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.     

Is GABA Involved in the Development of Caffeine Tolerance?

Caffeine (10 or 20 mg/kg per day, po)-induced stimulation of locomotor activity (LA) reached its peak following 4 consecutive days of caffeine administration. Caffeine-induced stimulation of LA was restored to the control values following caffeine tolerance after 16 or 12 consecutive days of caffeine treatment at a dose of 10 or 20 mg/kg per day, po. Biochemical studies showed that caffeine in the nontolerant condition reduced GABAergic activity in cerebral cortex, corpus striaturn, cerebellum, hypothalamus and pons-medulla; but tolerance to caffeine (10 or 20 mg/kg per day, po) pushed up the GABAergic activity to the control value in all these regions of brain. Further, it was found that muscimol reduced the LA while bicuculline stimulated LA in the caffeine tolerant condition. Thus, from the present study it may be concluded that: (a) caffeine-induced stimulation of LA is dependent on dose and duration of caffeine treatment, (b) development of tolerance to caffeine is dependent on the dosage of caffeine, and (c) the reduction of central GABAergic activity in the caffeine-nontolerant condition pushed up and restored the LA to the control level on the development of tolerance to caffeine.     

Antinociceptive effect of sumatriptan in mice.

Antinociceptive effect of the antimigraine drug sumatriptan (5-HT1A agonist) was studied against acetic acid-induced writhing in mice. Sumatriptan produced the effect in a dose-dependent manner (1, 5, 10 and 20 mg/kg, s.c.). Naloxone (1 mg/kg i.p.) an opiate antagonist failed to reverse sumatriptan-induced antinociception. Cholinomimetic physostigmine (0.05 mg/kg, i.p.) potentiated and the muscarinic antagonist atropine (5 mg/kg, i.p.) blocked the antinociceptive effect of sumatriptan, respectively. The antinociceptive effect of sumatriptan was compared with an another 5-HT agonist (5-HT1A) buspirone which also produced antinociception. Like sumatriptan-analgesia, the buspirone response was also potentiated by physostigmine in atropine sensitive way. Further, buspirone potentiated the analgesic effect of sumatriptan. These observations suggest that 5-HT1A agonists produce antinociception possibly by modulating central cholinergic activity.     

Role of nitric oxide in obsessive–compulsive behavior and its involvement in the anti-compulsive effect of paroxetine in mice

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive–compulsive disorder, patients with obsessive–compulsive disorder exhibit higher plasma nitrate levels, and drugs useful in obsessive–compulsive disorder influence nitric oxide, we hypothesized that nitric oxide may have some role in obsessive–compulsive behavior. We used marble-burying behavior of mice as the animal model of obsessive–compulsive disorder, and nitric oxide levels in brain homogenate were measured using amperometric nitric oxide-selective sensor method. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor—l-arginine (800 mg/kg), nitric oxide donor—sodium nitroprusside (3 mg/kg) or phosphodiesterase type 5 inhibitor—sildenafil (3 mg/kg) significantly increased marble-burying behavior as well as brain nitrites levels, whereas treatment with 7-nitroindazole—neuronal nitric oxide synthase inhibitor (20–40 mg/kg, i.p.) or paroxetine—selective serotonin reuptake inhibitor (5–10 mg/kg, i.p.) dose dependently attenuated marble-burying behavior and nitrites levels in brain. Further, co-administration of sub-effective doses of 7-nitroindazole (10 mg/kg) and paroxetine (2.5 mg/kg) significantly attenuated marble-burying behavior. Moreover, pretreatment with l-arginine (400 mg/kg, i.p.), sodium nitroprusside (2.0 mg/kg, i.p.) or sildenafil (2.0 mg/kg, i.p.) significantly attenuated the inhibitory influence of 7-nitroindazole (40 mg/kg) or paroxetine (10 mg/kg) on marble-burying behavior as well as on brain nitrites levels. None of the above treatment had any significant influence on locomotor activity. In conclusion, obsessive compulsive behavior in mice appears related to nitric oxide in brain, and anti-compulsive effect of paroxetine appears to be related to decrease central levels of nitric oxide.     

Effect of oxotremorine,physostigmine, and scopolamine on brain acetylcholine synthesis: A study using HPLC

The synthesis rate of brain acetylcholine (ACh) was estimated in mice following i.v. administration of [³H]choline (Ch). The measurements were performed 1 min after the tracer injection, using the [³H]ACh/[³H]Ch specific radioactivity ratio as an index of ACh synthesis rate. Endogenous and labeled Ch and ACh were quantified using HPLC methodology. Oxotremorine and physostigmine (0.5 mg/kg, i.p.) increased the steady state concentration of brain ACh by +130% and 84%, respectively and of Ch by +60% (oxotremorine); they decreased ACh synthesis by 62 and 55%, respectively. By contrast, scopolamine (0.7 mg/kg, i.p.) decreased the cerebral content of Ch by –26% and of ACh by –23% without enhancing the synthesis of ACh. The results show the utility of HPLC methodology in the investigation of ACh turnover.     

Effects of Catechol-O-Methyltransferase Inhibitors and L-3,4-Dihydroxyphenylalanine With or Without Carbidopa on Extracellular Dopamine in Rat Striatum

Abstract: The effects of two new catechol- O -methyltransferase (COMT) inhibitors, OR-611 and Ro 40-7592, in combination with L-3,4-dihydroxyphenylalanine (L-dopa) with or without carbidopa on extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3- O -methyldopa (3-OMD), and 5-hydroxyindoleacetic acid in rat striatum were studied. A dose of 10 mg/kg i.p. of Ro 40-7592 alone, in contrast to the same dose of OR-611, decreased the dialysate level of HVA and increased that of DOPAC; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. L-Dopa (50 mg/kg i.p.) alone slightly increased extracellular levels of DA, DOPAC, and HVA. The effects of L-dopa were potentiated by carbidopa (50 mg/kg i.p.), and even 3-OMD levels in dialysate samples became detectable. Both OR-611 and Ro 40-7592 significantly further increased the DA and DOPAC efflux from striatum produced by L-dopa. This increase was more pronounced when carbidopa was added to the treatment. OR-611 did not modify the effect of L-dopa or carbidopa/L-dopa on dialysate HVA levels, whereas Ro 40-7592 markedly reduced those levels. Both OR-611 and Ro 40-7592 very clearly suppressed dialysate 3-OMD levels produced by carbidopa/L-dopa. Ro 40-7592 was more effective than OR-611 in potentiating the effects of L-dopa or carbidopa/L-dopa. These in vivo data show that the new COMT inhibitors markedly inhibit the O -methylation of L-dopa and increase its availability to brain, which is reflected as increased DA formation. A significant effect can be achieved even by inhibiting only the peripheral COMT activity. The data suggest that COMT inhibitors may be of clinical importance as adjuncts in the treatment of Parkinson's disease.     

Effect of pentylenetetrazol on the carbaryl-induced changes of serotonin metabolism in rat-brain hypothalamus

Carbaryl (200 mg/kg or 400 mg/kg, p.o.) significantly elevated serotonin (5-HT) (57–109%) and 5-hydroxy-indoleacetic acid (5-HIAA) (60–78%) levels at 1.0 h in the hypothalamic region of adult male rat brain. Further, administration of carbaryl (200 mg/kg, p.o.) for different time intervals (0.5 h, 1.0 h, and 2.0 h) revealed that both 5-HT and 5-HIAA levels elevated maximally at 0.5 h in hypothalamus. These regional 5-HT and 5-HIAA levels were not significantly affected with pentylenetetrazol (PTZ) at any time after its treatment. But simultaneous administration of carbaryl (200 mg/kg, p.o.) and PTZ (60 mg/kg, s.c.) reduced the carbaryl-induced elevation of both 5-HT and 5-HIAA leveis. Measurement of (i) probenecid-induced (200 mg/kg, i.p.) accumulation and (ii) pargyline-induced (75 mg/kg, i.p.) depletion of hypothalamic 5-HIAA level in the absence or presence of carbaryl (200 mg/kg, p.o.) and/or PTZ (60 mg/kg, s.c.) revealed that (a) carbaryl enhanced the synthesis as well as the breakdown of 5-HT, (b) PTZ had no effect on either of these processes of 5-HT, and (c) carbaryl-induced increased catabolism of 5-HT became normal in the presence of PTZ.     

Lipoic Acid Alters δ-Aminolevulinic Dehydratase,Glutathione Peroxidase and Na+,K+-ATPase Activities and Glutathione-Reduced Levels in Rat Hippocampus After Pilocarpine-Induced Seizures

In the present study, we investigated the effects of lipoic acid (LA) in the brain oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (10 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (10 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before the administration of LA (LA plus pilocarpine group). After the treatments, all groups were observed for 1 h. The enzyme activities [δ-aminolevulinic dehydratase (δ-ALA-D), glutathione peroxidase (GPx), glutathione reductase (GR), and Na+,K+-ATPase] as well as the glutathione-reduced (GSH) and ascorbic acid (AA) concentrations were measured using spectrophotometric methods, and the results were compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA were also evaluated on the same parameters. In pilocarpine group, no changes were observed in GPx and GR activities and AA content. Moreover, in the same group, decrease in GSH levels as well as a reduction in δ-ALA-D and Na+,K+-ATPase activities after seizures was observed. In turn, in LA plus pilocarpine group, the appearance of seizures was abolished, and the decreases in δ-ALA-D and Na+,K+-ATPase activities produced by seizures as well as increases in GSH levels and GPx activity were reversed, when compared to the pilocarpine seizing group. The results of the present study demonstrated that preadministration of LA abolished seizure episodes induced by pilocarpine in rat, probably by reducing oxidative stress in rat hippocampus caused by seizures.     

Lipoic Acid Increases Hippocampal Choline Acetyltransferase and Acetylcholinesterase Activities and Improvement Memory in Epileptic Rats

In the present study we investigated the effect of seizures on rat performance in the Morris water maze task, as well as on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in rat hippocampus. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (20 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (20 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of LA (LA plus pilocarpine group). After the treatments all groups were observed for 1 h. The effect of lipoic acid administration was observed on reference and working spatial memory of seized rats. The ChAT and AChE activities were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Its activity was also determined after behavioral task. Results showed that pretreatment with lipoic acid did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant day’s effect with significant differences between control and pilocarpine-induced seizures and pretreated animals with lipoic acid. In LA plus pilocarpine group was observed a significantly increased in ChAT and AChE activities, when compared to pilocarpine group. Results showed that acute administration of lipoic acid alone did not alter hippocampal ChAT and AChE activities. Our findings suggest that seizures caused cognitive dysfunction and a decrease of ChAT and AChE activities that might be related, at least in part, to the neurological problems presented by epileptic patients. Lipoic acid can reverse cognitive dysfunction observed in seized rats as well as increase the ChAT and AChE activities in hippocampus of rats prior to pilocarpine-induced seizures, suggesting that this antioxidant could be used in clinic treatment of epilepsy.     

Subchronic-intermittent caffeine amplifies the motor effects of amphetamine in rats

Summary. Caffeine, the most widely consumed psychostimulant drug, acutely stimulates motor behaviour and enhances dopamine agonists actions whilst chronically it induces tolerance to either caffeine- or dopamine agonist-induced motor activating effects. The present study examined whether subchronic caffeine administration (15 mg/kg, on alternate days for 14 days) induces enduring modifications in caffeine- and amphetamine-mediated motor activity. To this end, motor activation and rotational behaviour stimulated by either caffeine or D-amphetamine (0.5, 2 mg/kg), given 3 days after the last caffeine administration, were evaluated in neurologically intact and unilaterally 6-hydroxydopamine-lesioned rats respectively. Subchronic caffeine resulted in an increase in caffeine-induced motor and turning behaviour. Furthermore, caffeine pretreatment potentiated the motor effects of amphetamine in both intact and 6-hydroxydopamine-lesioned rats. These results suggest that subchronic caffeine treatment results in an enhancement of its motor stimulant effects, rather than in tolerance, and induces neuroadaptive facilitatory changes in dopamine transmission.     

Dual action on central dopamine function of transdihydrolisuride,a 9, 10-dihydrogenated analogue of the ergot dopamine agonist lisuride

Transdihydrolisuride (TDHL), a 9, 10-dihydrogenated analogue of the ergot dopamine (DA) agonist lisuride (LIS), was investigated for its influence on central dopaminergic functions in rats and mice after single i.p. administration. TDHL (0.39–25 mg/kg) unexpectedly induced catalepsy and antagonized apomorphine-induced stereotypes in rats; it was approx. 3–5 times less potent than the DA antagonist haloperidol. TDHL (0.025–6.25 mg/kg) caused hypokinesia and antagonized the apomorphine-induced hyperactivity in rats. Pre-treatment with TDHL (0.78–12.5 mg/kg) which per se did not alter thermoregulation at room temperature, antagonized the hypothermia induced by the DA agonist apomorphine (5 mg/kg i.p.) in mice. These DA antagonistic properties contrasted with the prolactin (PRL) lowering effect of TDHL (0.01–10 mg/kg p.o.) in reserpinized female rats thus indicating DA agonist function. PRL inhibition tended to be longer lasting (>8h) than after LIS (0.01–1 mg/kg p.o.) with comparable potency. In healthy volunteers TDHL (0.2–1 mg p.o.) effectively lowered PRL levels with similar potency but with a markedly longer duration of action than LIS (>24h after 0.5 mg TDHL). In contrast to the side effects after acute LIS treatment, no comparable adverse reactions such as nausea, emesis or postural hypotension typical for DA agonists could be observed with effective PRL lowering doses of TDHL. The unique profile of TDHL on DA functions suggests its usefulness as a potent, longlasting PRL inhibitor with less unwanted effects. The behavioural findings indicate the potential usefulness of TDHL as a neuroleptic, which due to its partial DA agonistic action, should lack typical extrapyramidal or neuroendocrine side effects of classic DA receptor blocking agents. Possible implications of the dual function of TDHL upon central DA receptors are discussed with regard to the incidence of side effects or selectivity of action for other conceivable therapeutic indications.     

Effects of serotonin depletion byp-chlorophenylalanine,p-chloroamphetamine or 5,7-dihydroxytryptamine on central dopaminergic neurons: Focus on tuberoinfundibular dopaminergic neurons and serum prolactin

Three serotonin (5-HT) neurotoxins,p-chlorophenylalanine (PCPA, 125 and 250 mg/kg, i.p.),p-chloroamphetamine (PCA, 10 mg/kg, i.p.) and 5,7-dihydroxytryptamine (5,7-DHT, 200 µg/rat, i.c.v.) were used to examine whether depletion of central 5-HT has an effect on central dopaminergic (DA) neuronal activities or on prolactin (PRL) secretion. Adult ovariectomized Sprague-Dawley rats primed with estrogen (polyestradiol phosphate, 0.1 mg/rat, s.c.) were treated with one of three neurotoxins and then decapitated in the morning after 3–7 days. Blood sample and brain tissues were collected. The acute effect of PCA (from 30 to 180 min) was also determined. The concentrations of 5-HT, DA and their metabolites, 5-hydroxyindoleacetic acid and 3,4-dihydroxyphenylacetic acid, in the median eminence, striatum and nucleus accumbens were determined by HPLC-electrochemical detection. All three toxins significantly depleted central 5-HT stores by 11–20%. Except for PCPA, neither PCA nor 5,7-DHT had any significant effect on basal DA neuronal activities or PRL secretion. PCA also exhibited an acute effect on the release and reuptake of 5-HT and DA. In summary, depletion of central 5-HT stores to a significant extent for 3–7 days did not seem to affect basal DA neuronal activity and PRL secretion.     

Effects of some putative amino acid neurotransmitters on the stimulated TSH secretion in male rats

The importance of several amino acids (glycine, L-glutamic acid, L-serine, taurine and beta-alanine) in the regulation of the stimulated secretion of TSH was studied in male rats using both peripheral and central administration of the amino acids. Glycine (10-200 mg/kg i.p.), L-glutamic acid (10-500 mg/kg i.p.) and L-serine (500 mg/kg i.p.) decreased significantly the cold-induced TSH secretion whereas beta-alanine (1-500 mg/kg i.p.) and taurine (10-100 mg/kg i.p.) were not effective. The effect of L-glutamic acid (100 mg i.p.) was partially antagonized by bicuculline (1 mg/kg i.p.) but not by picrotoxin (1 or 2 mg/kg i.p.). Only glycine (50 and 100 mg/kg i.p.) inhibited the TRH-stimulated TSH secretion. When the intracerebroventricular route was used, L-serine (50 micrograms/rat) decreased the TSH could response whereas glycine and L-glutamic acid (1-50 micrograms/rat) had no clear effect. We conclude that glycine, glutamate and serine inhibit the cold-induced TSH secretion in the male rat. The action of serine and glycine is possibly mediated through the periventricular hypothalamus and the anterior pituitary, respectively. The inhibition caused by glutamate seems to be partially mediated through the bicuculline-sensitive GABA receptors in the hypothalamus. Taurine and beta-alanine play no role in the control of rat TSH secretion.     

Complete,reversible, drug-specific tolerance to stimulation of locomotor activity by caffeine

The development of tolerance to caffeine-induced stimulation of locomotor activity was evaluated in rats maintained chronically on average daily doses of 160 mg/kg or more of caffeine by the method of scheduled access to drinking water containing the drug. Dose-response curves were determined for caffeine (6.25–100 mg/kg) and $\text{d}$-amphetamine (0.39–6.4 mg/kg) during chronic drug treatment. In addition, the caffeine curve was redetermined 2–3 weeks after removal of the drug from the drinking water. A control group that had scheduled access to drug-free tap water was also tested. Caffeine produced dose-related increases in the locomotor activity of the controls but failed to modify locomotor activity of the chronic caffeine group. In contrast, $\text{d}$-amphetamine increased locomotor activity of both groups comparably. Spontaneous locomotor of the chronic caffeine group was reduced significantly for 4 days after drug-free tap water was substituted for the caffeine solution. The return of spontaneous locomotor activity to baseline values was associated with restored sensitivity to caffeine-induced stimulation of locomotor activity. Thus, chronic administration of caffeine to rats results in the development of tolerance to caffeine-induced stimulation of locomotor activity that is virtually complete, pharmacologically specific, and fully reversible when drug treatment is stopped. Decreases in spontaneous locomotor activity after abrupt termination of chronic caffeine administration follow a time course consistent with a drug withdrawal syndrome.     

Anxiolytic-like effect of neuropeptide S in the rat defensive burying

Neuropeptide S (NPS) has been recently identified as the endogenous ligand of a previously orphan G-protein-coupled receptor now named NPSR. Both NPS and its receptor are expressed in the brain, where they modulate different functions. In particular, it has been demonstrated that intracerebroventricular (i.c.v.) injection of NPS in rodents increases wakefulness and promotes anxiolytic-like effects. In the present study we used the defensive burying (DB) test in rats to further investigate the action of human NPS (0.1–10 nmol, i.c.v.) on anxiety-related behaviors. Diazepam (1.5 mg/kg, i.p.) and caffeine (20 mg/kg, i.p.) were used in parallel experiments as standard anxiolytic and anxiogenic drugs, respectively. None of the tested drugs produced statistical differences in the latency to contact the probe, burying behavior latency, number of shocks received or immobility/freezing duration. Caffeine increased cumulative burying behavior and the buried bedding height in a statistically significant manner thus promoting anxiogenic like effects. Opposite results were obtained with diazepam that significantly reduced these behavioral parameters. The anxiolytic-like action of diazepam was mimicked by NPS that reduced cumulative burying behavior in a dose dependent manner. Collectively, robust anxiolytic-like effects were recorded in response to NPS in the DB test. These results are of particular interest since the outcome of this assay is marginally influenced by drug effects on locomotor activity. In conclusion, we provide further evidence that NPS evokes genuine anxiolytic-like effects in the rat; therefore NPSR selective agonists are worthy of development as innovative drugs for the treatment of anxiety disorders.     

A physiological analysis of dissociative learning against a background of physostigmine and pentobarbital

Physostigmine (0.7-0.8 mg/kg, i.p.) decreased and pentobarbital (13.4-14.6 mg/kg) increased the locomotor and emotional activity of rats in the "open field". Both drugs induced the reversible amnesia to a conditioned reaction in a double T-maze with positive (nutritional) reinforcement. These changes in behavioral activity were correlated with dissociated learning of rats after the injection of the drugs: physostigmine largely decreased the number of errors during learning as compared with pentobarbital. However, in both cases rats reached the learning criterion sooner than the control animals due to the shorter reaction latency (physostigmine) and increase in general motor activity (pentobarbital).     

Action of GABA-B antagonist on cortical epileptic afterdischarges in rats is similar to that of GABA-A antagonist

Threshold intensities for epileptic phenomena induced by cortical stimulation were used for comparison of the action of GABA-B and GABA-A antagonists in rats with implanted electrodes. Both CGP 35348 (200 mg/kg i.p.) and bicuculline (4 mg/kg i.p.) significantly decreased thresholds for spike-and-wave afterdischarges and their motor counterpart (clonic seizures) whilst transition into the second, limbic type of afterdischarge as well as threshold for movements directly bound to stimulation remained uninfluenced by either drug.     

Increased antidepressant-like effect of desipramine combined with central stimulants (caffeine and amphetamine) in mice

Desipramine is a widely used antidepressive agent that inhibits the reuptake of noradrenaline and serotonin, and central stimulants such as caffeine and amphetamine help to release noradrenaline and serotonin. This work aimed to evaluate whether the combination of these agents could produce a stronger antidepressant-like effect than either of the drugs alone. To this end, male mice were treated with different doses of desipramine, caffeine, amphetamine, desipramine-caffeine and desipramine-amphetamine. The results showed that all drugs produced decreased immobility time in the forced swimming model. The combined treatment of desipramine (0.31, 1.0 or 3.1 mg/kg i.p.) with caffeine or amphetamine (0.31 or 1 mg/kg i.p.) reduced immobility time greater than either of those drugs alone. The combined treatment of desipramine (0.31, 1 and 3.1 mg/kg i.p.) with amphetamine or caffeine (0.1 and 1 mg/kg i.p.) did not increase the motor activity significantly compared to the control. These results also suggested that drugs which promote the release of noradrenaline and serotonin could increase antidepressant-like effect of desipramine.     

Bremazocine induces antinociception, but prevents opioid-induced constipation and catatonia in rats and precipitates withdrawal in morphine-dependent rats

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.     

Caffeine and accumbens shell dopamine

It has been reported that caffeine (1.5-30 mg/kg i.p.) as well as specific A1 (DPCPX, 8-cyclopentyl-1,3-dipropylxanthine) receptor antagonists fail to increase extracellular dopamine (DA) in the shell of the nucleus accumbens (NAc). However, it has also been reported that caffeine (10 and 30 mg/kg i.p.) and the A1 antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) increases NAc shell DA. To clarify this issue rats were implanted with microdialysis probes at different sites in the NAc shell, in the medial prefrontal cortex (PFCX, infralimbic cortex), and at the border between those areas. Irrespective of probe placement within the NAc shell and of the use of different surgical anesthetics (chloral hydrate and ketamine), we failed to observe changes in dialysate DA after 10 and 30 mg/kg i.p. of caffeine. Similarly negative results were obtained with DPCPX and CPFPX, two potent and selective A1 receptor antagonists. A significant increase of DA was obtained after caffeine when probes were located at the border between the NAc shell and the PFCX (10 and 30 mg/kg) or in the PFCX (10 mg/kg). In view of this and of our previous report that caffeine increases dialysate DA in the medial PFCX, we conclude that the increase in dialysate DA by caffeine observed by others arises from the medial PFCX rather than from the NAc shell as a result of placement of microdialysis probes at the border between the NAc shell and the PFCX.