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N R Oakley

Publications and source records attributed to N R Oakley.

At least 19 recordsLinked to original sources
PubMed1997

Development of tolerance in mice to the sedative effects of the neuroactive steroid minaxolone following chronic exposure.

Minaxolone is a potent ligand for the neurosteroid binding site of the GABAA, receptor. In radioligand binding studies to rat brain membranes, minaxolone caused a 69% increase in [3H]muscimol binding and a 25% increase in [3H]flunitrazepam binding and inhibited the binding of [3H]TBOB with an IC50 of 1 microM. In mice, minaxolone (100 mg/kg, orally) had marked sedative effects as indicated by a reduction in locomotor activity. Chronic dosing with minaxolone (100 mg/kg, orally, once daily for 7 days) resulted in a loss of sedative response to an acute dose of the drug, indicating development of tolerance. Chronic dosing with temazepam (10 mg/kg, orally, once daily for 7 days) resulted in the development of tolerance to an acute dose of temazepam; however, the two drugs did not appear to be cross-tolerant, indicating that they may have a different mechanism of action at the level of the GABAA receptor.

Anesthetics↗
PubMed1996

Exogenous melatonin entrains rhythm and reduces amplitude of endogenous melatonin: an in vivo microdialysis study.

The circadian rhythm of melatonin production was studied using on-line, in vivo microdialysis in the rat pineal gland. With this technique it was possible to record a pronounced melatonin rhythm with very high time resolution. Three phase-markers of the rhythm were calculated from the data, indicating increase (IT50), decrease (DT50) and amplitude of the rhythm. Comparing these phase markers led to several conclusions. Entrainment of the rhythm under constant darkness was performed with melatonin administration at different circadian stages [circadian time (CT) 8 and CT12] and for different periods of time (2 weeks and 4 weeks). Also, entrainment was established by applying 15 min light pulses at CT0. Entrainment of IT50 with melatonin partially uncoupled it from DT50. Four weeks entrainment in constant darkness (DD) caused a phase-delay in DT50 of 2.2 hr. Entrainment of IT50 with light at CT0 for 2 weeks in DD caused a phase-advance in DT50 of 1.3 hr. The entrainment with melatonin was restricted to a narrow window for melatonin to be applied, since injections at CT8 did not result in entrainment. Exogenous melatonin reduced the amplitude of the rhythm of endogenous melatonin. This effect was not circadian time dependent, since administration at CT8 for 2 weeks and at CT12 for 4 weeks resulted in a highly significant decrease. Light did not seem to have an effect on the amplitude. The data presented here provide us with new information about the nature of entrainment by melatonin. Since the present development of melatonergic agents for clinical use focuses on the entrainment capacity, effects of these compounds on amplitude of circadian rhythms needs to be addressed. In vivo microdialysis seems to be a good technique for that.

Animals↗
PubMed1992

Effect of 5-HT1A receptor agonists in two models of anxiety after dorsal raphe injection.

The purpose of the present study was two-fold. Firstly, to present a more comprehensive analysis of the disinhibitory effects of 5-HT1A receptor agonists after discrete dorsal raphe (DRN) injections (Higgins et al. 1988). Secondly, the effects of the 5-HT1B receptor agonist CGS12066B and the 5-HT1B/1C agonist mCPP were examined following injection into this nucleus. The increases in social interaction (SI) induced by intra-raphe injections of 8-OH DPAT (0.02-1 micrograms), buspirone (0.04-0.2 microgram), ipsapirone (0.2 microgram) and gepirone (0.2-1 micrograms) under a high light unfamiliar paradigm (HLU) were typically due to increased bout frequency, duration and a higher incidence of sniff, follow, allogroom behaviour. These increases were qualitatively similar to those seen in control animals tested under low light/familiar (LLF) conditions, thus supporting the belief that the drug-induced increases in SI reflected decreases in anxiety. Furthermore, at doses effective under the HLU condition, 8-OH DPAT, buspirone and gepirone failed to modify SI under conditions of minimal suppression (LLF paradigm). At doses which significantly increased punished responding in a water-lick conflict test 8-OH DPAT, ipsapirone and gepirone tended to also increase unpunished rates of drinking. However, in drug untreated rats, prior habituation to the test apparatus also increased unpunished drinking, suggesting some neophobia-induced suppression. At a comparatively high dose, the 5-HT1B agonist CGS12066B (2.5 micrograms), but not the putative 5-HT1B/1C agonist mCPP (0.5-12.5 micrograms), increased SI under the HLU condition.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Effect of typical and atypical neuroleptics on the behavioural consequences of activation by muscimol of mesolimbic and nigro-striatal dopaminergic pathways in the rat.

Direct injections of muscimol into the ventral tegmental area (VTA) or substantia nigra zona reticulata (SNR) have been used to selectively stimulate the mesolimbic and nigro-striatal dopamine pathways respectively. Such injections induced locomotor activity, rearing, sniffing and in some animals an intermittent grooming response. These responses were rapid in onset, dose-related and relatively short lasting (less than 40 min). Selective increases in dopamine turnover were seen in the nucleus accumbens and in the striatum following VTA and SNR injections of muscimol (100 ng) respectively. Haloperidol inhibited the behavioural consequences of VTA and SNR injections of muscimol with similar potency (ED50S 0.01-0.03 mg/kg IP), and fluphenazine did likewise (ED50S 0.05-0.16 mg/kg IP). However, thioridazine (ED50S VTA: 1.45-2.04 mg/kg IP, SNR 8.50-9.20 mg/kg IP) and in particular clozapine (ED50S VTA: 0.24-0.58 mg/kg IP, SNR: 6.10-9.70 mg/kg IP) were more potent at inhibiting the locomotor activity and sniffing responses due to VTA rather than SNR administered muscimol. Since dopamine D2 antagonists are believed to exert their anti-psychotic effects via an action on mesolimbic dopaminergic systems, and their ability to induce extrapyramidal side effects (EPS) is thought to be due to an action on nigro-striatal dopamine systems, these results suggest that the behavioural models described can be used to predict efficacy and side-effect liability of potential neuroleptic drugs.

Animals↗
PubMed1991

Evidence that the amygdala is involved in the disinhibitory effects of 5-HT3 receptor antagonists.

The effects of various 5-HT3 receptor antagonists were examined in the social interaction (SI) test following discrete microinjection into either the dorsal raphe nucleus (DRN) or amygdala of the rat. Following DRN injection, ondansetron, ICS205-930, and MDL72222 (5-500 ng) all failed to modify SI under high light/unfamiliar (HLU) test conditions relative to vehicle pretreated controls. The 5-HT3 receptor agonist, 2-Me 5-HT (100-2500 ng), was similarly ineffective under both HLU and low light/familiar (LLF) conditions, although 5-HT (20-100 ng) increased SI under the HLU paradigm. After amygdaloid injection, ondansetron (10-100 ng), granisetron (1-10 ng), ICS205-930 (10-100 ng), GR 65630 (1-10 ng), and MDL72222 (100-1000 ng) all significantly increased SI under the HLU but not LLF condition. Furthermore, a detailed behavioural analysis revealed that the behaviours underlying this increase were similar to those seen in vehicle pretreated animals tested in the LLF compared to HLU condition. The benzodiazepine, flurazepam (200 ng), increased both SI (HLU condition) and punished responding in a modified water-lick conflict model, after amygdaloid injection. Both ondansetron (10-1000 ng) and ICS205-930 (1-100 ng) were ineffective in the conflict test. Finally, 2-Me 5-HT and 5-HT (100-10,000 ng) reduced SI under the LLF test condition with no concomitant change in locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1989

The effects of ondansetron (GR38032F) in rats and mice treated subchronically with diazepam.

Using rat and mouse models of aversive behaviour, we have further investigated the properties of the 5-HT3 receptor antagonist ondansetron (GR38032F) that are relevant to its proposed use as an anxiolytic agent. Tolerance to the disinhibitory properties of diazepam was readily demonstrated in the social interaction test in the rat, but did not occur after subchronic treatment with ondansetron. In both the light/dark exploration test in mice and the social interaction test in rats, withdrawal from subchronic treatment with diazepam increased behavioural suppression, whereas this was not observed with ondansetron. The behavioural suppression and weight loss induced by either the withdrawal of diazepam or the administration of the benzodiazepine receptor antagonist, flumazenil, in animals treated subchronically with diazepam, was prevented or antagonised by diazepam or ondansetron. Buspirone was ineffective. It is concluded that, in rats and mice, tolerance to the disinhibitory effects of ondansetron does not occur, that withdrawal from subchronic treatment with ondansetron is not associated with any behavioural disturbances and that ondansetron is highly effective in preventing the behavioural suppression and weight loss following withdrawal from subchronic diazepam treatment. These data suggest that ondansetron may have major therapeutic advantages over currently available anxiolytic agents, particularly in patients who have previously received prolonged benzodiazepine therapy.

Animals↗
PubMed1988

Behavioural and biochemical consequences following activation of 5HT1-like and GABA receptors in the dorsal raphé nucleus of the rat.

The behavioural and biochemical response to the 5-HT1-like receptor compounds, 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and ipsapirone and the GABA agonist, muscimol, injected into the dorsal raphé nucleus (DRN) are reported. All compounds increased social interaction under high light, unfamiliar conditions and increased punished responding in a Vogel conflict test. At doses ranging from 5-25 times greater than those which were effective in these anxiety models, muscimol, 5-CT and 8-OH-DPAT induced a marked hypothermia and a flattening of body posture. Buspirone, on the other hand, failed to induce a significant reduction in core temperature or produce a marked flattening of posture in all animals, even at doses 100 times those effective in anxiety models. Following injection of muscimol, 5-CT, 8-OH-DPAT and buspirone into the dorsal raphé nucleus, all tended to reduce the 5-HIAA:5-HT ratios in the frontal cortex, hippocampus and hypothalamus. These findings, together with available electrophysiological data suggest that these behavioural responses are a consequence of a depression of the firing of cells in the dorsal raphé nucleus, with a corresponding decrease in functional activity of 5-HT in the forebrain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist.

1. The highly selective 5-HT3-receptor antagonist, GR38032F, has been tested in five animal models predictive for anxiolytic activity. 2. In the social interaction test in the rat and in a light/dark exploration test in the mouse, GR38032F dose-dependently released suppressed behaviour without modifying locomotor activity. 3. In the cynomolgus monkey and the marmoset, GR38032F reduced anxiety-related symptoms without causing sedation. In the marmoset, the effects were clearly dose-related. 4. GR38032F did not have any detectable activity in the water-lick conflict test in the rat. 5. We conclude that GR38032F is potentially a very potent anxiolytic agent without sedative, anticonvulsant or hypnotic activity.

Animals↗
PubMed1984

The benzodiazepine receptor ligand CL218,872 has both anxiolytic and sedative properties in rodents.

The triazolopyridazine, CL218,872, inhibited the binding of [3H]flunitrazepam in the cerebellum more potently than in cortex, both in vitro and in vivo. The relationship between this phenomenon and the selectivity of benzodiazepine receptor subtypes is considered. In a range of behavioural tests the overall profile of CL218,872 was similar to that of diazepam in the rat and mouse, although CL218,872 was half as potent as diazepam in the rat and some 20-fold weaker in the mouse. In particular contrast to published observations, CL218,872 reduced locomotor activity in rats and mice at doses only slightly larger than those required to inhibit conflict in rats and footshock-induced fighting in mice. The only qualitative difference between the compounds that could be detected was in the mouse where large doses of CL218,872 did not produce the marked degree of motor incoordination seen after diazepam. However, no such difference was observed in the rat. The presently held view that CL 218,872 is a non-sedative anxiolytic agent needs to be revised in the light of these observations.

Aggression↗
PubMed1982

Differential pharmacological effects of beta-carboline-3-carboxylic acid esters.

The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid have been studied in vitro and in vivo. All three esters were found to be potent inhibitors of 3H-flunitrazepam binding in the rat cerebellum and cerebral cortex in vitro. In vivo, the methyl and ethyl esters were potent proconvulsant agents, whereas the propyl ester was not. Furthermore, the methyl ester produced convulsions which were blocked by the ethyl and propyl esters as well as by diazepam. These in vivo differences may be due to the beta-carboline esters having different proportions of agonistic and antagonistic actions at their recognition sites.

Animals↗
PubMed1978

The dorsal and medial raphe projections to the substantia nigra in the rat: electrophysiological, biochemical and behavioural observations.

Electrophysiological experiments have been performed in urethane anaesthetized rats to investigate the projections from the dorsal (DRN) and medial raphe nuclei (MRN) to the substantia nigra. The biochemical and behavioural effects following discrete electrolytic lesions in the dorsal and medial raphe have also been investigated. Stimulation of the DRN produced predominantly inhibition of spontaneous activity of single neurones in the substantia nigra though some neurones were also excited. Bilateral stimulation of the substantia nigra produced antidromic spikes in DRN and MRN neurones. Lesions of the DRN and MRN produced a significant reduction in substantia nigra 5-HT concentration. Additionally, DRN lesions reduced striatal 5-HT, while MRN lesions reduced hippocampal 5-HT. Both lesions increased substantia nigra HVA concentration but did not affect DA concentration. Neither DRN nor MRN lesions affected striatal HVA, although DA levels were significantly elevated after 14 days. Animals with DRN lesions explored more than controls or MRN-lesioned animals. However, this behaviour was transient and was not observed after 14 days. On the other hand, MRN-lesioned animals were significantly hyperactive. These observations suggest that the substantia nigra receives a direct monosynaptic inhibitory input from the DRN and MRN and that these pathways use 5-HT as a neurotransmitter serving to tonically inhibit dopaminergic neurones. While 5-HT and dopamine appear to be involved in the control of motor behaviour, the precise relationship between these serotoninergic and dopaminergic systems in this respect is unclear.

Animals↗
PubMed1977

Methiothepin and a 5-HT pathway to rat substantia nigra.

Methiothepin reduced both median-raphe evoked and exogenous 5-HT depression of single substantia nigra neurones. While this is compatible with a serotonin releasing pathway, additional interactions of methiothepin with exogenous dopamine suggest the need for further pharmacological confirmation.

Acetylcholine↗
PubMed1976

Evidence for the existence of a raphe projection to the substantia nigra in rat.

The effect of electrical stimulation of the median raphe nucleus on the activity of spontaneously firing single neurones in the substantia nigra and mesencephalic reticular formation (MRF) has been investigated in urethane anaesthetized rats. Depression of activity was the predominant effect observed although this was sometimes accompanied by periods of excitation. Some neurones were only excited. The latency of inhibition of substantia nigra neurones was constant whereas that of MRF neurones was more variable. Microiontophoretically applied 5-hydroxy-tryptamine (5-HT) and dopamine (DA) produced mainly inhibition of neuronal activity, but excitation and biphasic effects were also seen. There was a good correlation between the direction of neuronal responses in the substantia nigra to median raphe stimulation and to the effects of 5-HT but not DA. Discrete electrolytic lesions of the median raphe nucleus were followed by a decrease in 5-HT but not GABA concentrations in the substantia nigra. In addition striatal 5-HT, GABA and NA concentrations were unchanged whereas striatal DA was increased. These observations strongly suggest that the substantia nigra receives a direct inhibitory input from the median raphe nucleus and this pathway uses a 5-HT-like neurotransmitter. This pathway probably contributes to the regulation of nigrostriatal dopaminergic transmission.

Animals↗