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PubMed1989

Blockade of conditioned avoidance responding by trazodone, etoperidone, and MCPP.

Phenylpiperazines, such as meta-chlorophenylpiperazine (MCPP) a serotonin agonist, have recently been reported to block conditioned avoidance responding (CAR) in the rat, which is an indication of possible antipsychotic utility. Since MCPP is a major metabolite of both antidepressant drugs trazodone (TZ) and etoperidone (ET), both were examined for activity in blocking CAR in a single-trial lever press task in Fisher 344 rats. Both TZ and ET produced dose-related falls in CAR with ED50 values (95% confidence limits) of 13.3 (9.6, 18.5) and 10.4 (8.5, 13.2) mg/kg IP, respectively. In contrast, MCPP had an ED50 value of 2.5 (1.8, 3.6) mg/kg IP TZ, ET, and MCPP were also examined for the production of catalepsy and the blockade of amphetamine-induced stereotypy to determine whether each was acting to block CAR via a dopaminergic mechanism of action. None, however, was found highly active. On the other hand, the serotonin receptor blocker metergoline (1.0 mg/kg IP) significantly reduced the CAR block produced by each, suggesting a serotonergic mechanism of action. Since TZ and ET are both less potent than MCPP, the data also suggest TZ and ET may block CAR via formation of MCPP.

Animals↗

PubMed1991

Oxaprotiline enantiomers stimulate ACTH and corticosterone secretion in the rat.

The effect of oxaprotiline (OXA) enantiomers--of which (+)-OXA inhibits noradrenaline (NA) uptake, whereas (-)-OXA does not--on the secretion of adrenocorticotropin hormone (ACTH) and corticosterone was studied in rats. Both enantiomers dose-dependently and with a similar potency increased the plasma level of ACTH and corticosterone, the effect of (-)-OXA on corticosterone being of a longer duration. The stimulation of ACTH secretion and the inability of (+)- and (-)-OXA to increase the plasma corticosterone concentration in animals pretreated with dexamethasone indicate that secretion of the latter hormone results from the action of the enantiomers at a level superior to the adrenal cortex, i.e. the hypothalamus/pituitary. The corticosterone response to (+)- or (-)-OXA was not modified in rats with a selective lesion of NA nerve endings induced by the neurotoxin DSP-4, nor was it affected by the selective alpha 1-antagonist prazosin, the selective alpha 2-antagonist yohimbine, the mixed alpha 1/alpha 2-antagonist phentolamine, the selective dopamine (D2) receptor antagonist sulpiride and the non-selective 5-hydroxytryptamine (5-HT) receptor antagonist metergoline. These results indicate that neither the NA system nor D2 and 5-HT receptors are involved in the hormonal response to the OXA enantiomers. Although the (+)- and (-)-OXA-induced stimulation of corticosterone secretion was not antagonized by diazepam, ipsapirone, naloxone, or propranolol, it cannot be excluded that both these enantiomers act as non-specific stressors.

Adrenergic alpha-Antagonists↗

PubMed1989

Arabinogalactan- and dextran-induced ear inflammation in mice: differential inhibition by H1-antihistamines, 5-HT-serotonin antagonists and lipoxygenase blockers.

Intravenous injection of arabinogalactan or dextran together with pontamine sky-blue dye into mice increased vascular permeability and led to marked blueing of the ears. Arabinogalactan caused a rapidly progressing ear blueing (maximal coloration 20-30 min after injection). This response was suppressed by pretreating the animals with the histamine H1-antihistamines levocabastine and loratadine. In contrast, dextran induced a slowly evolving ear inflammation (maximal coloration 60-90 min after injection), which was blocked by the 5-HT-serotonin antagonists cinanserin, metergoline and ritanserin. Furthermore, the dextran reaction was inhibited by the lipoxygenase (LO)/cyclooxygenase (CO) inhibitors BW540C, BW755C and phenidone and by the specific 5-LO inhibitor AA-861. Both arabinogalactan and dextran responses were inhibited by aprotinin, a kallikrein inhibitor, and the mixed H1/5-HT antagonists astemizole and azatadine. The inflammogenic activity of the polysaccharides was not affected by administration of the CO inhibitors indomethacin and suprofen, the thromboxane synthetase inhibitor dazoxiben, the H2-antihistamines cimetidine and ranitidine, the anticholinergics isopropamide or the PAF-antagonist L-652, 731. These data indicate the existence of distinctive endogenous molecules that mediate the pinnal extravasation reaction to both polysaccharides: histamine for arabinogalactan, serotonin and lipoxygenase-derived arachidonic acid metabolites for dextran.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1990

Paternal alcohol exposure: paradoxical effect in mice and rats.

Male mice consumed liquid alcohol diets containing 25%, 10% or 0% ethanol-derived calories (EDC). Animals receiving the 10 and 0% EDC diets were pair fed to those consuming the 25% EDC diet. After 7 or 14 weeks of consumption, males were bred to non-treated females. Offspring were tested for swimming behavior at 75 days of age. Offspring sired by alcohol-consuming males were more immobile regardless of duration of paternal alcohol consumption or housing conditions (group or isolated). Imipramine (5, 15 mg/kg) reversed this effect such that after drug treatment, alcohol-sired offspring were less immobile than controls. Propranolol (1, 3 mg/kg) eliminated the group differences. Yohimbine (1, 10 mg/kg) significantly increased immobility in all groups but did not reverse the effects of paternal alcohol consumption. Metergoline (1 mg/kg) increased immobility in all groups but did not reverse the effects of paternal alcohol exposure. When rat offspring of alcohol-consuming fathers were tested, their swimming behavior was opposite to that of mice (i.e., rats were less immobile). However, as observed in mice, the effect was reversed by imipramine. These results extend the evidence for paternally mediated behavioral mutagenesis. They also indicate that the direction of induced changes are species dependent and that some of these effects, regardless of direction of change, are mediated by neurochemical changes sensitive to imipramine.

Animals↗

PubMed1996

Injection of 5-HT into the nucleus accumbens reduces the effects of d-amphetamine on responding for conditioned reward.

Injection of d-amphetamine into the nucleus accumbens potentiates responding for stimuli paired with a primary reward. A previous study showed that this potentiating effect of d-amphetamine on responding for conditioned reward (CR) was attenuated by peripherally injected d-fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor. The present experiments further examined the effects of manipulating 5-HT function within the nucleus accumbens on responding for CR, and on the potentiation of CR responding following intra-accumbens injection of d-amphetamine. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase water was not delivered, but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers. Rats responded at a higher rate on the lever delivering this CR. d-Amphetamine (10 micrograms) injected into the nucleus accumbens enhanced responding on the CR lever. Co-injections of 5-HT (5 and 10 micrograms) into the nucleus accumbens abolished the response-potentiating effect of d-amphetamine but were without effect on the base-line level of responding for CR. This reduction by 5-HT of the response potentiating effect of d-amphetamine was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Responding for water was not altered by 5-HT and so the effects of 5-HT on responding for CR cannot be due to a change in the motivation to seek the primary reward. Thus, elevating 5-HT activity within the nucleus accumbens antagonises the effect of d-amphetamine on responding for CR within the nucleus accumbens. These results suggest that 5-HT within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.

Amphetamine↗

PubMed1995

Effects of high doses of theophylline on memory acquisition.

Intraperitoneal (IP) injection of high doses of theophylline decreased memory acquisition dose dependently. Low but not high doses of the dopamine receptor D2 antagonist sulpiride and the dopamine D1 receptor antagonist SCH 23390 decreased the theophylline response. Pimozide and the beta-adrenoreceptor propranolol also decreased the drug response. The anti-muscarinic agent atropine, the alpha-adrenoceptor phenoxybenzamine and the 5-HT antagonist metergoline did not affect the response induced by theophylline. It is concluded that dopamine and beta-adrenergic receptor mechanisms may be involved in the theophylline-induced attenuation of memory acquisition.

Adrenergic Antagonists↗

PubMed1989

Exploratory hypoactivity induced by m-trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (m-CPP).

The action of m-trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (m-CPP), inhibiting the exploratory activity (ambulation and peeping) of the rat was studied in the open field test. The effects of both these drugs were antagonized by mesulergine, metergoline and mianserin, and partly by methysergide. Spiperone showed an antagonistic action in one (mean) dose only. The effects of TFMPP and m-CPP were not antagonized by ipsapirone, gepirone, cyanopindolol, compound 21009, cyproheptadine, ritanserine, ICS 205930, idazoxan or atropine. The lesion produced by p-chloramphetamine attenuated the effects of TFMPP and abolished those of m-CPP. The obtained results permit an assumption that the TFMPP- and m-CPP-induced decrease in the exploratory activity is mediated probably by 5-HT1C receptors.

Animals↗

PubMedDate not supplied

Characterization of the chlorpropamide-alcohol-flush in patients with type 1 and type 2 diabetes.

The aim of the present paper was to evaluate the prevalence of the chlorpropamide-alcohol-flush (CPAF) in patients with type 2 and with type 1 diabetes. Ninety-seven patients with type 2 diabetes and 33 with type 1 diabetes drank 40 ml vermouth 12 h after placebo and again 12 h after 1 tablet of chlorpropamide (250 mg) or 12 h after the last of repeated administrations of chlorpropamide (250 mg b.i.d. for 2 days). Skin temperature was recorded in all patients by a thermocouple probe connected to the left cheek. In 47 patients serum concentrations of chlorpropamide and of its metabolite CBSU were also determined. The prevalence of CPAF was similar in type 1 and type 2 diabetes, was greater in women than in men, and was significantly greater after repeated administrations than after one single administration of chlorpropamide. The increase of skin temperature during a 30-min period was significantly higher in patients with CPAF than in patients without CPAF. Serum concentrations of chlorpropamide and of its metabolite CBSU were more elevated after 4 than after 1 tablet of chlorpropamide, but were not significantly different in patients with and without CPAF. These data indicate that both genetic factors and the amount of chlorpropamide used affect the appearance of CPAF. To assess the possible role of serotonin and of dopamine in the CPAF, some patients with CPAF were tested again after treatment with metergoline, an antiserotonin agent, or with bromocriptine, a dopamine-agonist. Neither drug influenced the CPAF, indicating that the two neurotransmitters are not involved in the CPAF.

Bromocriptine↗

PubMed1990

Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans.

The selective 5-HT1A receptor ligand ipsapirone (IPS) caused dose-related hypothermia in humans. The response was attenuated by the nonselective 5-HT1/2 receptor antagonist metergoline and was completely antagonized by the nonselective beta-adrenoceptor antagonist pindolol, which interacts stereoselectively with the 5-HT1A receptor. The selective beta 1-adrenergic antagonist betaxolol had no effect. The findings indicate that IPS-induced hypothermia specifically involves activation of (presynaptic) 5-HT1A receptors. Therefore, the hypothermic response to IPS may provide a convenient in vivo paradigma to assess the function of the presynaptic 5-HT receptor in affective disorders and its involvement in the effects of psychotropic drugs.

Adrenergic beta-Antagonists↗

PubMed1996

The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement.

Impulsive behaviour is an important component of many psychiatric syndromes. It is often expressed as aggressive or violent behaviour, but may also be non-violent. One important factor which might lead to aggression or violence is an inability to tolerate a delay of gratification, leading to frustration and aggressive outbursts. In animals and in man, tolerance to delay of gratification can be studied using delay of reinforcement (also known as self-control) procedures. Experiments with delay of reinforcement in rats show that serotonergic mechanisms may be involved in this form of impulsive behaviour, which seems to support clinical findings in this area. The present experiment examined the effects of a series of psychoactive drugs on delays of reinforcement using a steady state operant procedure involving lever-pressing by rats. Rats were trained to choose between one food pellet delivered immediately and three or five pellets delivered after varying delays which increased during the course of the session. Using this procedure the rats remained sensitive to within-and between-session variations in delay of reinforcement even after long periods of testing. It was used to demonstrate an increase in impulsivity (after d-amphetamine) and a reduction in impulsivity (after diazepam and metergoline), indicated by shifts in the choice/delay function. The other drugs tested, imipramine, citalopram, haloperidol and carbamazepine, had no consistent effects although tested at doses which are active in other procedures. This method has proved to be a useful way of examining the effects of drugs on choice of delay of reinforcement in the rat. Although the behavioural basis of tolerance to delay of reinforcement (self-control) has received considerable attention, little is yet known about the biological basis. The present data indicate that the procedure described here can be used to elucidate the pharmacological basis of this aspect of impulsive behaviour.

Animals↗

PubMed1998

The pharmacology of impulsive behaviour in rats II: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and other drugs on fixed consecutive number schedules (FCN 8 and FCN 32).

The effects of drugs on one aspect of impulsive behaviour were evaluated using a schedule in which rats were trained to complete a fixed consecutive number of responses on one of two levers before pressing the second to obtain a reinforcer (FCN). Terminating the chain before completing the FCN resulted in the omission of the food, and can be considered an impulsive decision. Two groups of food-deprived rats were trained to press either 8 or 32 times on the left lever (FCN lever) of a two lever operant chamber before pressing the right lever (Reinforcement lever) to deliver a food pellet. Responding on the Reinforcement lever before completion of the sequence resulted in a short time-out and the rat had to begin the sequence again. After responding had stabilised, the rats were treated with a range of doses of a number of drugs. Impulsivity was assessed by several measures, including the mean chain length and the proportion of chains terminating in food delivery, and the distribution of chain lengths was analysed. The efficiency of the rats was similar under both FCN 8 and FCN 32, although it was more difficult to maintain a consistent baseline under FCN 32. Under the FCN 8 schedule, significant decreases in chain length were obtained with d-amphetamine (0.8-2.4 mg/kg), haloperidol (0.1 mg/kg), ethanol (1 and 3 g/kg) and chlordiazepoxide (10.0 mg/kg), and there were alterations in other measures consistent with an increase in impulsivity. Imipramine (1-10 mg/kg), citalopram (1-10 mg/kg) and metergoline (0.3-3.0 mg/kg) had no effect on mean chain length, although the first two drugs shifted the chain length distribution to the left. d-Amphetamine (0.4-1.2 mg/kg) and PCPA (100 mg/kg) reduced chain length and had other effects consistent with increased impulsivity under FCN 32 schedule, whereas imipramine had little, and citalopram no, effect. Taken generally, effect of the active drugs was relatively non-specific, including both a reduction in response rate and alterations in choice measures proposed to reflect an increase in impulsivity. Detailed analysis of the effect of amphetamine revealed that three processes were at work: chain shortening, an increased preference for the lever most closely associated with food delivery, and a gradual shift in the control over responding from the response sequence (pattern) to the individual lever press (act).

Amphetamine↗

PubMed1998

The pharmacology of impulsive behaviour in rats IV: the effects of selective serotonergic agents on a paced fixed consecutive number schedule.

An impulsive cognitive style may affect behaviour in several different ways, including rapid decision making, intolerance of the delay of reward and a tendency to terminate chains of responses prematurely. It has been proposed to measure the last of these in rats using fixed consecutive number (FCN) schedules. The present study uses a modified version of the FCN procedure in which responding was paced by retracting the response lever for short periods between presses. In this way, the experimenter can control the maximum rate of responding. The procedure was made up of two components. In both, the schedule requirement was FCN 8, but in the Fast component lever presses were spaced by a minimum of 2.5 s and in the Slow component by a minimum of 5 s. Alterations in impulsivity were inferred from changes in the mean chain length and the distribution of chain lengths. The 5-HT1A agonist, 8-OH-DPAT (0.03-0.3 mg/kg), increased chain lengths within a narrow dose range, whereas the 5-HT1A antagonist, WAY 100 635 (0.03-0.3 mg/kg), reduced chain lengths. The 5-HT2 agonist, DOI (0.1-1.0 mg/kg), markedly reduced chain lengths, whereas the 5-HT2 antagonist, ritanserin (0.03-0.3 mg/kg), had no effect. The 5-HT1A/1b agonist, RU 24969 (0.03-0.3 mg/kg), reduced chain lengths. The 5-HT releaser, p-chloramphetamine (0.1-1.0 mg/kg), had a weak, biphasic effect, slightly reducing the number of short chains at the lowest dose tested and slightly increasing this number at the highest dose. Other drugs tested, citalopram (1.0-10.0 mg/kg), metergoline (0.3-3.0 mg/kg) and MDL-72222 (0.1-3.0 mg/kg), had no significant effects. These results suggest that stimulation of 5-HT1A receptors reduces impulsivity, whereas stimulation of 5-HT2 receptors increases it. These data are in agreement with previous results using the DRL-72 schedule, and indicate that there is no simple role for serotonin in the control of impulsivity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

Dopaminergic mechanism of imipramine action in an animal model of depression.

Rats, subjected chronically (10-12 weeks) to a variety of mild, unpredictable stressors, showed a decrease in their consumption of weak sucrose solutions; normal behavior was restored by chronic (5-9 weeks) treatment with the tricyclic antidepressant imipramine. Acute administration of the dopamine receptor antagonist pimozide or the specific dopamine D2 receptor antagonist raclopride had no effect in nonstressed animals and in vehicle-treated stressed animals, but both drugs selectively reversed the improvement of performance in imipramine-treated stressed animals. The 5HT antagonist metergoline increased sucrose consumption in all groups. The data suggest that the mechanism of action of imipramine in this model is an increase in functional activity at dopamine (DA) synapses.

Animals↗

PubMed1982

Pharmacological evidence for the involvement of serotonergic mechanisms in diffuse noxious inhibitory controls (DNIC).

The involvement of serotonergic mechanisms in diffuse noxious inhibitory controls (DNIC) acting on dorsal horn convergent neurones has been studied in the anaesthetized rat. 35 neurones activated by transcutaneous electrical stimulation of their hindpaw receptive fields giving clear large A-fibre and C-fibre responses were recorded. These activities were conditioned by DNIC, evoked by either noxious heat applied to the tail or noxious pinch of the nose. Cinanserin (4 mg/kg i.v.) and metergoline (5 mg/kg i.v.), serotonin (5-HT) receptor blockers, strongly reduced the inhibitory effects of DNIC whilst having no significant effect on the non-conditioned responses. 5-Hydroxytryptophan, a precursor of 5-HT synthesis, significantly potentiated the effect of DNIC. These results indicate an important role for descending serotonergic pathways in DNIC. The functional role of this system is discussed.

5-Hydroxytryptophan↗

PubMed1986

Characterization and quantitative autoradiography of [3H]tryptamine binding sites in rat brain.

[3H]Tryptamine binds with high affinity (Kd = 9.1 nM, Bmax = 54 fmol/mg wet wt.) to tissue sections of rat brain. The binding occurs rapidly and is reversible. Low concentrations of the beta-carbolines harmaline (IC50 = 25 nM) and tetrahydronorharman (tetrahydro-beta-carboline, IC50 = 50 nM) inhibit [3H]tryptamine binding. Serotonin (5-HT, IC50 = 2600 nM) as well as the 5-HT receptor antagonists methysergide and metergoline displace [3H]tryptamine at much higher concentrations from brain slices. The distribution of [3H]tryptamine binding sites in sections of rat brain has been analyzed by quantitative autoradiography. The highest density of binding sites is found in the nucleus (n.) interpeduncularis, a slightly lower one in the locus coeruleus. Moderately labelled are the n. accumbens septi, n. septi lateralis, n. medialis habenulae, n. tractus olfactorii lateralis, the central region of the amygdala, n. caudatus/putamen, n. reuniens and the hippocampal formation. A low density of binding sites is detected in the cerebral cortex and the subiculum. Even less binding sites are found in the n. dorsalis raphe and the substantia nigra. The pattern of distribution of [3H]tryptamine binding sites differs from that of [3H]5-HT (5-HT1), [3H]ketanserin (5-HT2) as well as [3H]imipramine binding sites. These data suggest unique tryptamine binding sites.

Animals↗

PubMed1990

The response of suprachiasmatic neurons of the rat hypothalamus to photic and serotonergic stimulation.

Single-unit activity of the rat suprachiasmatic nucleus and surrounding regions was recorded in vivo. Photically responsive neurons were typically inhibited by low intravenous doses of the serotonin (5-HT) agonist quipazine. The 5-HT antagonist, metergoline, administered in a low intravenous dose, reversed the effects of quipazine. The subsequent response to photic stimulation was essentially identical to the initial photic response. Thus the photic response of neurons in the suprachiasmatic nucleus (SCN) and adjacent regions is relatively uninfluenced by 5-HT blockade.

Action Potentials↗

PubMed1991

Interactions between serotonin and substance P in the spinal regulation of nociception.

Interactions between 5-hydroxytryptamine (5-HT) and substance P (SP) in the mouse spinal cord were investigated using the tail-flick test and the behavioral response evoked by intrathecal (i.th.) SP or i.th. 5-HT. I.th. injection of 5-HT (20 micrograms) or the 5-HT1 receptor agonists (+)-8-hydroxy-2-(di-n-propylamino)tetralin ((+)-8-OH-DPAT) (20 micrograms) or 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (RU 24969) (20 micrograms) markedly inhibited the tail-flick reflex. The effect of these compounds was reduced when SP (5 micrograms) was given i.th. 55 min, or 55 and 45 min before the agonists. The tail-flick latencies recorded 5 min before injection of a 5-HT receptor agonist were similar in animals treated with SP or vehicle. The changes in the tail-flick test were not due to changes in tail skin temperature since only minimal differences in the skin temperature were recorded between the groups injected with SP or vehicle. I.th. injection of SP (10 ng) or 5-HT (2 micrograms) produced a similar behavioral response consisting of biting, licking and scratching of the caudal part of the body, indicative of nociceptive stimulation. The responses both to i.th. SP and 5-HT were reduced after i.th. application of the SP receptor antagonist [D-Arg1,D-Trp7.9,Leu11]-SP (Spantide) (5 micrograms), as well as 5 min after i.th. injection of the 5-HT receptor antagonist metergoline (4 micrograms). The data may indicate functional interactions between SP and 5-HT in the mouse spinal cord, which may take place in neurons involved in the processing of nociception.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1995

Monoaminergic and cholinergic modulation of REM-sleep timing in rats.

The effects on sleep structure of systemic administration of benchmark cholinergic, serotonergic, and noradrenergic antagonists (QNB, ritanserin, metergoline, and prazosin) were characterized in rats using a new technique for identifying transitions (NRTs) from non-REM (NREM) sleep to REM sleep. In agreement with previous studies, all agents tested reduced REM-sleep expression (by 36-86%). In addition, the serotonergic and noradrenergic antagonists reduced NRT frequency (by 58-81%). The cholinergic antagonist QNB had no effect on NRT frequency. These findings suggest that blockade of serotonergic or noradrenergic receptors increases the interval between REM-sleep episodes, perhaps reducing the rate of accumulation of REM-sleep propensity. Blockade of cholinergic receptors, by contrast, decreases REM-sleep expression by interfering with REM-sleep maintenance, not by modulating REM-sleep timing. These conclusions are contrary to the predictions of a number of published models of REM-sleep timing.

Animals↗