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J J Hagan

Publications and source records attributed to J J Hagan.

At least 19 recordsLinked to original sources
PubMed1999

Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains.

Detailed characterisation of six inbred strains of mice commonly used in transgenic and knockout research was carried out using a battery of behavioural tests (SHIRPA) followed by discriminant analysis of the data. In the primary observation screen, DBA/2 mice were relatively irritable and vocalised during handling. C57BL/6 were hyperactive as measured by transfer arousal, arena activity and touch-escape tests. By contrast, C3H were markedly hypoactive, had significantly enhanced grip strength and were also significantly impaired on the visual placing task. In the elevated plus-maze, BALB/c mice showed the highest level of open arm entries and time spent in the open arms, indicating the lowest level of anxiety. There was a clear dissociation of strains on exploratory activity, as measured in the holeboard test and spontaneous locomotor activity (LMA). DBA/2 mice were hyperactive in LMA but demonstrated relatively low levels of holeboard exploration. None of the six strains learnt the water maze spatial learning task particularly well. C57BL/6 and 129/Sv demonstrated most ability and C3H showed no evidence of having acquired the task. The SHIRPA screening battery and discriminant analysis of the data have enabled us to determine the relevant contribution of a number of behavioural measurements to the marked differences in phenotype of mouse strains. These data confirm the importance of carrying out a comprehensive profile in order to accurately characterise the phenotype of gene-targeted and transgenic mice.

Animals↗
PubMed1999

Orexin A activates locus coeruleus cell firing and increases arousal in the rat.

The localization of orexin neuropeptides in the lateral hypothalamus has focused interest on their role in ingestion. The orexigenic neurones in the lateral hypothalamus, however, project widely in the brain, and thus the physiological role of orexins is likely to be complex. Here we describe an investigation of the action of orexin A in modulating the arousal state of rats by using a combination of tissue localization and electrophysiological and behavioral techniques. We show that the brain region receiving the densest innervation from orexinergic nerves is the locus coeruleus, a key modulator of attentional state, where application of orexin A increases cell firing of intrinsic noradrenergic neurones. Orexin A increases arousal and locomotor activity and modulates neuroendocrine function. The data suggest that orexin A plays an important role in orchestrating the sleep-wake cycle.

Animals↗
PubMed1999

Influence of peptide CRF receptor antagonists upon the behavioural effects of human/rat CRF.

The effects of the corticotropin-releasing factor (CRF) receptor antagonists, alpha-helical CRF-(9-41), [D-Phe12,Nle21,38, CalphaMe-Leu37]humanCRF-(12-41) (D-PheCRF-(12-41)) and astressin ([cyclo(30-33)[D-Phe12,Nle21,38,Glu30,Lys33]h umanCRF-(12-41) upon hypophagic and motor activation response to human/ratCRF (h/rCRF) were investigated. All three antagonists (100 microg intracerebroventricular (i.c.v.)) blocked the effects of h/rCRF (1 microg i.c.v.) upon food intake and body weight change in food-deprived rats. In contrast, alpha-helical CRF-(9-41) and astressin (both at 100 microg i.c.v., but not lower doses), but not D-PheCRF-(12-41) (up to 100 microg i.c.v.), blocked h/rCRF (0.3 microg i.c.v.)-induced motor activation in rats in a familiar environment. The ability of D-PheCRF-(12-41) to block CRF-induced hypophagia, but not motor activation, suggests a selective action of this antagonist upon the behavioural effects of centrally administered h/rCRF.

Animals↗
PubMed1999

Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells.

1. The aim of the present study was to characterize functional responses to ropinirole, its major metabolites in man (SKF-104557 (4-[2-(propylamino)ethyl]-2-(3H) indolone), SKF-97930 (4-carboxy-2-(3H) indolone)) and other dopamine receptor agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in Chinese hamster ovary cells using microphysiometry. 2. All the receptor agonists tested (ropinirole, SKF-104557, SKF-97930, bromocriptine, lisuride, pergolide, pramipexole, talipexole, dopamine) increased extracellular acidification rate in Chinese hamster ovary clones expressing the human D2, D3 or D4 receptor. The pEC50s of ropinirole at hD2, hD3 and hD4 receptors were 7.4, 8.4 and 6.8, respectively. Ropinirole is therefore at least 10 fold selective for the human dopamine D3 receptor over the other D2 receptor family members. 3. At the hD2 and hD3 dopamine receptors all the compounds tested were full agonists as compared to quinpirole. Talipexole and the ropinirole metabolite, SKF-104557, were partial agonists at the hD4 receptor. 4. Bromocriptine and lisuride had a slow onset of agonist action which precluded determination of EC50s. 5. The rank order of agonist potencies was dissimilar to the rank order of radioligand binding affinities at each of the dopamine receptor subtypes. Functional selectivities of the dopamine receptor agonists, as measured in the microphysiometer, were less than radioligand binding selectivities. 6. The results show that ropinirole is a full agonist at human D2, D3 and D4 dopamine receptors. SKF-104557 the major human metabolite of ropinirole, had similar radioligand binding affinities to, but lower functional potencies than, the parent compound.

Animals↗
PubMed1998

The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function both in vitro and in vivo.

5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.

Animals↗
PubMed1998

The behavioural effects of corticotropin-releasing factor-related peptides in rats.

The present study determined the behavioural effects of the corticotropin releasing factor (CRF)-related peptides, human/rat CRF (h/rCRF), ovine CRF (oCRF), sauvagine (SAUV), urotensin I (UT) and the recently discovered neuropeptide, rat urocortin (rUCN). All of the peptides dose-dependently increased motor activity in a familiar environment and reduced feeding in hungry rats. There was no apparent relationship between potency/affinity at CRF2 receptors and effects in these two tests. In a comparison of h/rCRF and rUCN upon discrete spontaneous behaviours, both peptides (3.0 microg i.c.v.) increased activity and grooming, induced a fore-paw tremor and reduced the incidence of motionlessness. However, h/rCRF reduced motionlessness to a greater extent and was a more potent inducer of defaecation, weight loss, oral movements and fore-paw tremor than rUCN. In the elevated X maze, both h/rCRF and rUCN (1.0 microg i.c.v.) had anxiogenic-like effects upon behaviour. In contrast, h/rCRF (1.0 microg i.c.v.), but not rUCN (1.0-10 microg i.c.v.) increased the startle response to an acoustic stimulus. In summary, all the CRF-related peptides increased motor activity and reduced feeding in rats in a similar manner and both rUCN and h/rCRF induced anxiogenesis. However, there were some behavioural differences between rUCN and h/rCRF which require further study. Further pharmacological investigation of the role of CRF receptor subtypes requires the use of subtype selective antagonists.

Animals↗
PubMed1998

Sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, reverses delay-induced deficits in the T-maze.

Sabcomeline, (SB-202026 [R-(Z)-alpha-(methoxyimino)-1 -azabicyclo [2.2.2] octane-3-acetonitrile]), a functionally selective muscarinic M1 receptor partial agonist, was tested in rats trained to perform a delayed, reinforced alternation task in a T maze, a test of short-term spatial memory. For comparison the cholinesterase inhibitor tacrine (THA-9-amino- 1,2,3,4-tetrahydroaminoacridine) and the non-selective muscarinic receptor agonist RS86 (2-ethyl-8-methyl-2,8 diazospiro [4.5]-decane-1,3-dione hydrobromide) were also tested and all three compounds were also compared using a conditioned taste aversion (CTA) task. Sabcomeline (0.001-1.0 mg/kg i.p.) significantly reversed the T-maze choice accuracy deficit induced by a 20-s delay at 0.03 and 0.1 mg/kg. RS86 (0.1-3.0 mg/kg i.p.) reversed the deficit at 1.0 mg/kg and THA (0.1-3.0 mg/kg i.p.) had no effect at any dose. All three compounds induced conditioned taste aversion with minimum effective doses (MED) of 0.3, 1.0 and 3.0 mg/kg, respectively. The results show that sabcomeline reverses delay induced deficits in T-maze choice accuracy in a rewarded alternation task at doses approximately 10 times lower than those required to induce conditioned taste aversion. RS86 was equipotent in both tests. These data support the findings of clinical studies which have shown that SB-202026 provides significant symptomatic improvement in patients with probable Alzheimer's disease at doses which do not induce cholinergic side effects.

Animals↗
PubMed1998

The effects of dopamine D3/D2 receptor agonists on intracranial self stimulation in the rat.

The effects of the dopamine D3/D2 receptor agonists quinpirole, quinelorane and (+/-)7-OH-DPAT [(+/-) 7-hydroxy-2(N,N-di-n-propylamino) tetralin] on intracranial self-stimulation (ICSS) were investigated. Rats implanted with bipolar electrodes into the lateral hypothalamus were trained to lever press on a continuous reinforcement schedule for positively reinforcing trains of electrical stimulation. Three measures of responding were calculated; the frequency at which responding was 50% of the maximum (M50), the asymptotic response rate and the total area under the curve (AUC) for each frequency sweep. Quinpirole (2.2-66.0 microg/kg SC) significantly increased M50 and reduced both asymptote and AUC. Quinelorane (0.25-79.0 microg/kg SC) had no significant effect on M50 values but significantly reduced both asymptote and AUC. (+/-)7-OH-DPAT (2.5-74.0 microg/kg) did not significantly affect any of the measures. The data show that low doses of quinpirole and quinelorane, but not (+/-)7-OH-DPAT, inhibit ICSS maintained by electrodes in the lateral hypothalamus. Either dopamine D2 or dopamine D3 receptor stimulation may play a role in mediating ICSS inhibition, but studies with more selective receptor agonists and antagonists are required to define the role of each receptor.

Animals↗
PubMed1998

A comparison of rectal and subcutaneous body temperature measurement in the common marmoset.

Two methods of measuring body temperature were compared in common marmosets. Subcutaneous temperatures were measured remotely via previously implanted subcutaneous microchips (Plexx BV, IPTT-100) prior to measurement of rectal temperature using a conventional rectal probe. Marmosets were treated with saline or the brain penetrant, 5-HT1A/B/D receptor agonist SKF-99101H (3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate) (0.3-3 mg/kg SC), which has previously been shown to induce hypothermia in guinea pigs. Body temperature was sampled immediately before drug administration and at 30-min intervals thereafter for a period of 2.5 h. SKF-99101H dose-dependently induced hypothermia in the common marmoset and there was close agreement between rectal and subcutaneous body temperatures, with an average difference in absolute body temperature of 0.26+/-0.02 degrees C. The data show that subcutaneously implanted microchips provide a simple, reliable measure of body temperature in common marmosets which is sensitive to pharmacological intervention, minimizes handling induced stress, and is minimally invasive.

Animals↗
PubMed1997

Stimulation of 5-HT1B receptors causes hypothermia in the guinea pig.

The selective, brain penetrant, 5-HT(1B/D) (formerly 5-HT(1D beta/alpha)) receptor agonist SKF-99101H (3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate) (30 mg/kg i.p.) causes a dose related fall in rectal temperature in guinea pigs which previous studies have shown to be blocked by the non-selective 5-HT(1B/D) receptor antagonist GR-127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1'biphenyl]-4-carboxamide oxalate). The present study shows that the hypothermic response to SKF-99101H is dose-dependently blocked by SB-224289G (1'-methyl-5-(2'-methyl-4'-[(5-methyl-1,2,4-oxadiazol-3-yl)bipheny l-4-yl]carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-pi peridone] hemioxalate) (0.3-10.0 mg/kg p.o.) (ED50 3.62 mg/kg), which is the first compound to be described which is more than 60 fold selective for the 5-HT1B receptor over the 5-HT1D receptor. SB-216641A (N-[3-(2-dimethylamino) ethoxy-4-methoxy-phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-car boxamide hydrochloride) (0.6-20.0 mg/kg i.p.), which is somewhat less selective (30 fold) for the 5-HT1B receptor over the 5-HT1D receptor had a similar effect (ED50 4.43 mg/kg). The brain penetrant 5-HT1D selective receptor antagonist, BRL-15572 (4-(3-chlorophenyl)-alpha-(diphenylmethyl)-1-piperazineethanol+ ++ dihydrochloride) (0.3-100.0 mg/kg i.p.) was inactive. When administered alone neither BRL-15572 (0.1-10 mg/kg i.p.) nor SB-224289G (2.2-22 mg/kg p.o.) had an effect on body temperature. These data demonstrate that 5-HT1B (formerly 5-HT(1D beta)) and not 5-HT1D (formerly 5-HT(1D alpha)) receptors mediate the hypothermic response to SKF-99101H (30 mg/kg i.p.) in guinea pigs. The compounds described are useful pharmacological tools for distinguishing responses to 5-HT1B and 5-HT1D receptors.

Animals↗
PubMed1997

Parkinson's disease: prospects for improved drug therapy.

L-Dopa has long been the mainstay of therapy for Parkinson's disease but its long-term shortcomings, principally uncoordinated, spasmodic or irregular movements (dyskinesias) and fluctuating control of motor symptoms (on/off fluctuations), are well documented. The postulated neuroprotective properties of L-deprenyl, often used as an adjunct to L-dopa, are under scrutiny and doubts have also been raised regarding its safety. Alternative therapeutic approaches are clearly needed. In this review, Jim Hagan, Derek Middlemiss, Paul Sharpe and George Poste outline some new approaches to treatment, with an emphasis on novel, selective dopamine receptor agonists. In addition, Parkinson's disease is commonly thought to be caused by the neurotoxic effects of an unidentified agent but recent data indicate a greater genetic component than previously recognized. Developments in the genetics of Parkinson's disease may provide the key to the next generation of therapeutics.

Animals↗
PubMed1997

Chronic mild stress-induced reductions in saccharin intake depend upon feeding status.

The consumption of a weak saccharin solution was examined in rats subjected to chronic mild stress (CMS). Intake of saccharin was reduced in stressed animals compared to isolated and group control animals but saccharin preference was not affected. Removal of water deprivation from the CMS schedule did not alter the effects of CMS upon saccharin intake. However, when food deprivation was omitted entirely from the CMS schedule the reduction in saccharin intake was eliminated. Similarly, in animals habituated to the full CMS procedure, reduction in saccharin intake was abolished by omitting food deprivation or by delaying the intake test for 24 h. Both CMS and food deprivation reduced water intake but had no effect on food consumed during the fluid-intake test. The presence of food deprivation during CMS appears to be a key factor affecting saccharin intake. Our data suggest that saccharin intake is not an appropriate measure of stress and anhedonia.

Animals↗
PubMed1996

A computer-controlled apparatus for measuring and analysing myoclonic jerk activity in guinea pigs.

Guinea pigs respond to 5-hydroxytryptophan (5-HTP) with a complex behavioural syndrome which includes distinctive whole-body jerks (myoclonic jerks). These are species-specific, involve all major muscle groups, are highly rhythmic and can occur with relatively high frequency (1-2/s). Current methods of quantifying the response, which rely on observer ratings are unsatisfactory. We report the development of a fully automated, PC-based system for detecting and analysing myoclonic jerks. Floor-mounted accelerometers generate a movement signal and detection is performed by an algorithm based on a detailed analysis of the topography of myoclonic jerk responses. The system can monitor the output from 10 purpose-built test enclosures and it provides for pseudorandom treatment allocation, flexible control of experimental parameters and automated data output to a spreadsheet which generates appropriate graphs, statistical summaries and data analysis. This robust response provides a useful means of exploring the role of novel 5-HT receptor subtypes in guinea-pig behaviour.

Algorithms↗
PubMed1995

The role of 5-HT1D and 5-HT1A receptors in mediating 5-hydroxytryptophan induced myoclonic jerks in guinea pigs.

Systemic administration of 5-hydroxytryptophan (5-HTP) to guinea pigs causes species-specific, rhythmic, whole body jerks (myoclonic jerks), the frequency and amplitude of which were measured in an automated apparatus. The brain penetrant 5-HT1D receptor agonist 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate (SKF 99101H) (3-30 mg/kg i.p.) and the selective 5-HT1A receptor agonist (+/-)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.3-3 mg/kg s.c.) dose dependently potentiated the frequency and intensity of myoclonic jerks caused by 5-HTP (100 mg/kg). Cotreatment of guinea pigs with 8-OH-DPAT (3 mg/kg s.c.) and SKF 99101H (30 mg/kg i.p.), which were inactive when given alone, gave a marked myoclonic jerk response. Conversely, the myoclonic jerk response to higher doses of 5-HTP (150 mg/kg i.p.) was dose dependently blocked by the 5-HT1D receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)[1,1'-biphenyl]4-carboxamide oxalate) (ED50 0.32 mg/kg i.p.) and the selective 5-HT1A receptor antagonist WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) (ED50 0.33 mg/kg i.p.). The response to 5-HTP (150 mg/kg i.p.) was also blocked by ritanserin (0.01-0.3 mg/kg i.p.). Our data therefore confirm previous reports concerning the effects of 5-HT2A/2C receptor blockade on 5-HTP induced myoclonic jerks and suggest that both 5-HT1D and 5-HT1A receptors play an important role in mediating this behavioural response.

5-Hydroxytryptophan↗