Biomedical subjects

J Harro

Publications and source records attributed to J Harro.

At least 55 records · Page 3Linked to original sources

PubMed1995

Impaired exploratory behaviour after DSP-4 treatment in rats: implications for the increased anxiety after noradrenergic denervation.

The effect of DSP-4, a neurotoxin selectively affecting the projections of the locus coeruleus, upon exploratory behaviour of rats was studied in a complex exploration test, including a choice between open and enclosed areas and both inquisitive and inspective exploration elements. One week after DSP-4 (50 mg/kg i.p.) administration, the neurotoxin-treated rats did not explore a novel open area to any extent on the first exposure to the apparatus; however, on the third day of testing, these animals began to explore the area and the novel objects. Diazepam (0.5 mg/kg) treatment did not change the behaviour of control rats, but significantly increased the exploratory activity of the DSP-4-treated animals. LY 288513, a selective CCKB receptor antagonist (0.01 mg/kg), prevented the increase in exploratory activity in the DSP-4-treated rats, but increased the exploratory activity of controls on the third exposure to the test situation. The results of this investigation suggest that DSP-4 treatment reduces neotic behaviour by increasing neophobia rather than by decreasing exploratory drive. The divergence reported between the relative potencies of CCKB receptor antagonists in exploratory activity and other anxiety tests may in part be due to the effects of these drugs on exploratory drive.

Adrenergic Agents↗

PubMed1994

Opposite effects mediated by CCKA and CCKB receptors in behavioural and hormonal studies in rats.

We compared the influence of two cholecystokinin (CCK) antagonists, devazepide and L-365,260 [3R-(+)-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3y l)-N'-(3-methyl-phenyl)urea], upon two distinct phenomena, behavioural and hormonal effects of caerulein (5 micrograms/kg s.c.), and unselective CCK agonist, in rats. Behavioural effects were assessed in the elevated plus-maze and open field tests. In separate experiments, effects on thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) levels in serum of male rats were studied. Caerulein inhibited the exploratory behaviour in the plus-maze. Time spent in the open part, the number of line crossings and closed arm entries were significantly decreased, whereas the ratio of failed attempts/closed arm entries was increased. The anti-exploratory effect of caerulein was antagonized by the pretreatment with L-365,260 (10 micrograms/kg), a preferential antagonist at CCKB receptors, but was increased by devazepide (1-100 micrograms/kg), a preferential CCKA antagonist. L-365,260 (1-100 micrograms/kg) and devazepide (1-100 micrograms/kg) given alone did not change the behaviour of rats in the plus-maze test. Caerulein (5 micrograms/kg) itself did not modify the locomotor activity of rats in open field. However, the concomitant administration of caerulein with devazepide (1-10 micrograms/kg) reduced the frequency of line crossings and rearings. In the hormonal studies caerulein significantly decreased the cold-induced increase of TSH levels in serum. GH and PRL levels were not markedly affected by caerulein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Evidence for potentiation by CCK antagonists of the effect of cholecystokinin octapeptide in the elevated plus-maze.

Systemic treatment with cholecystokinin octapeptide (CCK-8, 2.5-10 micrograms/kg, s.c.), a non-selective CCK agonist, decreased the exploratory activity of mice in an elevated plus-maze. At higher doses (5-10 micrograms/kg) CCK-8 reduced the frequency of rearing, but only 10 micrograms/kg of CCK-8 significantly inhibited the number of line crossings in the open-field test. A preferential CCKB antagonist L-365,260 (1 and 100 micrograms/kg, i.p.) and a non-selective CCK antagonist proglumide (0.1-1 microgram/kg, i.p.) potentiated the anti-exploratory effect of CCK-8 (2.5 micrograms/kg). Devazepide, a preferential CCKA antagonist, only at a high dose (100 micrograms/kg) tended to increase the action of CCK-8 in the plus-maze. However, the concomitant treatment of CCK-8 with L-365,260 and proglumide, differently from devazepide, also suppressed the locomotor activity in the open-field test. Therefore, it is likely that the potentiation by CCK antagonists of the anti-exploratory effect of CCK-8 is related to the suppression of motor activity. This peculiar interaction between CCK-8 and CCK antagonists could be explained in the light of the opposite role of CCKA and CCKB receptors in the regulation of motor activity in mice.

Animals↗

PubMed1994

Anxiolytic-like effect of the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA) on rat exploratory activity.

Vigabatrin (gamma-vinyl GABA, GVG) is an irreversible inhibitor of GABA-transaminase (GABA-T). This study addressed the question of whether or not the inhibition of GABA-T has an anxiolytic effect in rats. Diazepam (1.5 mg/kg) and GVG (50 and 500 mg/kg) increased the tendency of rats to explore in the elevated plus-maze test, whereas the effect of general locomotor activity was diminished. The sedative effect of GVG (500 mg/kg) was more pronounced 6 h than 2 h after IP administration. The present findings suggest that even a partial inhibition of GABA-T results in a reduction of anxiety measures in a novel environment.

4-Aminobutyrate Transaminase↗

PubMed1994

Cholecystokinin receptor binding in morphine analgesia: tolerance, withdrawal and abstinence.

The effect of morphine treatment on cholecystokinin (CCK) receptor binding in rat cerebral cortex was investigated. Subcutaneous implantation and removal of Alzet miniosmotic pumps, releasing morphine, permitted us to establish the phases of initial analgesia, tolerance to the analgesic action of morphine, morphine withdrawal and abstinence. CCK receptor binding in rat cerebral cortex never differed from the values obtained from animals implanted with saline-releasing minipumps. The results of the present study suggest that the putative changes in the interaction between opioidergic and CCKergic neurotransmission at different stages of morphine treatment and withdrawal are not caused by changes of CCK receptor binding properties.

Analgesia↗

PubMed1994

Subdiaphragmatic vagotomy does not prevent the anti-exploratory effect of caerulein in the elevated plus-maze.

We compared the action of subdiaphragmatic vagotomy upon the anti-exploratory and motor depressant effects of caerulein, an agonist of cholecystokinin (CCK) receptors, in male rats. Vagotomized rats entered more frequently into the open arms of elevated plus-maze compared to intact control rats. Caerulein (1 microgram/kg subcutaneously (s.c.)) significantly suppressed the exploratory behaviour in vagotomized rats but not in intact and sham-operated rats. In contrast, subdiaphragmatic vagotomy did not change the locomotor activity of rats in open field compared to intact and sham-operated animals. At a higher dose (10 micrograms/kg s.c.), the caerulein pretreatment markedly decreased the number of line crossings, rearings and head-dippings of intact animals in open field. In sham-operated rats caerulein also suppressed the locomotor activity, whereas in vagotomized rats it only tended to reduce the frequency of rearings. Consequently, the present study revealed the different action of vagotomy upon the motor depressant and anti-exploratory effects of caerulein. These results support the view that CCKA receptors in the gastrointestinal tract are mediating the motor depressant, whereas CCKB receptors in the brainstem are involved into the mediation of anti-exploratory effect of caerulein.

Animals↗

PubMed1994

Cholecystokinin receptor binding after long-term ethanol treatment in rats.

Brain cholecystokinin (CCK) receptors have been implicated in anxiety disorders and suicidal behaviour. We have examined the radioligand binding ability of CCK and benzodiazepine receptors in rat brain after long-term intermittent voluntary vs voluntary and forced low-dose ethanol exposure. During 58 weeks, one group of rats had a choice between ethanol and water as the drinking fluid for 24 hr each week. Another group of rats had the same weekly choice between ethanol and water, but at the end of each 24 hr choice period, ethanol (2.0 g/kg) was injected. During the second period of ethanol treatment, lasting for 32 weeks, both ethanol-treated groups had continuous free access to ethanol and water. These two treatments have previously been shown to induce partially different neurochemical alterations. In the present investigation, benzodiazepine receptor binding in the frontal cortex, hippocampus and striatum was similar in both ethanol treatment groups compared to controls. CCK receptor binding in the hippocampus and striatum did not differ between the three groups; however, in the frontal cortex, there was an increase in the apparent number of CCK binding sites in the group of rats submitted to voluntary plus forced ethanol exposure as compared to the control group or the voluntary intake group. These results suggest that long-term ethanol treatment may lead to alterations in brain CCK-ergic neurotransmission, but that the changes are specific to the treatment schedule.

Alcoholism↗

PubMed1993

Social isolation of rats increases the density of cholecystokinin receptors in the frontal cortex and abolishes the anti-exploratory effect of caerulein.

The role of cholecystokinin (CCK) receptors in the development of anxiety caused by social isolation of rats was studied using the elevated plus-maze and receptor binding techniques. The isolation of male Wistar rats significantly reduced their exploratory activity in the elevated plus-maze compared with that of rats kept in groups of four. Caerulein (0.1-5 micrograms/kg s.c.), an agonist at CCK receptors, only at the highest dose (5 micrograms/kg) significantly decreased the exploratory behaviour of rats housed in groups, but not in the isolated rats. By contrast, small doses of caerulein (0.1-0.5 microgram/kg) even tended to increase the behavioural activity of isolated rats in the plus-maze test. In parallel to the behavioural changes, isolation of the rats increased the number of [3H]pCCK-8 binding sites in the frontal cortex, but not in the other forebrain structures (the mesolimbic area, striatum and hippocampus). Isolation did not affect the density of benzodiazepine receptors in the frontal cortex. In conclusion, the isolation of rats for 7 days produced anxiogenic-like effect on the behaviour of rats and increased the number of CCK receptors in the frontal cortex without affecting benzodiazepine receptors.

Animals↗

PubMed1993

CCKB receptor activation reduces glutamate-induced depolarization in slices of rat cerebral cortex.

Recent studies on cell cultures have indicated that the neuropeptide cholecystokinin (CCK) can prevent glutamate-induced cytotoxicity. In a preparation of rat cortical tissue placed into a two-compartment bath, the cortical tissue could be depolarized, relative to the corpus callosum, by superfusions of KCl or glutamate (1.25-10 mM). Caerulein (1-100 nM), a CCK receptor agonist, caused a rightward shift of the glutamate dose-response curve. The effect of caerulein was abolished by adding L365,260 (1 microM), a selective CCKB receptor antagonist. These findings suggest that CCK may be a physiological antagonist of glutamate-mediated neurotransmission in the rat brain.

Animals↗

PubMed1993

Ondansetron, an antagonist of 5-HT3 receptors, antagonizes the anti-exploratory effect of caerulein, an agonist of CCK receptors, in the elevated plus-maze.

Systemic treatment with caerulein (0.25-5 micrograms/kg SC), non-selective agonist of cholecystokinin (CCK) receptors, dose-dependently suppressed the exploratory behaviour of rats in an elevated plus-maze without producing remarkable changes in the locomotor activity of animals in an open field test. Ondansetron, a selective antagonist of 5-HT3 receptors, increased the number of open arm entries in the plus-maze test only at a dose 10 micrograms/kg. The other doses of ondansetron (0.1, 1 and 100 micrograms/kg IP) did not significantly change either the locomotor activity or the exploratory behaviour of rats. Pretreatment of rats with ondansetron (at 10 micrograms/kg, but not at 0.1, 1 or 100 micrograms/kg) completely reversed the anti-exploratory effect of caerulein (5 micrograms/kg). The concomitant treatment with caerulein and ondansetron did not cause any major change in the locomotor activity of animals in open field. Consequently, we propose that 5-HT-ergic mechanisms are involved not only in the regulation of CCK release in the cerebral cortex and nucleus accumbens, but also in the modulation of the anti-exploratory effect of caerulein, a CCK agonist, in the elevated plus-maze.

Animals↗

PubMed1993

Cholecystokinin receptors and memory: a radial maze study.

CCK receptor agonists and antagonists have repeatedly been demonstrated to improve and impair, respectively, learning and memory functions. However, all studies to date have exploited avoidance paradigms. In the present study, the effect of some CCK receptor agonists and antagonists on the ability to learn an appetitively motivated task and to influence spatial working memory was investigated. In the first experiment, drugs were given immediately after each training session in the radial maze and the animals were tested, drug-free, during a 2-week period. After the initial treatments with caerulein, an unselective CCK receptor agonist (100 ng/kg SC), the animals were slightly less successful to obtain food pellets during the sessions on the first 2 days; whereas proglumide, an unselective CCK receptor antagonist (1 mg/kg SC) was without any effect. However, on the following days, all the three groups of rats (saline, caerulein, and proglumide) performed in a similar way. In the second experiment, drugs were given before each test session to well-trained animals. Scopolamine (0.15 and 0.3 mg/kg IP), the reference amnestic drug, produced dose-dependent impairment of working memory in the radial maze test. Proglumide (1 and 10 mg/kg SC) and devazepide, (a selective CCK-A receptor antagonist; 0.01 and 1 mg/kg SC), as well as caerulein (0.01, 0.1 and 1 microgram/kg SC) and CCK-4 (a selective CCK-B receptor agonist; 25 and 50 micrograms/kg SC) had no reliable effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

CCK in animal and human research on anxiety.

Much data has accumulated over the past decade supporting the hypothesis that CCK plays a role in the neurobiology of anxiety and panic attacks. These data originated from animal studies and human studies that were initiated independently, but the conclusions are remarkably consistent. In this review, Jacques Bradwejn and colleagues examine the evidence for a role of CCK in anxiety and panic attacks, and highlight the consistencies between animal and human studies.

Animals↗

PubMed1993

Anti-exploratory effect of N-methyl-D-aspartate in elevated plus-maze. Involvement of NMDA and CCK receptors.

N-Methyl-D-aspartate (NMDA, 20 mg/kg) produced a clear decrease in mouse exploration in open parts of an elevated plus-maze. Paradoxically, 40 mg/kg NMDA did not modify the behavior of the mice in the plus-maze. NMDA at a dose of 80 mg/kg again depressed the exploratory activity of mice, but this effect was accompanied with tremor and compulsive tail biting. The 'anti-exploratory' dose of NMDA (20 mg/kg) increased, whereas the 'tremorigenic' dose (80 mg/kg) significantly decreased the number of cholecystokinin (CCK) binding sites in the mouse cerebral cortex. The competitive NMDA antagonist (+/-)-CPP (2.5-5 mg/kg) and the non-competitive antagonist MK-801 (0.25 mg/kg) antagonized the anti-exploratory effect of NMDA (20 mg/kg). The tricyclic antidepressant imipramine (5 mg/kg, but not 1 or 10 mg/kg) also attenuated the inhibition of exploratory activity induced by NMDA. Of three CCK receptor antagonists tested, the unselective CCK antagonist proglumide (1 mg/kg, but not 0.1 and 10 mg/kg) significantly opposed the anti-exploratory action of NMDA. The selective CCK antagonists L-365,260 (1 microgram/kg) and devazepide (1 microgram/kg) were evidently weaker antagonists of NMDA. Furthermore, 10 micrograms/kg of L-365,260, a CCK-B receptor antagonist, and 1 mg/kg of devazepide, a CCK-A receptor antagonist, even tended to augment the effect of NMDA in the plus-maze. The results of the present study seem to give some support to the notion that not only NMDA receptors, but also CCK-ergic mechanisms are involved in the modulation of anti-exploratory action of NMDA in the elevated plus-maze.

Analysis of Variance↗

PubMed1992

Changes in cholecystokinin receptor binding in rat brain after selective damage of locus coeruleus projections by DSP-4 treatment.

Brain cholecystokinin (CCK)- and noradrenergic activities are two neurochemical systems implicated in anxiety and deficits in novelty-related behaviour. In order to clarify a possible interaction between CCK- and noradrenergic neurotransmission in the brain, DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a neurotoxin that selectively destroys noradrenaline-containing nerve terminals originating from the locus coeruleus, was administered to rats IP (10 and 50 mg/kg) seven days before decapitation. Noradrenaline uptake was very markedly reduced in the frontal cortex and hippocampus of the DSP-4 treated animals, whereas the decrease in the hypothalamus was smaller but still statistically significant. Dopamine uptake in the corpus striatum, as well as serotonin uptake in the frontal cortex, hippocampus and hypothalamus, were not influenced by DSP-4 treatment. Concomitantly, CCK receptor binding in certain brain regions was markedly affected. Thus, CCK receptor density was significantly higher in the frontal cortex and hippocampus of DSP-4-treated rats. If desipramine (25 mg/kg) was administered before DSP-4 treatment, the DSP-4-induced changes both in noradrenaline uptake and CCK receptor binding were not present, suggesting that both effects were exerted after uptake of the neurotoxin by the nerve terminals. The time-course of the development of changes in CCK-8 binding paralleled with some lag the development of changes in noradrenaline uptake. These findings demonstrate the denervation of noradrenergic input from the locus coeruleus induces certain alterations in the CCKergic neurotransmission. These alterations are similar to those seen in rats with deficits in response to novel stimuli, and may therefore mediate the neophobic responses observed in animals after lesions of noradrenergic innervation of the forebrain.

Animals↗

PubMed1992

Possible role of cholecystokinin-A receptors in regulation of thyrotropin (TSH) secretion in male rats.

We studied the importance of cholecystokinin (CCK) system in the regulation of thyrotropin (TSH) and prolactin (PRL) secretion in male rats. To this end, we tested the effects of both unselective CCK agonists CCK-8 and caerulein, and CCK-B selective agonists CCK-4 and pentagastrin as well as the selective CCK antagonists (devazepide and L-365,260) at wide dose-ranges on the cold-stimulated and TRH-induced TSH and PRL secretion. Caerulein, given s.c. 15 min before sacrifice, decreased TSH levels at 5 micrograms/kg. In time course-studies, the maximum inhibition was seen at 15 min but the effect lasted at least 30, but less than 60 min. Also CCK-8 decreased TSH levels at the doses of 20 and 50 micrograms/kg at 15 min. Devazepide and L-365,260 did not affect TSH or PRL levels at any dose. The effect of caerulein (5 micrograms/kg) was antagonized by devazepide, a CCK-A antagonist, at 100 micrograms/kg, but not by a CCK-B antagonist L-365,260 tested at a wide dose range. PRL levels were not affected by any treatment. Caerulein (5 micrograms/kg), given at the same time as TRH (500 ng/kg), inhibited the TRH-induced TSH levels at 15 min, but not at 30 or 60 min. CCK-8 (50 micrograms/kg), CCK-4 (100 micrograms/kg) and pentagastrin (500 micrograms/kg) did not affect the TRH-induced TSH secretion. The results probably indicate that CCK-A receptor stimulation inhibits TSH secretion at the level of the anterior pituitary gland. PRL levels in male rats are not affected by CCK system.

Animals↗

PubMed1992

Age-related differences of cholecystokinin receptor binding in the rat brain.

1. Cholecystokinin and benzodiazepine receptor binding was evaluated in 2-, 9- and 18-month old rats in the brain regions where cholecystokinin octapeptide and gamma-aminobutyric acid are known to coexist in common nerve cells (frontal cortex, hippocampus). 2. There was a regionally selective alteration of hippocampal 3H-CCK-8 binding in the oldest age group, if compared to both young and adult animals. Non-linear regression analysis of binding data revealed significantly lower apparent number of binding sites (Bmax), and twofold (but not statistically significantly) higher binding affinity for the radiolabelled ligand. No differences between any age groups in 3H-flunitrazepam binding to benzodiazepine receptors were found. 3. The results suggest that changes in cholecystokinin receptor characteristics might contribute to the behavioural impairments in aged rats.

Aging↗

PubMed1992

Changes at cholecystokinin receptors induced by long-term treatment with diazepam and haloperidol.

Fourteen days administration of haloperidol (1 mg/kg daily) prevented the motor depressant effect of caerulein (an agonist at cholecystokinin receptors, 15 micrograms/kg) and the antagonistic effect of caerulein (100 micrograms/kg) against (+)-amphetamine (5 mg/kg) induced hyperlocomotion in mice. The antiaggressive effect of caerulein (40 micrograms/kg) in saline-treated mice was replaced by increased aggressiveness after long-term haloperidol and diazepam (5 mg/kg daily) treatment. The anticonvulsant effect of caerulein (125 micrograms/kg) against picrotoxin (10 mg/kg) induced seizures was abolished after 14 days diazepam, but not after haloperidol, treatment. The above described changes in the mouse behaviour are probably related to the development of subsensitivity at CCKA receptors, whereas the CCKB receptor subtype becomes more sensitized to the action of caerulein after long-term haloperidol and diazepam treatment.

Aggression↗

PubMed1992

Alterations in brain cholecystokinin receptors in suicide victims.

Cholecystokinin (CCK) and benzodiazepine receptor binding characteristics were analyzed in the brain tissue samples from 19 suicide victims and 23 control cases. In the frontal cortex, significantly higher apparent number of CCK receptors and affinity constants were found in the series of suicide victims. These differences between suicides and controls were present in similar proportions when the suicide cases with depressive syndrome or violent or non-violent means of self-killing were compared to matched controls. However, when the samples were split into subgroups consisting of persons either below or over the age of 60 years, significant differences in the CCK receptor characteristics in the frontal cortex were observed only between younger suicides and controls. Furthermore, the younger suicide victims had a higher density of CCK receptors in the cingulate cortex, whereas in older suicides the value was lower as compared to age-matched controls. No difference in benzodiazepine receptor binding was found between control and suicide groups. The results of this investigation suggest that CCK-ergic neurotransmission is linked to self-destructive behaviour, probably through its impact on anxiety and adaptational deficits.

Adolescent↗