortex than in the striatum. Pirenperone (0,07-0,3 mg/kg), antagonist of serotonin2 -receptors, selectively decreased the intensity of apomorphine aggressiveness. The antiaggressive action of haloperidol (0,01-0,2 mg/kg) was in correlation with its antistereotypic activity. Long-term administration of naloxone (0,5; 15,0 mg/kg), together with apomorphine (0,5 mg/kg) reduced the number of head-twitches caused by quipazine (2,5 mg/kg). The administration of quipazine 48 hours after the last injection of naloxone and apomorphine caused spontaneous aggressiveness that did not differ from apomorphine aggressiveness. Intracerebroventricular injection of cholecystokinin tetrapeptide (CCK-4) markedly enhanced the foot-shock aggression. The same dose of CCK-4 also decreased the intensity of quipazine (2,5 mg/kg) head-twitches. Compared to haloperidol, pirenperone was a more selective antagonist of CCK-4. After long-term apomorphine treatment (0,5 mg/kg during 10 days, twice daily), the effect of CCK-4 on aggressive behaviour was markedly enhanced. It is possible that two subtypes of serotonin2 -receptors exist in the brain and have opposite action on the aggressive behaviour. CCK-4 may play the role of an endogenous modulator of sensitivity of serotonin2 -receptors involved in the control of aggressiveness.     

Effects of the alpha 1-adrenergic agonist cirazoline on locomotion and brown adipose tissue thermogenesis in the rat.

Anorexia is induced by injection of alpha 1-adrenergic receptor agonists into the hypothalamic paraventricular nucleus (PVN) in rats. Of the agonists tested to date, cirazoline is the most potent when administered either into the PVN or systemically. The present experiments assess the effects of systemically administered cirazoline, at doses that suppress food intake, on dopamine and norepinephrine systems as evident in locomotion and stereotypy and in the induction of brown adipose tissue (BAT) thermogenesis. In Experiment 1, adult male rats were treated with either vehicle (0) or 0.05, 0.1, 0.2 or 0.4 mg/kg cirazoline (IP) prior to 30 minutes assessment of horizontal and vertical locomotion and stereotypy in Omnitech activity chambers. Horizontal activity and stereotypy were significantly suppressed at 0.05 mg/kg cirazoline but these effects waned at higher cirazoline doses. In Experiment 2, interscapular BAT temperature in adult male rats was monitored for 30 minutes after injection (IP) of either vehicle or 0.4 mg/kg cirazoline. Cirazoline, at 0.4 mg/kg did not influence BAT temperature whereas a positive control treatment (phenylpropanolamine: 40 mg/kg) rapidly increased BAT temperature during a 15 minute period after injection. These results suggest that cirazoline-induced anorexia is not the result of competing motor responses and that this drug, at a dose that produces maximal suppression of feeding, does not alter BAT thermogenesis.     

Tolerance develops to the haloperidol-induced increase in the efflux of dopamine metabolites from the brains of unanesthetized, freely-moving rats

The lateral cerebral ventricles of freely moving rats were perfused by means of chronically implanted push-pull cannulae every second day for 2 weeks. Perfusates were analyzed for metabolites of dopamine [dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] and of 5-hydroxytryptamine [5-hydroxyindoleacetic acid (5HIAA)] using high performance liquid chromatography and an amperometric detector. Rats received daily subcutaneous injections of haloperidol (1 mg/kg) or its vehicle. After the first injection of haloperidol the concentrations of DOPAC and HVA were markedly increased while that of 5HIAA was unchanged. Complete tolerance developed to the haloperidol-induced increased efflux of dopamine metabolites by day 9, although a higher dose of haloperidol (2 mgf/kg) on day 15 was still capable of eliciting a modest increase in the efflux of DOPAC and HVA.     

Compartive behavioral effects of dibutyryl cyclic AMP and prostaglandin E1 in mice.

Three behavioral tests, spontaneous locomotor activity (SLMA), exploratory behavior (EB) and rotarod performance (RP), a measure of neuromuscular coordination, were used to stuey the interaction of PGE1 (1 mg/kg i.p., 10 min. pretreatment) with DBcAMP (25 mg/kg i.p., 25 min. pretreatment) in mice. A dose-response relationship of PGE1 (0.01-5.0 mg/kg) to SLMA was determined, with a significant decrease in SLMA produced by a dose of 0.1 mg/kg. decreases in SLMA were produced by PGE1 (79%), DBcAMP (41%) and DBcAMP-PGE1 combination (71%). Similar decreases in EB were observed. Although no significant difference between controls and DBcAMP was observed in RP, 52% of mice tested were RP failures following PGE1 and a 100% failure rate was induced by the combination. Mice were treated with a second injection of DBcAMP or PGE1 or the combination 24 hr following the first injection. Behavioral activity of these mice was observed 25 min (DBcAMP) or 10 min (PGE1) after the second dose was administered. A second injection of DBcAMP failed to decrease SLMA and EB from controls; moreover, SLMA began to return towards control levels as early as 2 hr between injections. The second injection of PGE1 or DBcAMP+PGE1 produced the same behavior as that produced by the first injection. On the basis of these results, the relationship of cyclic nucleotides and PGs to behavioral activity is discussed.     

Relationship of the homovanillic acid content in the rat brain after the administration of a neuroleptic and the degree of dopamine receptor sensitivity to an agonist

In the experiments on male Wistar rats it was established that the intensity of apomorphine stereotypy gradually increased 6--12 hours after a single injection of haloperidol in a dose of 1 mg/kg. 24 hours later the stereotypy was much higher than in the control animals, its intensity being negatively correlated with the homovanillic acid (HVA) concentration in the rat forebrain. It is suggested that HVA concentration reflects the degree of dopamine receptor sensitivity to the agonist.     

Comparative neurochemical changes associated with chronic administration of typical and atypical neuroleptics: implications in tardive dyskinesia

An important goal of current neuroleptic research is to develop antipsychotic compounds with the low incidence of extrapyramidal side effects. The therapeutic success and less side-effect of atypical anti-psychotics such as clozapine and risperidone has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptics-associated extrapyramidal side effects. The present study compares the effect of chronic administration of typical and atypical antipsychotics on neurochemical profile in rat forebrain. The study was planned to study changes in extracellular levels of norepinephrine, dopamine and serotonin in forebrain region of brain and tried to correlate them with hyperkinetic motor activities (vacuous chewing movements (VCM's), tongue protrusions and facial jerking) in rats, hall mark of chronic extrapyramidal side-effect of neuroleptic therapy tardive dyskinesia. Chronic administration of haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) resulted in significant increase in orofacial hyperkinetic movements where as clozapine and risperidone showed less significant increase in orofacial hyperkinetic movements as compared to control. There were also significant decrease in the extracellular levels of neurotransmitters dopamine, norepinephrine and serotonin in fore-brain as measured by HPLC/ED after chronic administration of haloperidol and chlorpromazine. Chronic administration of atypical neuroleptics clozapine and risperidone resulted in the decrease in extracellular concentration of dopamine and norepinephrine but the effect was less significant as compared to typical drugs. However, treatment with atypical neuroleptics resulted in 3 fold increase in serotonin levels as compared to forebrain of control rats. Typical and atypical neuroleptics showed varying effects on neurotransmitters, especially serotonin which may account for the difference in their profile of side effects (Tardive dyskinesia).     

Rat behavior in the "open field" next day after haloperidol injection: dependence on experimental conditions

Wistar rats were injected with haloperidol (3.5 mg/kg) that resulted in a high level of cataplexy. Next day after haloperidol injection rat behavior was studied in the open field. The animals were divided in two groups. The first group of animals was tested in the daylight without additional illumination of the open-field chamber. The second group was tested in a darkened room with additional intense illumination of the open-field center with a 60W bulb. The testing time was 240 s. The high level of the open-field locomotor activity in the first group was attributed to anxiety. The low level of locomotor activity in the second group was qualified as depressive state.     

Acute and subchronic influences of tetrahydrocannabinols on water and food intake, body weight, and temperature in rats.

Experiment 1. The acute effects of delta9-THC (1.25, 2.50, 5.00, and 10.00 mg/kg) and delta8-THC (1.25, 2.50, 5.00, and 10.00 mg/kg) was an approximately equipotent, dose related depression of water intake in water-deprived rats. Animals given hashish, inhaled as smoke, showed a depression of water consumption comparable to rats given the highest dose of either of the synthetic THCs. Water intake after chevril smoke was similar to that seen after vehicle injections. Experiment 2. A dose related depression of water-and-food intake, and reduction of body weight with a gradual recovery was found in rats, maintained on a Limited Time of drinking schedule (LT, 2 hr) and subchronically (21 days) treated with delta9-THC (1.25, 2.50, or 5.00 mg/kg). From the 22nd day all animals were given the vehicle only for 10 days. There were no indications of withdrawal effects due to the drug termination. Reinstating the drug after the 10 day drug free period suggested an increased sensitivity to THC as compared to the 21st injection. Experiment 3. In non-deprived rats delta9-THC caused similar effect as in Exp. 2, although to less extent. From both experiments it is concluded that there is an inhibition or even loss of body weight and that food intake seems more severely depressed than water intake. The temperature recordings suggest that the predominant consequence of lower, behaviorally, effective doses of THC on rectal temperature of rats is hyperthermia rather than hypothermia. Initially this effect was most pronounced for the lowest dose (1.25 mg/kg) but with repeated injections the two higher doses (2.50 and 5.00 mg/kg) showed hyperthermia to the same extent as the lowest dose. Hypothermia was seen after a high dose of delta8-THC (20.00 mg/kg) but after 3 daily injections this effect was gone.     

Thermoregulatory, motor, behavioural, and nociceptive responses of rats to 3 long-acting neuroleptics

We investigated physiological effects of intramuscular injections of the following 3 long-acting neuroleptics commonly used in wildlife management: haloperidol (0.05, 0.1, and 0.5 mg/kg body mass), zuclopenthixol acetate (0.5, 1, and 5 mg/kg), and perphenazine enanthate (1, 3, and 10 mg/kg), in a rat model. Body temperature and cage activity were measured by intra-abdominal telemeters. Nociceptive responses were assessed by challenges to noxious heat and pressure. Haloperidol (0.5 mg/kg) produced a significant nocturnal hypothermia (p < 0.05) and decreased nighttime cage activity and food intake. Zuclopenthixol (5 mg/kg) significantly decreased nighttime body temperature and cage activity and, at 1 mg/kg and 5 mg/kg, significantly decreased food intake 5-17 h after injection (p < 0.05). Perphenazine (10 mg/kg) significantly decreased nighttime body temperature and cage activity and, at all doses, significantly decreased food intake 5-17 h after injection (p < 0.05). Significant analgesic activity was evident in rats given 5 mg/kg zuclopenthixol up to 40 h after injection, and 10 mg/kg perphenazine from 48 to 96 h after injection (p < 0.0001). Zuclopenthixol (5 mg/kg) and perphenazine (10 mg/kg) had significant antihyperalgesic activities at 16 h postinjection and 24-48 h postinjection, respectively (p < 0.0001). Haloperidol had no significant antinociceptive activity at doses tested. Motor function was impaired in rats given 0.5 mg/kg haloperidol, 5 mg/kg zuclopenthixol and 10 mg/kg perphenazine. Effects of long-acting neuroleptics on body temperature, feeding, and activity were short-lasted and should not preclude their use in wildlife. Antinociceptive actions were longer-lasting, but were nonspecific, and we recommend additional analgesics for painful procedures during wildlife management.     

Protective Effect of L-type Calcium Channel Blockers Against Haloperidol-induced Orofacial Dyskinesia: A Behavioural, Biochemical and Neurochemical Study

Haloperidol is a classical neuroleptic drug that is still in use and can lead to abnormal motor activity such as tardive dyskinesia (TD) following repeated administration. TD has no effective therapy yet. There is involvement of calcium in triggering the oxidative damage and excitotoxicity, both of which play central role in haloperidol-induced orofacial dyskinesia and associated alterations. The present study was carried out to investigate the protective effect of calcium channel blockers [verapamil (10 and 20 mg/kg), diltiazem (10 and 20 mg/kg), nifedipine (10 and 20 mg/kg) and nimodipine (10 and 20 mg/kg)] against haloperidol induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical alterations in rats. Chronic administration of haloperidol (1 mg/kg i.p., 21 days) resulted in a significant increase in orofacial dyskinetic movements and significant decrease in % retention, coupled with the marked increase in lipid peroxidation and superoxide anion generation where as significant decrease in non protein thiols and endogenous antioxidant enzyme (SOD and catalase) levels in rat brain striatum homogenates. All these deleterious effects of haloperidol were significantly attenuated by co-administration of different calcium channel blockers. Neurochemically, chronic administration of haloperidol resulted in significant decrease in levels of catecholamines (dopamine, serotonin) and their metabolites (HVA and HIAA) but increased turnover of dopamine and serotonin. Co-administration of most effective doses of verapamil, diltiazem, nifedipine and nimodipine significantly attenuated these neurochemical changes. Results of the present study indicate that haloperidol-induced calcium ion influx is involved in the pathogenesis of tardive dyskinesia and calcium channel blockers should be tested in clinical trials with nifedipine as the most promising one.     

Design, synthesis and anticonvulsant activities of novel 1-(substituted/unsubstituted benzylidene)-4-(4-(6,8-dibromo-2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)phenyl) semicarbazide derivatives

Novel quinazolinone derivatives 5a-5n were designed, synthesized and screened for antiepileptic activity using MES and scPTZ seizures tests. Neurotoxicity study was performed by rotorod test. Compounds 5c, 5d, 5g, 5j and 5k were found active in the preliminary screening in MES model and/or scPTZ model. Further all these five compounds were administered to rats, 5c and 5d showed better activity than Phenytoin in oral route. Among all the title compounds tested, the most active one was 5c that revealed protection in MES at a dose of 30 mg/kg (ip) after 0.5 and 4h. This molecule also provided protection in the scPTZ at a dose of 100mg/kg (0.5h) and 300 mg/kg (4h).     

NEUROCHEMICAL PARAMETERS IN THE HYPERRESPONSIVE PHASE AFTER A SINGLE DOSE OF NEUROLEPTICS TO MICE

Abstract— Four days after a single dose of teflutixol (5 mg/kg i.p.), at which time mice are superresponsive to dopamine agonists, e.g. apomorphine, the specific binding of [³H]haloperidol, [³H]cis (Z)-flupenthixol, [³H]apomorphine, [³H]dopamine, [³H]propylbenzilylcholine mustard and [³H]GABA to striatal membranes in vitro is equal to that of saline-treated mice. Specific binding of [³H]haloperidol is also unchanged 3 days following a single dose of fluphenazine (5mg/kg i.p.) and 2 days following haloperidol (5 mg/kg i.p.), but slightly decreased 3 days following cis(Z)-flupenthixol (5 mg/kg i.p.).
The possibility that remaining neuroleptic or active metabolites could obscure a slight increase in dopamine receptor binding was rejected, since remaining amounts of [³H]teflutixol in the final binding assay 4 days after intraperitoneal injection of [³H]teflutixol (5 mg/kg) were too small to influence the binding of [³H]haloperidol in vitro .
It is concluded that the pharmacological superresponsiveness and the decrease in dopamine synthesis and release seen after the initial receptor blockade following a single dose of neuroleptic drugs in mice are nor accompanied by changes in dopamine, muscarine or GABAergic receptor characteristics in corpus striatum. The possibility that changes occur in a small number of functional operative dopamine receptors cannot be excluded, however.     

Évaluation des effets prosexuels des extraits de Bridelia ferruginea chez le rat mâle naïf

The stem barks and the leaves from Bridelia ferruginea (BF, Euphorbiaceae), a medicinal plant, are used in traditional medicine for the treatment of several ailments including male impotency. The present study was aimed at investigating the effects of the dried stem bark of BF on the sexual behaviour of normal and castrated sexually inexperienced male Wistar rats. Animals were orally administered with 100 mg/kg of either the aqueous or the ethanol extracts of BF whilst the neutral control group received in the same way 10 ml/kg of distilled water. The positive control group was treated with a subcutaneous injection of testosterone propionate (20 mg/kg/day/3days) prior to the experiment. The sexual behaviour of all rats was monitored on days 0, 1 and 7 by measuring frequencies of penile erection, mount, intromission and ejaculation. In a separate group of normal sexually inexperienced rats, the pro-sexual effects induced by a single dose of the aqueous extract (100 mg/kg) were measured after pre-treatment with either haloperidol (10 mg/kg), atropine (10 mg/kg) or L-omega-nitro-arginine methyl ester (Lω-NAME, 10 mg/kg). Results obtained showed a significant influence of the duration of treatment on the frequencies of penile erection, mount and intromission of both normal and castrated rats. An increase in all sexual performance parameters was observed when compared to respective controls. The intromission frequency of normal animals was significantly increased (P < 0.05–0.01) on day 1 of treatment and the effect was more expressed in rats receiving the aqueous extract. In castrated animals, a statistical increase was noticed on day 7 for rats treated with testosterone. The sexual effects induced by the aqueous extract of BF were completely abolished after pre-treatment of rats with atropine or haloperidol while pre-administration of Lω-NAME did not produce any significant effects. Flavonoids and sterols revealed in the aqueous and ethanolic extracts from the barks of BF may account for the enhancement of sexual activity in naive rats which could be expressed through dopaminergic and/or cholinergic receptor(s). Results of this work also give value to the traditional use of the plant for the improvement of male sexual behaviour.     

Anaphe venata larva extract-induced purposeless chewing in rats: the role of cholinergic, GABAergic and opioid systems

Seasonal ataxia was reported in humans following the consumption ofAnaphe venata larva as protein supplement in diet and altered motor function in rodents when the extract was administered intraperitoneally. In this study we investigated the effect of the crude aqueous and Phosphate Buffer Saline (PBS) extracts of this larva on altered spontaneous rat behavior in a novel environment particularly chewing behaviour, with a view to determine the mechanism(s) involved in these behavioural alteration. Animals were randomly assigned into four groups (n = 6-12 per group) and graded doses of aqueous and PBS extracts (100-400 mg/kg) were administered dissolved in saline intraperitoneally (i.p.) to each animal in the experimental groups. The control group received an equivalent volume of saline. Behavioral scores were recorded for a period of 30 minutes after the administration of saline or extract. The role of various receptors in the extract induced chewing was evaluated using known receptor agonist/antagonists. Results revealed a significant increase in purposeless chewing (F (7, 95) = 7.85; p <0.05) by the aqueous extract compared to saline control at all dose levels, which was significantly attenuated by scopolamine (3 mg/kg, i.p) and thiamine (1 mg/kg, i.p) respectively (p <0.05); while flumazenil (2 mg/kg, i.p) and naloxone (2.5 mg/kg, i.p) did not alter the induced purposeless chewing behaviour. Also, administration of PBS induced a significant (F (7, 95) = 6.11; p <0.05) increase in chewing behaviour but only at 400 mg/kg dose level which was attenuated by scopolamine (3 mg/kg, i.p); while flumazenil (2 mg/kg, i.p), naloxone (2.5 mg/kg, i.p), and thiamine (1 mg/kg, i.p) potentiated purposeless chewing behaviour respectively. It may therefore be concluded from this study that Anaphe extract-induced purposeless chewing behaviour in rat is mediated via the activation of cholinergic neurotransmission which is modulated by GABAergic and opioid receptor systems.     

Proceedings: Influence of tryptophan on the hypotensive effect of arachidonic acid

When arachidonic acid (AA) was given to a rabbit which was previously heparinized, its arterial pressure began to fall. Indomethacin erased this vasodepressive power without modifying the sensitivity of the cardiovascular apparatus to prostaglandins. Thus, it seems to depend on the biosynthesis of the prostaglandins. This hypotensive action is used as an indication of natural factors which modify the biosynthesis of prostaglandins in living subjects. Tryptophan was used on 8 male rabbits who had been fed normally, weighing 2.3-2.8 kg. The standard dose of .12 mg/kg of AA was injected in 80 seconds. 3 experiments were done without heparin, using a manometer in which the liquid had been made incoaguable by citrate. With 5 others, after injection of AA, the isotonic liquid with citrate was replaced by a manometer with heparin (20 mg/kg of heparin to avoid reabsorption of citrate during hypotension). Several injections of AA were given until a constant hypotensive action resulted; then 4 mg/kg of tryptophan were given and 10 minutes later, a new injection of AA. The results were: 1) With .12 mg/kg there was no hypotensive effect in the rabbit without heparin. 2) A previous treatment with 4 mg/kg of tryptophan achieved a fall of 5-15%. 3) In heparinized rabbits, after AA injections, there were falls of pressure which intensified and attained 25% 40 minutes after the heparin injection. 4) The injection of tryptophan obtained hypotensions of 45-50% in 5 rabbits. It is concluded that in rabbits tryptophan is an activator of the biosynthesis of prostaglandins.     

Acute effects of caffeine injection on neutral amino acids and brain monoamine levels in rats

The injection of caffeine (100 mg/kg, i.p.) into male rats acutely increased brain levels of trytophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). Blood levels of glucose, nonesterified fatty acids (NEFA) and insulin also increased, while those of the aromatic and branched-chain amino acids fell. Serum tryptophan levels either did not fall, or increased. Consequently, the serum ratio of trypthopahn to the sum of other large neutral amino acids (LNAA) increased. Less consistently noted were increases in serum free tryptophan levels. Brain tyrosine levels were not appreciably altered by caffeine, nor was the serum tyrosine ratio. In dose-response studies, 25 mg/kg of caffeine was the minimal effective dose needed to raise brain tryptophan, but only the 100 mg/kg dose elevated all three indoles in brain. In no experiments did caffeine, at any time or dose, alter brain levels of dopamine or norepinephrine. Caffeine thus probably raises brain tryptophan levels by causing insulin secretion, and thereby changing plasma amino acid levels to favor increased tryptophan uptake into brain. The rises in brain 5-HT and 5-HIAA may follow from the increase in brain tryptophan, although further data are required clearly to establish such a mechanism.