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In order to verify whether striatal group I metabotropic glutamate (mGlu) receptors undergo functional alteration in ageing, the effects induced by the selective agonist 3,5-dihydroxyphenylglycine (DHPG) in the striatum of young (3 months) and aged (24-25 months old) rats were compared. The ability of DHPG to stimulate phosphoinositide (PI) hydrolysis (striatal slices), to influence striatal dopamine release (in vivo microdialysis) and to potentiate the effects of NMDA on extracellular field potential amplitude (extracellular recordings on striatal slices) was reduced in the striatum of old vs young rats. These results show an age-dependent reduction in the functional response of striatal group I mGlu receptors, which may be one of the factors underlying the reduced ability aged striatum to integrate information.

Adenosine A1 receptors antagonistically and specifically modulate the binding and functional characteristics of dopamine D1 receptors. In the striatum this interaction seems to take place in the GABAergic strionigro-strioentopeduncular neurons, where both receptors are colocalized. D1 receptors in the strionigro-strioentopeduncular neurons are involved in the increased striatal expression of immediate-early genes induced by the systemic administration of psychostimulants and D1 receptor agonists. Previous results suggest that a basal expression of the immediate-early gene c-fos tonically facilitates the functioning of strionigro-strioentopeduncular neurons and facilitates D1 receptor-mediated motor activation. The role of A1 receptors in the modulation of the expression of striatal D1 receptor-regulated immediate-early genes and the D1 receptor-mediated motor activation was investigated in rats with a unilateral lesion of the ascending dopaminergic pathways. The systemic administration of the A1 agonist N6-cyclopentyladenosine (CPA, 0.1 mg/kg) significantly decreased the number of contralateral turns induced by the D1 agonist SKF 38393 (3 mg/kg). Higher doses of CPA (0.5 mg/kg) were necessary to inhibit the turning behaviour induced by the D2 agonist quinpirole (0.1 mg/kg). By using in situ hybridization it was found that CPA (0.1 mg/kg) significantly inhibited the SKF 38393-induced increase in the expression of NGFI-A and c-fos mRNA levels in the dopamine-denervated striatum. The increase in jun-B mRNA expression could only be inhibited with the high dose of CPA (0.5 mg/kg). A stronger effect of the A1 agonist was found in the ventral striatum (nucleus accumbens) compared with the dorsal striatum (dorsolateral caudate-putamen). The results indicate the existence of antagonistic A1-D1 receptor-receptor interactions in the dopamine-denervated striatum controlling D1 receptor transduction at supersensitive D1 receptors.

Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine. The GABAergic striatopallidal neurons are regulated by interacting adenosine A2A and dopamine D2 receptors. On the other hand, the GABAergic striatonigral and striatoentopeduncular neurons seem to be regulated by interacting adenosine A1 and dopamine D1 receptors. Furthermore, behavioural studies have revealed interactions between adenosine A2A and dopamine D1 receptors that occur at the network level. These adenosine-dopamine receptor-receptor interactions might offer new therapeutic leads for basal ganglia disorders.

Baseline electroencephalographic (EEG) tracings recorded from 'acute' and 'chronic' rabbits were compared by computerized spectral analysis. The results showed that baseline EEG activity of rabbits differ significantly and markedly according to acute or chronic preparation. It is suggested that this finding should be taken into account when studying the EEG effects of centrally acting drugs.

The influence of cholecystokinin (CCK), bilaterally injected into the rostral nucleus accumbens, on the EEG and behavioural effects induced by phencyclidine (PCP) has been studied in rats. CCK (10 ng) significantly inhibited PCP-induced EEG effects (increase of spectral power with respect to pre-drug tracing; increase of relative power distribution in the slowest frequency bands), and behavioural effects (circling and ataxia). The inhibitory effects of CCK were completely antagonized by 1 ng PD 135-158, a selective CCKB receptor antagonist, but not by lorglumide (1 microgram), a selective CCKA receptor antagonist. Since the effects induced by PCP in rodents have been proposed to be an experimental correlate of the psychotic symptoms it induces in humans, these results indicate that CCK may act as a neuroleptic. They also suggest that CCKB receptors located in the rostral nucleus accumbens may be involved in the neuroleptic-like activity of CCK.

Behavioural and biochemical evidence for the existence of a powerful specific postsynaptic interaction between adenosine A1 and dopamine D1 receptors in the mammalian brain was found. Behavioural data showed that A1 receptor stimulation induced a decrease in the D1-induced motor activation in reserpinized mice and a decrease in the D1-dependent oral dyskinesia in rabbits. Biochemical data suggested that A1 receptor stimulation could produce a GTP-independent uncoupling of the rat striatal D1 receptor to the G protein. The A1-D1 receptor-receptor interaction might represent an important additional mechanism of action responsible for the motor depressant effects of adenosine agonists and for the motor stimulant effects of adenosine antagonists, like the methylxanthines caffeine and theophylline.

The intraperitoneal injection of d-amphetamine (5 mg/kg i.p.), preceded (10 min before) by intrastriatal injection of an adenosine A2 receptor agonist (CGS 21680, 5-10 micrograms) or followed (5 min later) by an intrastriatal adenosine A1 receptor agonist (N6-cyclopentyladenosine, CPA, 30 micrograms), induced ipsilateral rotations in rats. The opposite effect (contralateral rotations) was observed with adenosine receptor antagonists (A2 antagonist, 3,7-dimethyl-1-propargylxanthine, DMPX, 10 micrograms; A1 antagonist, 8-cyclopentyl-1,3-dimethylxanthine, CPT, 2.5 micrograms). These results confirm that both adenosine A2 and A1 receptors modulate striatal dopaminergic neurotransmission.

The influence of CGS 21680 (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenos ine), an adenosine A2 receptor agonist, was tested in an animal model of Huntington's disease. Male Wistar rats received bilateral intrastriatal injections of quinolinic acid and then, 1 and 2 weeks later, they were treated with intrastriatal CGS 21680 (3 micrograms/2 microliters) or saline. While quinolinic acid-lesioned rats not treated with CGS 21680 showed the typical motor hyperresponsiveness to d-amphetamine (1 mg/kg i.p.), the intrastriatal injection of CGS 21680 completely prevented this effect.

The N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors are involved in the electrical and behavioural generalization of epileptiform activity within the brain. In rats, both competitive and non-competitive NMDA antagonists induce three dose-dependent stages of EEG patterns: 1) increase in cortical desynchronization periods; 2) increase in amplitude of cortical high frequency (20-30 Hz), low voltage (30-50 microV) background activity; 3) appearance of cortical slow (2-3 Hz) wave-sharp wave complexes. These EEG changes are accompanied by stimulatory-depressive behavioural effects such as stereotypy (circling, head weaving) and ataxia. In the present study, the influence of the prototypic anticonvulsant diphenylhydantoin (DPH) has been tested on the EEG and behavioural effects induced by the non-competitive NMDA antagonists phencyclidine (PCP) and dizocilpine (MK-801) and by the competitive NMDA antagonist cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755). Even though DPH (up to 100 mg/kg IP) did not markedly affect basal cortical EEG activity, at doses of 10-100 mg/kg IP it potentiated all the EEG effects induced by the NMDA antagonists. These data support involvement of NMDA neurotransmission in the pharmacological effects of DPH.

The interactions between dopamine D1 and D2 receptors in the model of thyrotropin-releasing hormone (TRH)-induced behavioural excitation were assessed in adult male rabbits. As we had previously observed with the dopamine D1 receptor antagonist SCH 23390 (0.01 mg/kg i.v.), sulpiride (12 mg/kg i.v.), a dopamine D2 receptor antagonist, also significantly antagonized the scratching behaviour elicited by TRH (100 micrograms/10 microliters i.c.v.). Sulpiride (6 and 12 mg/kg i.v.) also induced marked grooming. SKF 38393 (10 mg/kg i.v.), a dopamine D1 receptor agonist, did not modify the TRH-induced scratching. However, LY 17155 (0.5 mg/kg i.v.), a dopamine D2 receptor agonist, significantly increased it. The potentiating effects of LY 171555 were completely antagonized by SCH 23390. These results demonstrate that a concomitant activation of both dopamine D1 and D2 receptors is required for the expression of TRH-induced scratching. They also suggest that scratching behaviour may be a D2-dependent, D1-enabled response. The involvement of dopamine D1 and D2 receptors on grooming behaviour is also discussed.

The effects of the morphinan drugs dextrorphan, dextromethorphan and levorphanol were tested towards the cataleptic activity induced by 1 mg/kg of haloperidol i.p. in rats. The influence of the morphinans was compared to that of the N-methyl-D-aspartate competitive antagonist, 2-amino-5-phosphonovaleric acid. 2-Amino-5-phosphonovaleric acid (0.5 mumoles, i.c.v.), dextrorphan (7.5-15 mg/kg, i.p.) and dextromethorphan (15-30 mg/kg, i.p.) significantly reduced the degree of catalepsy in the haloperidol-treated rats within 15 min. Conversely, levorphanol (15-30 mg/kg, i.p.) significantly increased the degree of catalepsy in the haloperidol-treated rats within 15 min. Naloxone (2 mg/kg, i.p.) counteracted the potentiating effects of levorphanol. These findings demonstrate a differential influence of the morphinan stereoisomers dextrorphan and levorphanol on experimental catalepsy, and suggest a potential use of dextromethorphan in the treatment of Parkinson's disease.

Phencyclidine (PCP) and sigma ligands produce a typical excitatory behaviour in rats, characterized by circling and head- and body-weaving. Excitatory amino acid antagonists such as 2-amino 5-phosphonovaleric acid (AP5) or 3-(+/-)-2-carboxypiperazin-4-yl)propyl-l-phosphonic acid (CPP) also produce a PCP-like excitatory behaviour in rats. In the present paper, the interactions between PCP/sigma drugs or excitatory amino acid receptor antagonists and haloperidol have been investigated in rats. In addition, the influence of two other butyrophenones having a different affinity for the sigma/haloperidol receptors, such as spiperone and 3-(4-(3(4-fluorobenzoyl)-propyl-piperazino-l-yl-isoquinolino (HR 375), has been tested on the behavioural and EEG effects of PCP/sigma drugs and excitatory amino acid antagonists. PCP (2.5-5 mg/kg IP), (+) or (-) SKF 10,047 (1-15 mg/kg IP), (+) or (-) cyclazocine (2-8 mg/kg IP) and AP5 (0.5 mumol ICV) dose-dependently and significantly (P less than 0.01) antagonized the haloperidol-induced catalepsy in the horizontal bar and podium tests in rats. On the other hand, either haloperidol (1 mg/kg IP) or spiperone (1 mg/kg IP) reduced the head-weaving induced by (+) SKF 10,047, PCP, or AP5. On the contrary, HR 375 (6 mg/kg IP) was ineffective in blocking the excitatory effects of these drugs. In addition, either haloperidol (1 mg/kg IP) or spiperone (1 mg/kg IP), but not HR 375 (6 mg/kg IP) reduced the amplitude increase of the fast (20-30 Hz) frequency/low (30-50 microV) voltage background cortical activity elicited by PCP or (+) SKF 10,047. The results demonstrate an interaction between dopamine and excitatory amino acid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of nimodipine and/or diltiazem on the EEG and behavioural effects induced by phencyclidine (PCP) was assessed in adult male Wistar rats. Nimodipine (2 and 10 mg/kg i.p.) and diltiazem (25-100 mg/kg i.p.) significantly potentiated both EEG (increase in background activity voltage, incidence of clustered slow waves) and behavioural (ataxia mean intensity) effects of PCP (5 mg/kg i.p.). A synergistic effect between low, ineffective doses of both nimodipine (0.5 mg/kg i.p.) and diltiazem (5 and 10 mg/kg i.p.) was also found. These data confirm the recent finding of a positive allosteric modulation existing between benzothiazepine (diltiazem) and dihydropyridine (nimodipine) binding sites. They also suggest that the modulation of calcium channels may play a pivotal role in the expression of PCP-induced effects.

The present work deals with an EEG and behavioral study on the effects of the calcium antagonist flunarizine against the convulsions due to pentylenetetrazole in rats. Flunarizine (1.5-18 mg/kg, i.p.) has a dose-dependent protective effect against pentylenetetrazole-induced seizures (50 mg/kg, i.p.). Tonic seizures were primarily affected by flunarizine. N6-L-phenylisopropyl-adenosine (an A1 adenosine receptor agonist) potentiated the anticonvulsant effects of flunarizine at the dose of 0.05 mg/kg, i.p. Conversely, caffeine (10 and 50 mg/kg, i.p.) reverted the antiepileptic activity of flunarizine in a dose-related way. These results confirm some previous reports on the anticonvulsant effects of flunarizine in various experimental models. They also suggest that some interesting interactions may exist between flunarizine and the adenosine system.

1. Clonidine, an alpha-2 adrenergic agonist, induced in rats a synchronization of the electrical activity of the brain (EEG) accompanied by sedation starting from the dose of 0.05 mg/kg, i.p. 2. This drug (0.05 mg/kg, i.p.) was also able to influence both the EEG and behavioural effects elicited by two "dissociative anaesthetics", PCP and KT. 3. At low and moderate doses of these two drugs, clonidine fully inhibited the EEG and behavioural effects, whereas at high doses of both drugs clonidine potentiated these effects. 4. Yohimbine was able to revert the inhibitory and potentiating effects produced by clonidine. It was also able to revert sedation accompanied by EEG synchronization. 5. Prazosin, on the other hand, was not able to produce such effects. This fact suggests that the alpha-2 adrenoceptors are involved in these effects. 6. Based on our findings, the interaction of the dissociative anaesthetics (PCP-KT) with the central adrenergic receptors seems to be very complex. The possible relevance of clonidine on both the improvement of KT-induced anaesthesia and the treatment of PCP-intoxication is also discussed.

The influence of the dopamine D-1 receptor antagonist, SCH 23390, on thyrotropin-releasing hormone (TRH)-induced behaviour was assessed in adult male rabbits. SCH 23390 prevented the effects of TRH (100 micrograms i.c.v.), starting at a very low dose (0.01 mg/kg i.v.). This finding seems to indicate that dopamine D-1 receptors are involved in TRH-induced behaviour.

The present work deals with an EEG and behavioral study on the effects of the calcium antagonist nimodipine against the convulsions due to pentylenetetrazole (PTZ) in rats and rabbits. In rats, nimodipine (0.25-1 mg/kg i.p. 15 min before) has a dose-dependent protective effect against PTZ-induced seizures (50 mg/kg i.p.). This effect was reverted by the calcium channel activator BAY K 8644 (1-2 mg/kg, i.p.) showing that the anticonvulsant properties of nimodipine depend upon its calcium antagonistic activity. In rabbits, nimodipine (0.05-4 mg/kg i.v. 5 min before) did not prevent the seizures induced by PTZ (20 mg/kg i.v.). However, the lowest dose of nimodipine (0.05 mg/kg i.v.) was able to prevent or suppress the spike-and-wave complexes elicited by PTZ (10 mg/kg i.v.). These results suggest that the modulation of the calcium influx in the CNS might influence the epileptic phenomena.

In a randomized, multicenter study, 168 evaluable patients with colorectal adenocarcinoma at B2, C1 or C2 stages of the Dukes, Astler and Coller classification, were treated after radical surgery with BCG and 5-fluorouracil alone (regimen A) or in combination with hydroxyurea, methyl-CCNU and mitomycin C (regimen B). Radiation therapy was mandatory after surgery for rectal cancer. Response to therapy was evaluated for length of disease-free interval after surgery and was analyzed in comparison to the data obtained upon entrance to the study. The results are reported as life curves of the duration of the disease-free interval for treatment in comparison to the presence or absence of various signs or symptoms of disease. Also reported are responses obtained using the Cox method for linear regression analysis on non-parametric data, that gave information on the importance of various prognostic factors.

A behavioral study on the stereotypy induced by caffeine and carbamazepine or caffeine and haloperidol was assessed in adult male rabbits. The stereotypy induced by caffeine + carbamazepine was not reduced by pretreatment with haloperidol (0.1 mg/kg) or SCH 23390 (0.01 mg/kg). N-ethylcarboxamidoadenosine (NECA, 0.01 mg/kg), an A2 adenosine receptor agonist, completely prevented the appearance of caffeine + carbamazepine-, but not of caffeine + haloperidol-induced stereotypy. An EEG investigation was also performed in order to evaluate the influence of the blockade of D-1 and D-2 dopamine receptors on the desynchronized tracing induced by caffeine (50 mg/kg). Neither haloperidol (0.1 mg/kg) nor SCH 23390 (0.01 mg/kg) were able to influence this EEG effect of caffeine. Present data support the hypothesis that A2 adenosine receptors may be involved in the control of pathological movements. The relationship between the purinergic system and D-1/D-2 dopamine receptors is also discussed.

The EEG and behavioral effects of caffeine, carbamazepine and haloperidol were assessed in adult male rabbits. Caffeine (50 mg/kg i.v.) induced a long-lasting EEG desynchronization (45.6/60 min in mean) which was not modified by pretreatment of the rabbits with carbamazepine or haloperidol. All these drugs, administered alone, failed to induce stereotypy in rabbits. The administration of caffeine in combination with carbamazepine and/or haloperidol induced stereotyped behavior.

In the present work we have investigated some of the excitatory effects of caffeine in rabbits. Caffeine (5-50 mg/kg i.v.) elicited a cortical EEG desynchronization and an activation of the theta hippocampal rhythm but failed to affect the red nucleus activity. The EEG effects of caffeine were counteracted by L-PIA (1-3 mg/kg i.v.). Caffeine (25-50 mg/kg i.v.) completely reverted the EEG and motor effects due to L-PIA (1-5 mg/kg); the drug also counteracted the cortical and hippocampal EEG modifications elicited by diazepam (1-10 mg/kg), but failed to influence the diazepam-induced effects at the red nucleus level. In addition, caffeine (25 mg/kg) significantly increased the duration of the epileptiform EEG response (afterdischarge) elicited by electrical stimulation of the dorsal hippocampus. This caffeine-potentiating effect was reduced by administration of both L-PIA (0.05-2 mg/kg) and diazepam (1 mg/kg); Ro 15-1788 (1 mg/kg) was unable to affect it. Present data suggest that the analeptic action of caffeine is different from that of the drugs acting through the GABA-benzodiazepine system. Our results show the importance of the limbic system in the excitatory effects of caffeine and suggest that purinergic drugs may have a modulatory role in the control of limbic convulsions.