Mechanism of action of apomorphine on rat gastric secretion

The effects of apomorphine on the volume of gastric secretion and its content of H+, K+, Na+ and Cl- were determined in conscious rats having gastric cannulas. Apomorphine dose-dependently (0.25-0.5 mg/kg s.c.) decreased the volume of gastric secretion, its acid concentration and, at the highest dose, Cl- concentration. However, Na+ and K+ concentrations were unchanged. The alpha 1- and alpha 2-adrenoceptor antagonists prazosin (0.25-0.5 mg/kg i.p.) and yohimbine (5-10 mg/kg i.p.), the beta 1- and beta 2-adrenoceptor antagonist propranolol (5 mg/kg i.p.), the beta 2-adrenoceptor antagonist ICI 118551 (1 mg/kg i.p.) and the dopamine receptor antagonists haloperidol (0.25-2.5 mg/kg i.p.), metoclopramide (2.5-10 mg/kg i.p.) or domperidone (2.5 mg/kg i.p.), administered alone, had little or no effect on the volume, H+, Na+ or Cl- concentrations of gastric secretion. Propranolol prevented the action of apomorphine to reduce the volume of gastric secretion but failed to modify the reductions in H+ and Cl- concentrations. The action of propranolol was mimicked by ICI 118551 but not by the beta 1-adrenoceptor antagonist atenolol. Yohimbine, prazosin or domperidone had little or no effect on the actions of apomorphine. Haloperidol (0.5 mg/kg i.p.) and metoclopramide (10 mg/kg i.p.) antagonised apomorphine's action to reduce H+ and Cl- concentrations but significantly enhanced the action of apomorphine to reduce the volume of gastric secretion. The results suggest that the ability of apomorphine to reduce the volume of gastric secretion is mediated via beta 2-adrenoceptors whilst acid concentration is reduced via an action on neuroleptic sensitive receptors.     

Influence of (-)-sulpiride and YM-09151-2 on stereotyped behavior in chicks and catalepsy in rats

In this paper, the effects of three antipsychotic agents using the avian species laboratory model are described. d-Amphetamine (2-5 mg/kg, s.c.) dose-dependently antagonized catalepsy induced by haloperidol (0.25 mg/kg, i.p.), YM-09151-2 (0.02-0.04 mg/kg, i.p.) and (-)-sulpiride (20-40 mg/kg, i.p.) in rats. (-)-Sulpiride (10-40 mg/kg, i.p.) dose-dependently antagonized apomorphine (0.125 mg/kg, s.c.)-induced stereotyped behavior in young chicks. Similarly, YM-09151-2 (0.04 mg/kg, i.p.) antagonized apomorphine (0.125 mg/kg, s.c.)-induced stereotyped behavior in young chicks. (-)-Sulpiride (40 mg/kg, i.p.) significantly antagonized apomorphine (0.25 mg/kg, s.c.)-induced stereotyped behavior in 6 week old chicks. Parachlorophenylalanine (PCPA, 300 mg/kg, i.p.) significantly reduced the intensity of stereotyped behavior induced by apomorphine (0.125 mg/kg, s.c.) in young chicks. However, (-)-sulpiride (40 mg/kg, i.p.) did not significantly influence the effect of PCPA on apomorphine-induced stereotyped behavior. Similarly, catalepsy induced by (-)-sulpiride (40 mg/kg, i.p.), haloperidol (0.25 mg/kg, i.p.) and YM-09151-2 (0.04 mg/kg, i.p.) in male rats was profoundly suppressed by PCPA (300 mg/kg, i.p.). The present results indicate that apomorphine-induced stereotyped pecking in young (4-6 day old) chicks may serve as a suitable laboratory model for testing potential antipsychotic drugs. In addition, the data indicates that endogenous 5-hydroxytryptamine mechanisms may be involved in the genesis of drug-induced catalepsy in rats.     

Differential effects of dopamine D-1 and D-2 receptor agonists on EEG activity and behaviour in the rabbit

SKF 38393, a selective agonist for dopamine D-1 receptors, LY 171555, a selective agonist for D-2 receptors and apomorphine, an agonist for both receptor sites, all induced activation of the electrical activity of the brain (EEG) in the rabbit. While SKF 38393 induced EEG changes without concomitant signs of stereotyped behaviour, the injection of both LY 171555 and apomorphine also elicited marked behavioural effects, mostly stereotyped mouth and head movements. The EEG effects of SKF 38393 were prevented by SCH 23390 (0.003 mg/kg i.v.), but not by (-)-sulpiride (6.2-25 mg/kg i.v.). Haloperidol attenuated the effects induced by SKF 38393 only at a dose (1 mg/kg) that induced EEG changes of its own. Similarly, effects of apomorphine on both EEG and behaviour were prevented by SCH 23390 and to a lesser extent by haloperidol, but not influenced by (-)-sulpiride. Different patterns of interactions were observed when D-2 receptors were selectively stimulated by LY 171555. Behavioural effects induced by LY 171555 were fully inhibited by both (-)-sulpiride (6.2-12.5 mg/kg i.v.) and haloperidol (0.1-0.3 mg/kg i.v.). The drug SCH 23390 attenuated some behavioural components at 0.3 mg/kg (i.v.), a dose at least 100-fold that effective on the EEG effects induced by SKF 38393. However, all these antagonists exerted weak or no effects on EEG activation induced by LY 171555 and did not restore the control patterns at any doses examined.(ABSTRACT TRUNCATED AT 250 WORDS)     

A central site of dopamine agonist action to modify gastric secretion in the rat

2-Di-n-propylamino-5,6-dihydroxytetralin (tetralin) administered subcutaneously (6.25-25 micrograms/kg s.c.) or into the cerebral ventricles (i.c.v. 0.5-10 micrograms) dose-dependently reduced the volume and acid concentration of gastric secretion collected from rats having chronically implanted gastric and intracerebral cannulas. Apomorphine or dopamine given i.c.v. also reduced gastric secretory volume and acid concentration. Tetralin-induced reductions (s.c. or i.c.v.) in gastric acid concentrations were antagonised by the dopamine antagonists metoclopramide, sulpiride or haloperidol and by the alpha 2-adrenoceptor antagonist yohimbine given systemically or i.c.v. The alpha 2-adrenoceptor antagonist idazoxan or the beta-adrenoceptor antagonist propranolol (i.c.v.) also antagonised the tetralin-induced (i.c.v.) reduction in gastric acid concentration. In contrast, the reduction in gastric secretory volume effected by centrally or peripherally administered tetralin could only be antagonised by propranolol. Previous observations that apomorphine can reduce gastric secretory volume and acid concentration are thus extended to 2-di-n-propylamino-5,6-dihydroxytetralin. Both agents reduce gastric secretory volume via an action on beta-adrenoceptors, and reduce gastric acid concentration via dopamine receptors, with alpha 2-adrenoceptor and, more speculatively, beta-adrenoceptor mechanisms contributing to the effect of the tetralin compound. These actions may be mediated, at least in part, via central mechanisms.     

Behavioural correlates of modified dopaminergic/anticholinergic responses following chronic treatment with neuroleptic agents of differing activity spectra.

An attempt was made to differentiate the mechanisms of action of these “neuroleptic” agents having antidyskinetic properties from the classical neuroleptics by studying the effects of chronic treatment on the responses to a dopamine agonist and cholinergic antagonist. Rats were chronically treated with haloperidol (2 mg/kg i.p.), oxiperomide (8 mg/kg i.p.), pimozide (8 mg/kg p.o.), tiapride (100 mg/kg i.p.), sultopride (100 mg/kg i.p.), sulpiride (100 mg/kg p.o.) and metoclopramide (100 mg/kg i.p.) for 7 consecutive days. On days 1, 3 and 7 after neuroleptic withdrawal rats were assessed for their sensitivity to the stereotypic effects of apomorphine (0.25–1.0 mg/kg s.c.) and the locomotor stimulant effects of dexetimide (0.32–1.25 mg/kg s.c.). A supersensitivity phase to apomorphine, persisting for 1–3 days, was noted in all drug-treated groups and, during this time, the responses to dexetimide were decreased (haloperidol, oxiperomide and pimozide groups), increased (metoclopramide group) or remained similar to control values (sultopride-, sulpiride- and tiapride-treated animals). The responses to dexetimide returned to control values in all treatment groups as the apomorphine sensitivity phase declined. It is suggested that chronic treatment with neuroleptic agents may enhance the sensitivity of those cerebral receptors responsible for mediating the stereotypic effects of apomorphine, and that the relationship between such dopamine function and interacting cholinergic mechanisms may differ for the different groups of neuroleptic agent. However, these differentiations did not directly correlate with the known ability of the neuroleptics to induce or antagonise dyskinetic phenomena.     

Sedation and sleep induced by high doses of apomorphine after blockade of D-1 receptors by SCH 23390

The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.     

The rise of body temperature induced by the stimulation of dopamine D1 receptors is increased in acutely reserpinized mice

In naive mice, the selective D1 agonist, SK&F 38393 (7.5-30 mg/kg s.c.), induced a significant rise of body temperature (0.5-1 degree C) which was antagonized by SCH 23390 (100 micrograms/kg s.c.) and by flupenthixol (0.4 mg/kg i.p.). In mice treated with reserpine (5 mg/kg s.c.) 18 h before testing, which on its own caused intense hypothermia (10-12 degrees C), SK&F 38393 (1.87-30 mg/kg s.c.) induced a dose-dependent and more marked rise of body temperature (5-7 degrees C). Similarly, SK&F 38393 (30 mg/kg s.c.) partially prevented reserpine-induced hypothermia. The central origin of the SK&F 38393 effects in reserpine-treated mice is indicated by the rise of body temperature induced by the i.c.v. administration of the drug (12.5-50 micrograms per mice). The SK&F 38393-induced rise of body temperature in acutely reserpinized mice was antagonized by SCH 23390 (50-200 micrograms/kg s.c.), clozapine (1.87-30 mg/kg i.p.) or chlorpromazine (2-32 mg/kg i.p.) but not by metoclopramide (25 or 100 mg/kg i.p.) or amisulpride (12.5 or 50 mg/kg). In naive mice, apomorphine (1 mg/kg s.c.) or LY 171555 (0.4 mg/kg s.c.) induced hypothermia which was antagonized by amisulpride (12.5 mg/kg i.p.); a transiently increased body temperature was even measured 30 min after apomorphine injection in amisulpride-treated mice. Apomorphine (1 mg/kg s.c.) induced a rise of body temperature in acutely reserpinized mice which was significantly reduced by SCH 23390 (50 and 200 micrograms/kg s.c.) and significantly increased by amisulpride (12.5 and 50 mg/kg i.p.). These data suggest that pharmacologically different dopamine receptor subtypes mediate different effects on body temperature in mice: D1 dopamine receptors mediate a rise of body temperature which is increased in hypothermic reserpinized animals and dopamine receptors of the D4 subtype mediate the decrease of body temperature in naive mice.     

Effect of apomorphine on oxytocin concentrations in different brain areas and plasma of male rats

The effect of the dopamine (DA) agonist, apomorphine, on oxytocin concentrations in the hypothalamus, hippocampus, septum and plasma was studied in male rats. Apomorphine dose dependently increased the concentration of oxytocin in the plasma and hippocampus, the minimal effective dose being 80 micrograms/kg s.c., which induced a 65% increase in plasma and a 45% increase in the hippocampus. The maximal effect (210 and 125% above controls) was induced with 240 micrograms/kg s.c. In contrast, there was a significant decrease (32%) in the oxytocin concentration in the hypothalamus, but only after the highest doses of apomorphine, while no change was found in the septum. The apomorphine effect in the hippocampus and hypothalamus was prevented by the mixed DA D-1/D-2 receptor blocker, haloperidol (0.3 mg/kg i.p.), and by the DA D-2 receptor blocker, (-)-sulpiride (20 mg/kg i.p.), but not by the DA D-1 receptor blocker, SCH 23390 (0.2 mg/kg s.c.). Similar effects were found in plasma, although SCH 23390 inhibited the apomorphine effect by 45%. Our results suggest that apomorphine stimulates oxytocinergic transmission in male rats and provide biochemical support for the hypothesis that a DA-oxytocin link exists in the central nervous system.     

Dopamine D2 receptors and spinal cord excitation in mice

Spinal cord excitation was induced in mice by morphine and the effects of dopamine D1 and D2 receptor antagonists on the Straub tail reaction were investigated. The dopamine D2 receptor antagonist, sulpiride (25-100 mg/kg i.p.), or haloperidol (0.25-1.0 mg/kg dose dependently inhibited the Straub tail reaction induced by subcutaneously injected morphine. A low dose of apomorphine (50 micrograms/kg s.c.) also reduced the Straub tail reaction. The dopamine D1 receptor antagonist, SCH-23390 (25-100 micrograms/kg i.p.), had no significant effect. Sulpiride (50 mg/kg i.p.) significantly inhibited the Straub tail reaction induced by intrathecally injected morphine (6 microgram/mouse). Intrathecal injection of apomorphine (12.5-25 micrograms/mouse) induced the Straub tail reaction dose dependently. The Straub tail reaction induced by intrathecally injected apomorphine was significantly inhibited by sulpiride. SCH-23390 had no significant effect on the Straub tail reaction induced by intrathecally injected morphine or apomorphine. These results support the proposal that the dopamine response involved in the Straub tail reaction is mediated by postsynaptic dopamine D2 receptors in the spinal cord of mice.     

Participation of angiotensin II in learning and memory. II. Interactions of angiotensin II with dopaminergic drugs

The effect of angiotensin II (ATII) and of its interactions with dopaminergic drugs injected post-trial on retention in active avoidance tasks in shuttle-box-trained rats were studied. ATII at doses of 0.10 and 0.50 micrograms administered intracerebroventricularly (i.c.v.) immediately after training improved retention. The dopaminergic receptor agonist apomorphine at a dose of 0.10 mg/kg injected intraperitoneally (i.p.) facilitated retention whereas elymoclavine (a dopaminergic agonist) at a dose of 2.5 mg/kg i.p. had no effect. ATII at a dose of 0.10 micrograms i.c.v. administered after apomorphine 0.10 mg/kg or elymoclavine 2.5 mg/kg exerted a stronger retention-facilitating effect. The dopaminergic receptor antagonist haloperidol at a dose of 1 mg/kg i.p. markedly impaired retention. ATII at a dose of 0.50 micrograms administered after haloperidol (1 mg/kg) did not exercise its retention-facilitating effect. It is concluded that the retention facilitating effects of ATII are realized through interactions with brain dopaminergic transmission.     

The role of serotonin and dopamine in brain in the antidepressant-like effect of clonidine in the forced swimming test.

The effect of clonidine (0.1 mg/kg, i.p.), as a three-injection course, on behaviour in the forced swimming test was studied in rats injected intracerebroventricularly (i.c.v.) with 150 micrograms 5,7-dihydroxy-tryptamine (5,7-DHT) to destroy serotonin (5-HT) neurones or treated with 100 mg/kg (i.p.) (+/-)-sulpiride or 0.5 micrograms/0.5 microliter (-)-sulpiride in the nucleus accumbens. Clonidine significantly increased struggling and reduced floating and the effects were antagonized by both treatments with sulpiride but not by 5,7-DHT which markedly depleted 5-HT in brain. The results suggest that the mesolimbic dopaminergic system but not 5-HT neurones, plays a permissive role in the antidepressant-like effect of clonidine in the forced swimming test.     

Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew).

The anti-emetic mechanism of action of fentanyl to inhibit nicotine (5 mg/kg, s.c.)-induced emesis was investigated in Suncus murinus. The anti-emetic action of fentanyl (40 microg/kg, s.c.) was antagonised by the opioid receptor antagonists naltrexone (1 mg/kg, s.c.), naloxone (1 mg/kg, s.c.), M8008 (16S-methylcyprenorphine; 1 mg/kg, s.c.) and MR 2266 (5,9-diethyl-2-(3-furylmethyl)2'-hydroxy-7,7-benzomorphan; 1 mg/kg) but not by naloxone methylbromide (1 mg/kg, s.c.), naloxone methyliodide (1 mg/kg, s.c.), naltrindole (1 mg/kg, s.c.), DIPPA (2-(3,4-dichlorophenyl)-N-methyl-N-[1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)-ethyl]acetamide; 3 mg/kg, i.p.) or naloxonazine (35 mg/kg, i.p.). This indicates an involvement of mu2-opioid receptors within the brain to mediate the anti-emetic effect of fentanyl. In other studies, naloxone 10-60 mg/kg, s.c. induced dose-related emesis but naltrexone was only emetic at 60 mg/kg, s.c. and naloxone methylbromide failed to induce emesis at doses up to 60 mg/kg, s.c. The emesis induced by a high dose of naloxone 60 mg/kg, s.c. was antagonized by CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; 3-30 mg/kg, i.p.), 8-OH-DPAT, ((+/-)-8-hydroxy-dipropylaminotetralin; 0.003-0.3 mg/kg, s.c.), buspirone (3 mg/kg, s.c.) and fluphenazine (1-3 mg/kg, i.p.) but not by naltrexone (1-30 mg/kg, s.c.), metoclopramide (0.3-3 mg/kg, i.p.), sulpiride (0.3-3 mg/kg, i.p.), domperidone (0.1-3 mg/kg, i.p.), ondansetron (0.3-3 mg/kg, i.p.), granisetron (0.3-3 mg/kg, i.p.), scopolamine (0.3-3 mg/kg, i.p.) or promethazine (0.3-3 mg/kg, i.p.). The data is discussed in relation to opioid receptor mechanisms moderating emesis and the identification of potential sites of drug action available to inhibit the emetic reflex.     

Possible involvement of nigrostriatal dopamine system in the inhibition of thyrotropin secretion in the rat

The dopaminergic inhibition or cold-stimulated thyrotropin (TSH) secretion was studied in male rats. Serum TSH levels were decreased by apomorphine (1 mg/kg i.p.) but not by dopamine (DA. 0.2–5 mg/kg s.c.). This effect of apomorphine was abolished b haloperidol (1 mg/kg i.p.), meioclopramide and sulpiride (10 mg/kg i.p.) but not by domperidone (0.1–5 mg/kg i.p.) does not cross the blood-brain barrier while the other DA receptor antagonists do so. Higl doses of domperidone itself inhibited the cold-induced TSH secretion whereas the other DA antagonists did not. DA (1–10 μg/rat) into the medial basal hypothalamus (MBH) had no effect but 10–50 μg/rat into the 3rd ventricle inhibited the cold-stimulated TSH secretion. 6-Hydroxydopamine infusion after dcsipramine pretreatment (25 mg/kg i.p.) did not affect TSH secretion when given into the MBH (2 μg/rat), the 3rd ventricle (10 μg/rat) or unilaterally into the substantia nigra (SN. 6 μg/nucleus), but bilateral nigral infusions abolished the TSH cold The inhibitory effect of apomorphine (0.1 and 0.5 mg/kg i.p.) was amplified only in the rats whose SN was unilaterally destroyed. These results show that tuberoinfundibular DA neurons do not affect TSH secretion. Instead, the inhibition is mediated through the hypothalamic projections of the nigrostriatal DA system.     

Evidence for a dopamine interaction with the central respiratory control system in the rat

Respiratory activity was studied in adult rats during light halothane anesthesia. Dopamine agonists and antagonists were injected intracerebroventricularly (i.c.v.) or systemically. The respiratory parameters were recorded after exposure to O2 or to CO2 in O2. Apomorphine (i.c.v. 300 microgram) induced a biphasic response with an initial decrease in respiratory frequency (f) followed by pronounced tachypnoea after 5 min. The changes in tidal volume (VT) showed an inverse pattern. When apomorphine was administered into the fourth ventricle, only the later phase of the biphasic response was observed. Haloperidol (2 mg/kg i.p.) antagonized the apomorphine-induced response in contrast to domperidone (2 mg/kg i.v.), a dopamine receptor blocking agent which does not pass the blood brain barrier. Administered i.c.v., haloperidol as well as domperidone induced a decrease in f while VT was increased. The same response was observed after the presynaptic dopamine receptor agonist 3-PPP, 3-(3-hydroxyphenyl)-N-n-propylpiperidine. Hypercapnea was found to decrease the tachypnea in apomorphine-treated animals. Apomorphine also induced a decrease in blood pressure and heart rate, which was not reversed by haloperidol. It is concluded that there is a centrally located, tonically activated dopamine system involved in respiratory regulation. The predominant effect seems to be of a respiratory stimulating nature. The possible role of presynaptic and different postsynaptic dopamine receptor mechanisms is discussed.     

Is domperidone a selective peripheral dopamine-receptor antagonist in vivo?

The ability of domperidone (DOM) to antagonize dopamine (DA) receptor agonist-induced hypothermia or hyperactivity was investigated in rats. Apomorphine (APO) or RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane), two DA receptor agonists, produced dose-dependent hypothermia following subcutaneous (s.c.) administration. Also, RDS-127 produced hypothermia following lateral ventricular (i.c.v.) administration. The hypothermia produced by apomorphine or RDS-127 (given s.c. or i.c.v.) was antagonized by pretreatment with pimozide (0.25 mg/kg, i.p.) or domperidone (0.2, 1.0 and 5.0 mg/kg, i.p.) The hyperactivity produced by apomorphine was unaffected by pretreatment with domperidone. These data suggested that central DA receptors mediating temperature regulation, but not those mediating locomotor activity are accessible to peripherally administered domperidone. Therefore, domperidone may not be useful to differentiate hypothalamic (central) vs peripheral sites of action for DA receptor agonists in the rat.     

Characterisation of alpha2-adrenoceptor subtypes involved in gastric emptying, gastric motility and gastric mucosal defence

The effect of clonidine on ethanol-induced gastric mucosal damage, gastric emptying and gastric motility was compared. The clonidine-induced gastroprotective effect (0.03-0.09 micromol/kg, s.c.) was antagonised by yohimbine (5 micromol/kg, s.c.), prazosin (0.23 micromol/kg; alpha2B-adrenoceptor antagonist) and naloxone (1.3 micromol/kg, s.c.). Clonidine also inhibited the gastric emptying of liquid meal (0.75-3.75 micromol/kg, s.c.) and gastric motor activity (0.75 micromol/kg, i.v.) stimulated by 2-deoxy-D-glucose (300 mg/kg, i.v.). Inhibition of gastric emptying and motility was reversed by yohimbine (5 and 10 micromol/kg, s.c., respectively), but not by prazosin (0.23 micromol/kg, s.c.) or naloxone (1.3 micromol/kg, s.c.). Oxymetazoline-an alpha2A-adrenoceptor agonist-inhibited both gastric emptying (0.67-6.8 micromol/kg, s.c.) and motility (0.185-3.4 micromol/kg, i.v.), whereas it failed to affect gastric mucosal lesions. The results indicate that in contrast to the gastroprotective effect, which is mediated by alpha2B-adrenoceptor subtype, alpha2A-adrenoceptor subtype may be responsible for inhibition of gastric emptying and motility. However, the site of action (central, peripheral, both) remains to be established.     

Dopaminergic Involvement in Improving Effects of Dynorphin A-(1-13) on Galanin-Induced Impairment of Passive Avoidance Learning in Mice

The present study was designed to clarify whether dopaminergic systems are involved in the effects of dynorphin A-(1-13), an endogenous κ-opioid receptor agonist, on the galanin-induced impairment of passive avoidance learning in mice. Galanin (0·3 μg, i.c.v.) shortened step-down latency of passive avoidance learning, while the dopamine D₁ receptor agonist SKF 38393 (3 and 10 mg/kg, s.c.), the dopamine D₂ receptor agonist RU 24213 (0·3 and 1 mg/kg, s.c.), the dopamine D₁ receptor antagonist SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or the dopamine D₂ receptor antagonist S(−)-sulpiride (10 and 30 mg/kg, i.p.) failed to influence it. Dynorphin A-(1-13) (3 μg, i.c.v.) and SKF 38393 (10 mg/kg, s.c.) markedly improved the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. However, RU 24213 (0·3 and 1 mg/kg, s.c.), SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not affect the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. In contrast, SCH 23390 (0·3 mg/kg, i.p.) significantly reversed the improving effects of dynorphin A-(1-13) (3 μg, i.c.v.) on the galanin (0·3 μg, i.c.v.)-induced dysfunction of passive avoidance learning, although SKF 38393 (1 and 3 mg/kg, s.c.), RU 24213 (0·3 and 1 mg/kg, s.c.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not influence the effects of dynorphin A-(1-13) (3 μg, i.c.v.). These results suggest that dynorphin A-(1-13) improves the galanin-induced amnesia resulting from indirect stimulation of dopamine D₁ receptors. © 1997 John Wiley & Sons, Ltd.     

Assessment of the ambulation-increasing effect of ketamine by coadministration with central-acting drugs in mice.

The coadministration of ketamine (12.5 mg/kg, but not 3.1 mg/kg, s.c.) with methamphetamine (2 mg/kg, s.c.), cocaine (10 mg/kg, s.c.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) and MK-801 (0.1 mg/kg, i.p.) significantly enhanced the ambulation-increasing effects. Furthermore, in the coadministration with morphine (10 mg/kg, s.c.) and GBR-12909 (10 mg/kg, i.p.), not only 12.5 mg/kg but also 3.1 mg/kg of ketamine produced a significant enhancement. On the other hand, the ambulation-increasing effect of ketamine (12.5 mg/kg, s.c.) was significantly suppressed by ceruletide (0.01 mg/kg, i.p.), alpha-methyl-p-tyrosine (100 and 300 mg/kg, i.p. x 2), nimodipine (1 and 3 mg/kg, i.p.), haloperidol (0.03 and 0.1 mg/kg, s.c.), a low dose of apomorphine (0.1 mg/kg, s.c.), physostigmine (0.1 mg/kg, s.c.) and N6-(L-2-phenylisopropyl)-adenosine (0.1 mg/kg, s.c.). However, imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (100 mg/kg, s.c.), a high dose of apomorphine (0.5 mg/kg), reserpine (0.3 and 1 mg/kg, s.c.), propranolol (0.3 and 1 mg/kg, s.c.), phenoxybenzamine (3 and 10 mg/kg, s.c.) and naloxone (0.3 and 1 mg/kg, s.c.) scarcely interacted with ketamine. These results suggest that ketamine increases the ambulatory activity in mice by facilitating dopamine release from a newly synthesized pool at the presynaptic level, which is affected by a calcium-dependent mechanism.     

Clonidine produces mydriasis in conscious mice by activating central alpha 2-adrenoceptors

Intraperitoneal (i.p.) injection of the alpha 2-adrenoceptor agonist clonidine (1-3000 micrograms/kg) produced dose-dependent pupil dilatation in conscious C57/Bl/6 mice with an ED50 of 54 micrograms/kg (95% confidence limits 40-74 micrograms/kg). This response was rapid in onset and of approximately 30 min duration. The alpha 2-adrenoceptor antagonists idazoxan (1 or 3 mg/kg i.p.) and yohimbine (1 or 3 mg/kg i.p.) both produced dose-related miosis, but the alpha 1- and beta-adrenoceptor antagonists prazosin (1 or 3 mg/kg i.p.) and pindolol (1 or 3 mg/kg i.p.) were without effect. These doses of idazoxan and yohimbine potently reversed the mydriasis induced by clonidine (100 micrograms/kg i.p.), while prazosin and pindolol were again ineffective. Clonidine-induced mydriasis was also unaltered by the 5-HT antagonists, methysergide (2.5 mg/kg i.p.) and ketanserin (0.1 mg/kg i.p.) or 0.1 mg/kg i.p. of the dopamine antagonists, haloperidol, SCH 23390 and BRL 34778. A dose of 0.25 microgram clonidine, which was ineffective when administered i.p., produced marked mydriasis after intracerebroventricular (i.c.v.) injection. In addition, the mydriasis produced by i.p. injection of clonidine (100 micrograms/kg) was abolished by i.c.v. dosing of 2.5 micrograms idazoxan or yohimbine, but again not by prazosin or pindolol. Together, these data provide strong evidence to indicate that clonidine-induced mydriasis is exclusively mediated via central alpha 2-adrenoceptors and that this response provides a useful model for studying the function of these receptors.     

An analysis of the hypothalamic sites at which substituted benzamide drugs act to facilitate gastric emptying in the guinea-pig

An analysis of the hypothalamic sites at which the substituted benzamides, metoclopramide and clebopride, act to facilitate gastric emptying was undertaken in the guinea-pig. Standard stereotaxic techniques for intracerebral injection via chronically indwelling intracerebral guides were combined with measurement of gastric emptying by fluoroscopic following of the passage of barium sulphate spheroids from the stomach. Injections were made at 7 different locations within the hypothalamus at Ant. 8.0, 8.9 and 9.6, Lat. +/- 1.0, +/- 1.6, +/- 2.2 (relative to the stereotaxic frame) and at 7.0, 8.0 and 9.0 mm below guide tips in the cortex. The most sensitive sites for gastric facilitation by the substituted benzamides were located at Ant. 8.9, Lat. +/- 1.6, Vert. -8.0, -9.0, the "perifornical area". As the distance of the injection site from the area of the fornix increased, so the facilitatory gastric action diminished, with marked delays or loss in response occurring when injection sites were moved 1 mm above, 0.6 mm lateral, 0.4 mm medial, 0.9 mm posterior or 0.7 mm anterior. The facilitatory gastric actions of metoclopramide and clebopride in the perifornical area of the hypothalamus were not mimicked by haloperidol, domperidone or sulpiride. Atropine, injected into the hypothalamus, markedly reduced gastric emptying; hexamethonium was less effective, and phentolamine, propranolol and methysergide were inactive. Atropine (but not hexamethonium, phentolamine, propranolol or methysergide), injected into the hypothalamus, dose-dependently antagonised the facilitatory gastric action of metoclopramide injected at the same site. Carbachol (but not serotonin, noradrenaline, dopamine or apomorphine), injected into the perifornical area, caused marked facilitation of gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)