Effect of repeated treatment with desipramine in the behavioral "despair" test in rats: antagonism by "atypical" but not "classical" neuroleptics or antiadrenergic drugs

A 7-day treatment with 20 mg/kg/day desipramine reduced the immobility time in the behavioral "despair" test in rats. The effect of DMI was antagonized by sulpiride (100 mg/kg i.p.), metoclopramide (20 mg/kg i.p.) and clopazine (20 mg/kg i.p.) but not by haloperidol (0.5 mg/kg i.p.) or chlorpromazine (5 mg/kg i.p.). Alpha-adrenoreceptor blockers (prazosin 3 mg/kg s.c.; aceperone 10 mg/kg i.p.; azapetine 24 mg/kg s.c.; phentolamine 20 mg/kg i.p.), dl-propranolol (5 mg/kg i.p.) and clonidine (0.1 mg/kg i.p.) failed to modify the anti-immobility effect of DMI. The data suggest that a particular subtype of dopamine receptors is involved in the anti-immobility effect of a 7-day treatment with DMI in the behavioral "despair" test in rats.     

The role of dopamine and serotonin in the prolongation of post-decapitation convulsions in mice.

L-DOPA (320 mg/kg, i.p.) increased the duration of the clonic phase of post-decapitation convulsions (PDC) by 60% in mice pretreated with the peripheral decarboxylase inhibitor, Ro 4-4602 (50 mg/kg, i.p.). Assays of brains at the time of decapitation showed a 300% increase in dopamine (DM), an 80% reduction in serotonin (5-HT) and no change in norepinephrine (NE) levels. The effect of L-DOPA on PDC was not blocked by haloperidol (0.5 – 5.0 mg/kg), a blocker of DM receptors, nor by diethyldithiocarbamate (400 mg/kg) an inhibitor of NE synthesis. Parachlorophenylalanine (300 mg/kg × 3 days) produced an 80% reduction in 5-HT and a prolongation of PDC similar to that observed after L-DOPA. Prolongation of PDC was also seen after the 5-HT antagonists methysergide (5 mg/kg) and cinanserin (10 mg/kg), but not after cyproheptadine (10 mg/kg). The 5-HT precursor, 5-hydroxytryptophan (100 mg/kg), produced no change in PDC when used alone but inhibited L-DOPA's prolongation of PDC. The results suggest that L-DOPA acts by depleting 5-HT in bulbospinal pathways and thus enhancing reflex activity in the spinal cord.     

Antidepressant-like effect of 17beta-estradiol: involvement of dopaminergic, serotonergic, and (or) sigma-1 receptor systems

17beta-estradiol has been reported to possess antidepressant-like activity in animal models of depression, although the mechanism for its effect is not well understood. The present study is an effort in this direction to explore the mechanism of the antidepressant-like effect of 17beta-estradiol in a mouse model(s) of behavioral depression (despair behavior). Despair behavior, expressed as helplessness to escape from a situation (immobility period), as in a forced swim test in which the animals are forced to swim for a total of 6 min, was recorded. The antiimmobility effects (antidepressant-like) of 17beta-estradiol were compared with those of standard drugs like venlafaxine (16 mg/kg, i.p.). 17beta-estradiol produced a U-shaped effect in decreasing the immobility period. It had no effect on locomotor activity of the animal. The antidepressant-like effect was comparable to that of venlafaxine (16 mg/kg, i.p.). 17beta-estradiol also exhibited a similar profile of antidepressant action in the tail suspension test. When coadministered with other antidepressant drugs, 17beta-estradiol (5 microg/kg, i.p.) potentiated the antiimmobility effect of subeffective doses of fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.), or bupropion (10 mg/kg, i.p.), but not of desipramine (5 mg/kg, i.p.) or tranylcypromine (2 mg/kg, i.p.), in the forced swim test. The reduction in the immobility period elicited by 17beta-estradiol (20 microg/kg, i.p.) was reversed by haloperidol (0.5 mg/kg, i.p.; a D(2) dopamine receptor antagonist), SCH 23390 (0.5 mg/kg, i.p.; a D(1) dopamine receptor antagonist), and sulpiride (5 mg/kg, i.p.; a specific dopamine D(2) receptor antagonist). In mice pretreated with (+)-pentazocine (2.5 mg/kg, i.p.; a high-affinity sigma-1 receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced a synergistic effect. In contrast, pretreatment with progesterone (10 mg/kg, s.c.; a sigma-1 receptor antagonist neurosteroid), rimcazole (5 mg/kg, i.p.; another sigma-1 receptor antagonist), or BD 1047 (1 mg/kg, i.p.; a novel sigma-1 receptor antagonist) reversed the antiimmobility effects of 17beta-estradiol (20 microg/kg, i.p.). Similarly, in mice pretreated with a subthreshold dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A serotonin receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced an antidepressant-like effect. These findings demonstrate that 17beta-estradiol exerted an antidepressant-like effect preferentially through the modulation of dopaminergic and serotonergic receptors. This action may also involve the participation of sigma-1 receptors.     

Participation of 5-HT1A-receptors in regulating various types of aggressive behavior

We studied the effects of selective agonists of 5-HT1A receptors 8-OH-DPAT and flesinoxan on aggressive behavior of C57BL/6 male mice in the "resident-intruder" test and on defensive aggression of Norway rats toward man. 8-OH-DPAT (0.4 mg/kg, i.p.) significantly reduced the intermale aggression in mice and defensive aggression in rats (0.1-0.5 mg/kg, i.p.). In the dose of 0.5 mg/kg, flesinoxan inhibited the aggressive behavior in mice. These results suggest that activation of 5-HT1A receptors reduces different kinds of affective aggression. The results are discussed in terms of interaction between the well-known anxiolytic effects of 5-HT1A agonists and their antiaggressive properties.     

Inhibition of peripheral adrenergic neurotransmission by lergotrile in spontaneously hypertensive rats

Intraperitoneal injection of lergotrile (0.5 mg/kg) produced arterial hypotension and bradycardia for 120 and 90 minutes, respectively, in anesthesized spontaneously hypertensive rats (SHR). During this time frame, lergotrile (0.5 mg/kg, i.p.) greatly attenuated diastolic blood pressure and cardiac rate responses to electrical stimulation (0.062-4 Hz) of the sympathetic outflow in pithed SHR, but had no significant effect on comparable increments in pressure and rate produced by exogenous norepinephrine (0.01–10 μg/kg, i.v.). Pretreatment of SHR with haloperidol (2 mg/kg, i.p.) prevented lergotrile-induced hypotension and partially reversed its inhibitory effect on neurogenic vasoconstrictor responses. Haloperidol alone had no significant effect on baseline arterial blood pressure or responses to sympathetic nerve stimulation. Administration of hexamethonium (20 mg/kg, i.v.) to SHR antagonized the hypotensive response to lergotrile (0.5 mg/kg, i.p.), although hydralazine (2 mg/kg, i.p.) still produced a marked reduction in pressure.These results suggest that lergotrile produces arterial hypotension and bradycardia primarily by inhibiting peripheral sympathetic nerve function through a dopaminergic mechanism. The probable site of action of lergotrile is at presynaptic (neuronal) dopamine receptors which are known to be inhibitory to neurogenic release of norepinephrine.     

The bombesin/gastrin releasing peptide receptor antagonist RC-3095 blocks apomorphine but not MK-801-induced stereotypy in mice

Bombesin (BN)-like peptides might be involved in the pathogenesis of neuropsychiatric disorders such as schizophrenia. Stereotyped behaviors induced by the dopamine receptor agonist apomorphine or the N-methyl-D-aspartate glutamate receptor antagonist dizocilpine (MK-801) in rodents have been proposed as animal models of schizophrenic psychosis. In the present study we evaluated the effects of the BN/gastrin-releasing peptide receptor (GRP) antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) on apomorphine and MK-801-induced stereotyped behavior in mice. An intraperitoneal (i.p.) injection of RC-3095 (1.0, 10.0 or 100.0 mg/kg) blocked apomorphine-induced stereotypy. The inhibitory effect of RC-3095 on apomorhine-induced stereotypy was similar to that induced by haloperidol (0.5 mg/kg). RC-3095 did not affect stereotyped behavior induced by MK-801 (0.5 mg/kg). The results provide the first evidence that BN/GRP receptor antagonism blocks stereotyped behavior induced by a dopamine agonist. Together with previous evidence, the present study indicates that the BN/GRP receptor can be considered a drug target in the investigation of potential new agents for treating neuropsychiatric disorders.     

Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats

The substituted amphetamine 3,4 methylenedioxyamphetamine (MDA) is a popular recreational drug of abuse. Administration of MDA to experimental animals has been shown to induce damage to serotonergic axons and nerve terminals. However, there is a lack of information on whether these treatments can produce any long-term changes in behavioural performance particularly under stressful conditions. In the present study, MDA (7.5 mg/kg; i.p.) was administered twice daily to adult male Sprague Dawley rats for four days. Four weeks following the last dose, spontaneous behaviors of these animals were tracked and scored in a novel "open field" environment using an automated video registration and computer interpretation system. Changes in behavior were observed in MDA treated animals including reductions in exploratory oriented behaviors (locomotion and rearing) and increases in grooming behavior when compared to vehicle treated controls. MDA-treated animals also displayed an enhanced locomotor and stereotyped response to d-amphetamine (12 mg/kg; i.p.). Significant reductions in 5-HT concentrations (20-30%) were observed in the frontal cortex, amygdala, striatum, and hypothalamus as a result of MDA treatment. In addition, [3H] paroxetine binding was reduced by (40%) in the cortex of MDA treated rats indicating that the decrease in 5-HT concentrations were accompanied by a reduction in intact presynaptic 5-HT nerve terminals. Changes in behavioural performance in a novel "open field" environment and following d-amphetamine challenge might be considered as a behavioural model of serotonergic deficit induced by MDA. The findings of this study also suggest that MDA use may increase both the abuse potential, and the propensity to develop psychosis as a result of abusing other psychostimulants such as d-amphetamine.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Central antidopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride

2-Bromolisuride (2-Br-LIS), a derivative of the ergot dopamine (DA) agonist lisuride, was investigated in rodents in comparison with the DA antagonist haloperidol with regard to its influence on DA related behaviour, cerebral DA metabolism and prolactin (PRL) secretion. 2-Br-LIS produced catalepsy in mice (ED50 3.3 mg/kg i.p.), antagonized apomorphine-induced stereotypies in mice (ED50 0.4 mg/kg i.p.), antagonized DA agonist-induced stereotypies in rats (0.1-1.56 mg/kg i.p.), inhibited locomotor activity in rats (0.025-6.25 mg/kg i.p.), antagonized the hyperactivity produced by various DA agonists in rats (0.025-6.25 mg/kg i.p.) and inhibited the apomorphine-induced hypothermia in mice (0.05-0.78 mg/kg i.p.). 2-Br-LIS (0.03-10 mg/kg i.p.) stimulated DA biosynthesis and DOPAC formation in the striatum and DA rich limbic system of rats, but had no effect on serotonin turnover. In striatum and limbic forebrain of gamma-butyrolactone-pretreated rats 2-Br-LIS reversed the apomorphine-induced inhibition of DOPA accumulation. 2-Br-LIS (0.03 - 3 mg/kg) enhanced PRL secretion in intact male rats. These findings indicate DA antagonistic properties of 2-Br-LIS presumably due to blockade of central pre- and postsynaptic DA receptors being of approximately the same order of potency as haloperidol. 2-Br-LIS is the first ergot compound with definite antidopaminergic properties suggesting its potential usefulness as a neuroleptic.     

Higher environmental temperature-induced increase in body temperature: Involvement of serotonin in GABA mediated interaction of opioidergic system

Exposure (2 h) of adult male albino rats to higher environmental temperature (HET, 40°C) significantly increased body temperature (BT). Administration of (a) 5-HTP (5 mg/kg, i.p.) or morphine (1 mg/kg, i.p.) or physostigmine (0.2 mg/kg, i.p.) alone significantly increased and (b) methysergide (1 mg/kg, i.p.) or naloxone (1 mg/kg, i.p.) or atropine (5 mg/kg, i.p.) reduced the BT of both normal and HET exposed rats. Further, it was observed that morphine prevented the methysergide-induced hypothermia and 5-HTP potentiated the morphine-induced hyperthermia in both normal and HET exposed conditions. Biochemical study also indicates that serotonin metabolism was increased but GABA utilization was reduced following exposure to HET. 5-HTP or bicuculline-induced hyperthermia in control and HET exposed rat was potentiated with the coadministration of bicuculline and 5-HTP. The cotreatment of bicuculline with methysergide prevented the methysergide-induced attenuation of BT of heat exposed rat, rather BT was significantly enhanced indicating that inhibition of GABA system under heat exposed condition may activate the serotonergic activity. Further (a) enhancement of (i) morphine-induced hyperthermia with physostigmine (ii) physostigmine- or morphine + physostigmine-induced increase of BT with 5-HTP and (b) reduction of (i) morphine- or morphine + 5-HTP-induced hyperthermia with atropine and (ii) atropine-induced hypothermia with 5-HTP in both normal and HET exposed conditions suggest that HET exposure activates the cholinergic system through the activation of opioidergic and serotonergic system and hence increased the BT. Thus, it may be concluded that there is an involvement of serotonergic regulation in the opioidergic-cholinergic interaction via GABA system in HET-induced increase in BT.     

L-prolyl-l-leucyl-glycinamide and its peptidomimetic analog 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) attenuate haloperidol-induced c-fos expression in the striatum

Acute treatment of rats with haloperidol results in a rapid and transient increase in striatal c-fos mRNA and Fos immunoreactivity. The induction of immediate early genes by haloperidol may be involved in the development of extrapyramidal side effects. L-Prolyl-L-leucyl-glycinamide (PLG, or MIF-1) has been observed to antagonize the development of haloperidol-induced D(2) receptor supersensitivity in rats. We investigated the modulatory effects of PLG on haloperidol-induced c-fos and Fos protein expression in the rat striatum. We report that coadministration of either PLG or the potent analog of PLG, 3(R)-[(2(S)-pyrrolidylcarbonyl)amino]-2-oxo-1-pyrrolidineacetam ide (PAOPA), attenuated haloperidol-induced c-fos and Fos expression. Haloperidol induced [2 mg/kg, intraperitoneally (i.p.)] c-fos and Fos expression by 500% and 100%, respectively. These responses were attenuated by 170% and 75%, respectively, when coadministered with PLG (20 mg/kg, i.p.) or by 79% by PAOPA (10 microg/kg, i.p.).     

Effects of cholecystokinin tetrapeptide (CCK(4)) and of anxiolytic drugs on GABA outflow from the cerebral cortex of freely moving rats

The effect of cholecystokinin tetrapeptide (CCK(4)) and of different anxiolytic drugs on GABA outflow from the cerebral cortex was investigated in freely moving rats, by using the epidural cup technique. CCK(4) (3-30 microg/kg, i.p.) increased GABA outflow and induced objective signs of anxiety. These neurochemical and behavioral responses were prevented by the CCK(B) antagonist GV150013 at 0.1 microg/kg (i.p.). At higher doses (up to 30 microg/kg) this compound per se reduced GABA release and caused sedation, suggesting the presence of a CCKergic positive tonic modulation on GABA interneurons. Similarly the GABA(A) receptors modulator, diazepam (2mg/kg, i.p.) and the 5-HT(1A) agonist buspirone (3mg/kg, i.p.) reduced GABA outflow and caused the expected behavioral effects (reduced muscle tone, mild 5-HT syndrome) which were prevented by the respective, selective antagonists, flumazenil (1mg/kg, i.p.) and NAN-190 (3mg/kg, i.p.). These findings support the idea that GV150013, diazepam and buspirone inhibit GABAergic cortical activity, through the respective receptors. This neurochemical effect may represent the end-effect of various anxiolytic compounds affecting the cortical circuitry.     

Effects of atypical antidepressants on LSD potentiated apomorphine hypermotility in rats

The model of LSD potentiated apomorphine hypermotility [5] was used to classify different atypical antidepressants (danitracen, mianserin, cyproheptadine) and pizotifen. All drugs have been shown to inhibit specifically the locomotor activity potentiating effect of LSD in a low dosage range (0.1-0.5 mg/kg i. p.) without influencing the apomorphine effect. Since there is some evidence that the effect of LSD is due to the inhibition of the activity of serotonergic raphe neurons, the marked antagonizing effects of danitracen, mainserin, cyproheptadine and pizotifen are regarded to be an expression of pronounced antiserotonin activity.     

The role of putative 5-HT1A and 5-HT1B receptors in the control of feeding in rats

8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) and 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H indole succinate (RU 24969), two agonists on the putative serotonin 1A and serotonin 1B receptors, were used for exploring the role of these sites in the inhibitory effect of serotonin (5-HT) on feeding. In free-feeding rats, 2.5-5 mg/kg RU 24969 significantly reduced food intake while doses of 8-OH-DPAT ranging from 0.125 to 0.5 mg/kg increased eating. The effects of the highest doses were associated with hyperlocomotion and hyperreactivity for RU 24969 and a typical motor syndrome (flat body posture and forepaw treading) for 8-OH-DPAT. The motor syndrome caused by 0.5 mg/kg 8-OH-DPAT was much more obvious in food-deprived rats in which food intake was also markedly reduced. RU 24969 1.25 and 5 mg/kg reduced food intake by food-deprived rats and caused hyperlocomotion not different from that in free-feeding animals. Pretreatment with metergoline (2 mg/kg i.p.) prevented the effect of 5 mg/kg RU 24969 on food intake by food-deprived rats but had no effect on the reduction of eating caused by 0.5 mg/kg 8-OH-DPAT. The motor syndrome caused by 8-OH-DPAT was not changed by metergoline but the hyperlocomotion caused by RU 24969 was potentiated. Haloperidol (0.1 mg/kg i.p.) completely blocked the hyperlocomotion but did not change the reduction of food intake caused by RU 24969 in food-deprived rats. It is suggested that the putative serotonin 1B receptors specifically mediate the inhibitory effect of 5-HT on feeding whereas serotonin 1A sites act by enhancing eating only in free-feeding animals.     

Influence of cholinergic and adrenergic blocking drugs on hyperglycemia and brain glycogenolysis in diazinon-treated animals

Diazinon, an organophosphorous compound, produced hyperglycemia and reduced the glycogen content of the brain 2 h after its administration to rats (40 mg/kg, i.p.). The activities of the glycogenolytic enzymes, glycogen phosphorylase and phosphoglucomutase, were significantly increased, while that of glucose-6-phosphatase was not altered. Atropine (20 mg/kg, i.p.) given immediately after diazinon abolished the changes; tolazoline or propranolol (each at 10 mg/kg, i.p.) injected 30 min before the administration of diazinon significantly reduced the hyperglycemia and the increase in brain glycogenolysis. A combination of tolazoline and propranolol was more effective than either of them alone and completely abolished the hyperglycemia and the changes in brain glycogenolysis. It may be concluded that diazinon initially activates central cholinergic processes leading to hyperglycemia and increased cerebral glycogenolysis in animals.     

Regionally and functionally distinct serotonin3 receptors control in vivo dopamine outflow in the rat nucleus accumbens

Central serotonin(3) (5-HT(3)) receptors control the mesoaccumbens dopamine (DA) pathway. This control is thought to be conditional and might involve regionally distinct subpopulations of 5-HT(3) receptors. Here, using in vivo microdialysis in rats, we assessed the relative contribution of nucleus accumbens (Nacc) 5-HT(3) receptors to the overall influence exerted by 5-HT(3) receptors on accumbal DA release induced by different drugs or treatments. In freely moving rats, pre-treatment with 5-HT(3) antagonists (0.1 mg/kg ondansetron and/or 0.03 mg/kg MDL 72222, s.c.) reduced DA efflux enhanced by morphine (1-10 mg/kg, s.c.) and haloperidol (0.01 mg/kg, s.c.), but not amphetamine (1-2.5 mg/kg, i.p.) or cocaine (10-20 mg/kg, i.p.), the latter two drugs do not trigger depolarization-stimulated DA exocytosis. Intra-Nacc administration of ondansetron (1 microm) in freely moving rats reduced the DA effects elicited by 10 mg/kg morphine, but not 1 mg/kg morphine or haloperidol. The 5-HT(1A) agonist 8-OH-DPAT (0.1 mg/kg, s.c.), known to decrease central 5-HT tone, reduced 10 but not 1 mg/kg morphine-stimulated DA outflow in freely moving rats. In halothane-anaesthetized rats, intra-Nacc ondansetron (1 microm) application reduced dorsal raphe nucleus electrical stimulation (20Hz)-induced DA outflow. Our results show that regionally distinct populations of 5-HT(3) receptors control the depolarization-dependent exocytosis of DA and suggest that the involvement of Nacc 5-HT(3) receptors occurs only when central DA and 5-HT tones are concomitantly increased.     

Effect of chronic neuroleptic or L-DOPA administration on GABA levels in the rat substantia nigra

Male albino rats were administered daily with haloperidol, clozapine or L-DOPA and sacrificed 18 hours after the last dose of the drug. Acutely haloperidol (5mg/kg, i.p.) greatly lowered nigral GABA levels whereas after 167 daily doses the nigral GABA levels were not significantly different from controls, but were significantly increased as compared with the acutely treated animals. In contrast, acute L-DOPA (2 × 100mg, p.o.) greatly raised nigral GABA levels whereas after chronic L-DOPA (167 days) nigral GABA levels were not significantly different from controls and were significantly lower as compared with the animals receiving the acute treatment. Clozapine (20 mg/kg, i.p. either acutely or chronically) did not have as marked an effect on nigral GABA levels as did haloperidol. Of these various drug regimens only chronic L-DOPA significantly affected nigral GAD activity, producing a moderate decrease.     

Effect of piperine,the active ingredient of black pepper,on intestinal secretion in mice

We have investigated the effect piperine on castor oil-stimulated fluid accumulation in the mouse small intestine. Piperine (2.5-20 mg/kg, i.p.) dose-dependently reduced castor oil-induced intestinal fluid accumulation. The inhibitory effect of piperine (10 mg/kg i.p.) was strongly attenuated in capsaicin (75 mg/kg in total, s.c.)-treated mice but it was not modified by the vanilloid receptor antagonist capsazepine (30 mg/kg i.p.). Pretreatment of mice with hexamethonium (1 mg/kg i.p.), naloxone (2 mg/kg i.p.), yohimbine (1 mg/kg i.p.) or the cannabinoid CB(1) receptor antagonist SR141716A (0.3 mg/kg i.p.) did not modify the inhibitory effect of piperine (10 mg/kg i.p.). These results suggest that piperine reduces castor oil-induced fluid secretion with a mechanism involving capsaicin-sensitive neurons, but not capsazepine-sensitive vanilloid receptors.     

The non-benzodiazepine anxiolytic buspirone inhibits stress-induced renin secretion and lowers heart rate

The non benzodiazepine drug, buspirone, produces a dose-dependent biphasic effect on plasma renin activity in non-stressed rats. Low doses (0.1 - 2.0 mg/kg i.p.) decrease while high doses (10.0 - 50.0 mg/kg i.p.) increase plasma renin activity. The maximal decrease in plasma renin activity produced by buspirone (1.0 mg/kg i.p.) was observed 30 minutes post-injection. In addition, buspirone (0.5 and 2.0 mg/kg i.p.) blocked the stress-induced rise in plasma renin activity. This effect of buspirone is in contrast to the previously observed failure of the benzodiazepine anxiolytics to alter the effect of stress on plasma renin activity. Administration of buspirone (0.5 mg/kg i.p.) produced a sustained reduction (15%) in heart rate but did not affect mean arterial pressure. The present data support the view that the mechanism of the anxiolytic action of buspirone is different from that of the benzodiazepines.     

Effects of clozapine on the efflux of serotonin and dopamine in the rat brain: the role of 5-HT1A receptors

In vivo microdialysis in conscious rats was used to examine the effect of clozapine on serotonin (5-hydroxytryptamine, 5-HT) efflux in the prefrontal cortex and dorsal raphe nucleus and dopamine efflux in the prefrontal cortex. Both systemic and local administration of clozapine (systemic, 10 or 20 mg/kg, i.p.; local, 100 microM) increased 5-HT efflux in the dorsal raphe. However, in the prefrontal cortex, dialysate 5-HT increased when clozapine (100 microM) was administered through the probe, while no effect was observed when it was administered systemically. By pretreatment with the selective 5-HT1A receptor antagonist p-MPPI (3 mg/kg, i.p.), systemic treatment of clozapine (10 mg/kg, i.p.) significantly increased 5-HT efflux in the prefrontal cortex. This result suggests that the ability of clozapine to enhance the extracellular concentrations of 5-HT in the dorsal raphe attenuates this drug's effect in the frontal cortex, probably through the stimulation of 5-HT1A somatodendritic autoreceptors in the dorsal raphe. We also found that pretreatment with p-MPPI (3 mg/kg, i.p.) attenuated by 45% the rise in cortical dopamine levels induced by clozapine (10 mg/kg, i.p.). These findings imply that the reduction in serotonergic input from the dorsal raphe nucleus induced by clozapine could lead to an increase in dopamine release in the prefrontal cortex.