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Paul J Fletcher

Publications and source records attributed to Paul J Fletcher.

26 records · Page 2Linked to original sources
PubMed2003

The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism.

In the present series of studies, we have investigated the effects of antagonists selective for the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors on motor and 'impulsive'-type behaviours elicited by the non-competitive N-methyl- d-aspartate (NMDA) antagonist dizocilpine. The selective 5-HT(2A) receptor antagonist M100,907 (0.5 mg/kg) attenuated the hyperlocomotion and stereotypy produced by dizocilpine (0.1-0.3 mg/kg). The selective 5-HT(2B) receptor antagonist SB215,505 (3 mg/kg) and the selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg/kg) had no effect against either measure, except that SB242,084 produced a small potentiation of the hyperactivity response. Dizocilpine (0.03 mg/kg) increased premature responding in rats performing the 5-choice serial reaction time task (5-CSRTT), and increased response frequency consequently reducing the mean inter-response time (IRT) and efficiency of responding in a DRL24 task. M100,907 (0.5 mg/kg) attenuated each of these effects, as well as the increased premature responding produced by the NMDA NR2B selective antagonist Ro 63-1908 (1 mg/kg) in the 5-CSRTT. In contrast SB242,084 (0.5 mg/kg) did not attenuate the dizocilpine-induced premature responding or increased responding in the DRL24 task. Rather, SB242,084 (0.05-0.5 mg/kg) produced qualitatively similar effects to dizocilpine, increasing premature responding and reducing IRT. The results suggest that 5-HT(2A) receptor antagonists may normalise certain 'impulsive' behaviours produced by NMDA receptor hypofunction. The 5-HT(2C) receptor antagonist SB242,084 failed to exert equivalent effects, rather a trend toward exacerbation of the behavioural changes produced by dizocilpine was apparent.

Aminopyridines↗
PubMed2003

Up-regulated dopamine D1 receptor binding can be detected in vivo following repeated SCH 23390, but not SKF 81297 or 6-hydroxydopamine, treatments.

Three different pharmacological treatments, previously shown to cause dopamine D1 receptor supersensitivity in rats, were studied for changes in the binding of R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) labeled with carbon-11. Rats treated subchronically with the full dopamine D1 receptor agonist R/S-(+/-)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 81297) showed no significant difference in dopamine D1 receptor binding. Similarly, unilateral 6-hydroxydopamine lesioning, followed by apomorphine screening for contralateral rotation, failed to cause significant differences in the rat brain distribution of [11C]SCH 23390 in the lesioned versus the nonlesioned striatal sides. In contrast, repeated exposure with the dopamine D1 receptor antagonist SCH 23390 significantly enhanced the uptake of [11C]SCH 23390 in the dopamine D1 receptor-rich striatum and olfactory tubercles. These results demonstrate that [11C]SCH 23390 can significantly detect enhanced binding in rat brain regions expected to have up-regulated dopamine D1 receptors. The failure of [11C]SCH 23390 to reveal any differences after subchronic agonist or 6-hydroxydopamine treatments suggests that the behavioural supersensitization induced by these treatments is possibly due to changes to the high-affinity state or to components downstream of dopamine D1 receptors in the signal transduction pathway. The present study has implications for studies imaging dopamine D1 receptors in neuropsychiatric disorders with abnormal dopamine stimulation using positron emission tomography.

Animals↗
PubMed2002

Cyclooxygenase inhibitor modulation of dopamine-related behaviours.

The sequential action of phospholipase A(2) and cyclooxygenase leads to the production of prostaglandins in the brain, an event hypothesised to cause dopaminergic stimulation. To investigate this further, we examined the effect of the nonselective cyclooxygenase inhibitors indomethacin and piroxicam on several indices of dopaminergic function in adult male rats. Both drugs inhibited catalepsy induced by the dopamine D1-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), the dopamine D2-like receptor antagonist raclopride and by haloperidol, findings in agreement with a dopaminergic effect of cyclooxygenase inhibitors. However, neither cyclooxygenase inhibitor had an effect upon disruption of prepulse inhibition of the auditory startle reflex by amphetamine or on the rate of amphetamine self-administration. Both drugs reduced amphetamine-stimulated locomotor activity. Our data indicate that the mechanism by which cyclooxygenase inhibitors alter motor behaviour is unlikely to be due to a simple direct action at the dopaminergic synapse. Their apparent ability to antagonise hypoactivity without generalised dopaminergic stimulation suggests that other, possibly multiple, neurotransmitter systems may be involved.

Amphetamine↗
PubMed2002

Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement.

RATIONALE: Responding for conditioned reinforcement is increased by the dopamine releasing agent amphetamine, but reduced by drugs that enhance serotonin (5-HT) function. The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) releases both monoamines. OBJECTIVES: The primary purpose of this study was to examine the effects of MDMA on responding for conditioned reinforcement as well as on locomotor activity. The roles of several 5-HT receptor sub-types in mediating these behavioural effects of MDMA were also examined. METHODS: Locomotion was measured in photocell activity monitors. For conditioned reinforcement experiments thirsty rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were available; responding on one lever delivered the CS, while responding on the second lever had no consequences. Drug effects on this operant response were measured. RESULTS: MDMA dose-dependently increased locomotion but reduced responding for conditioned reinforcement. This latter effect differs from that induced by amphetamine, which potentiates conditioned reinforcement responding. The stimulant effect of MDMA was attenuated by GR127935 and ketanserin, indicating facilitatory roles of 5-HT(1B) and 5-HT(2A) receptors in mediating this effect. The 5-HT(2C) antagonist SB242084 enhanced the stimulant effect of MDMA. Only SB242084 attenuated the suppressant effect of MDMA on responding for conditioned reinforcement. CONCLUSIONS: The results show that 5-HT(2A) and 5-HT(1B/1D) receptors play a facilitatory role in mediating the stimulant effect of MDMA, whereas 5-HT(2C) receptors are inhibitory. Activation of 5-HT(2C) receptors also contributes to the deficit in operant responding. Multiple 5-HT receptor sub-types appear to contribute to the behavioural effects of MDMA.

3,4-Methylenedioxyamphetamine↗
PubMed2002

Neonatal ablation of the nigrostriatal dopamine pathway does not influence limb development in rats.

Hemiparkinson-hemiatrophy syndrome (HP-HA) is associated with skeletal hemiatrophy and the later development of parkinsonism. It is generally assumed that this phenotype is due to the combination of dysfunction of the basal ganglia (e.g., substantia nigra compacta and/or other related structures), causing parkinsonism, and of other areas (e.g., cerebral cortex), causing hemiatrophy. The occurrence of asymmetry of limb size in a patient with very asymmetric involvement of dopa-responsive dystonia encouraged Greene et al. (2000, Mov. Disord. 15: 537-541) to propose that lifelong deficits in nigrostriatal dopamine could account for limb asymmetry in HP-HA. The purpose of this study was to determine whether skeletal hemiatrophy could be produced in rats by unilateral, neonatal ablation of the nigrostriatal dopamine pathway. Infusion of 6-hydroxydopamine into the striatum of rat neonates resulted in loss of dopamine neurons in the ipsilateral substantia nigra, reduced striatal dopamine levels, and stimulant-induced motor asymmetry. Saline infusions neither altered the number of dopamine neurons nor produced behavioral changes. Both groups incurred discrete lesions of the ipsilateral motor cortex surrounding the infusion site and atrophy of the corresponding cerebral peduncle. Cortical, but not nigrostriatal, lesions were associated with significant atrophy of ipsilateral femora, humeri, and innominate bones, as assessed radiographically. Skeletal hemiatrophy was not observed in naive animals or in experimental animals that did not exhibit corticospinal abnormalities. The results of this study indicate that early skeletal development in rats is not affected by loss of nigrostriatal dopamine per se, but is markedly attenuated by corticospinal lesions sustained during the neonatal period.

Animals↗
PubMed2002

Activation of 5-HT(1B) receptors in the nucleus accumbens reduces self-administration of amphetamine on a progressive ratio schedule.

Brain serotonin interacts with dopamine function in a complex fashion. Previous work from our laboratory showed that activation of 5-HT(1B) receptors within the nucleus accumbens attenuates the ability of amphetamine to increase responding for conditioned reinforcement. The primary purpose of these experiments was to determine the impact of 5-HT receptor stimulation, with particular focus on 5-HT(1B) receptors in the nucleus accumbens on the reinforcing effect of amphetamine. To this end several experiments determined the effects of injecting 5-HT, and various 5-HT agonists, into the nucleus accumbens on responding for intravenous infusions of amphetamine (60 microg/kg) delivered according to a progressive ratio schedule of reinforcement. Both 5-HT (2.5, 5 and 10 microg) and the selective 5-HT(1B) receptor agonist CP93,129 (0.625, 1.25 and 2.5 microg) dose-dependently reduced responding for amphetamine. Injections of 5-HT but not CP93,129 also reduced responding for food under a similar PR schedule. The 5-HT(1A) agonist 8-OH-DPAT (5 microg) and the nonselective 5-HT(2) agonist DOI (10 microg) failed to alter amphetamine self-administration. Pretreatment with the selective 5-HT(1B/1D) receptor antagonist GR127935 (3 mg/kg) attenuated the ability of 5-HT and CP93,129 to reduce amphetamine self-administration following their injection into the nucleus accumbens. These results extend our previous findings that increasing 5-HT activity in the nucleus accumbens inhibits dopamine-dependent behaviour, and further indicate that activation of 5-HT(1B) receptors is particularly important in this regard.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding.

These studies investigated the effects of antagonists selective for the 5-HT(2A), 5-HT(2B), or 5-HT(2C) receptor subtypes on behaviors elicited or maintained by cocaine. The selective 5-HT(2A) receptor antagonist M100907 (0.5 mg/kg, SC) attenuated the locomotor activity elicited by 10 mg/kg cocaine, whereas the selective 5-HT(2C) receptor antagonist SB242084 (0.5 mg/kg IP) potentiated the locomotor stimulant effect of 10 mg/kg cocaine. The selective 5-HT(2B) antagonist SB215505 (3 mg/kg PO) did not alter cocaine-induced locomotor activity. In a second series of experiments, the effects of M100907 and SB242084 were examined in rats self-administering cocaine intravenously according to a progressive ratio schedule. M100907 (0.5-2 mg/kg) did not alter responding for cocaine at an infusion dose of 0.25 mg. Similarly M100907 (0.5 mg/kg) failed to alter responding for cocaine at infusion doses of 0.0625, 0.125 and 0.25 mg. SB242084 (0.5-1 mg/kg) increased responding for cocaine with the infusion dose set at 0.125 mg. Examination of the effects of SB242084 (0.5 mg/kg) on the cocaine dose response curve revealed significant increases in responding at the lowest doses of 0.0625 and 0.125 but not 0.25 mg. After completion of the self-administration experiments responding was extinguished. M100907 (0.5 mg/kg) attenuated the ability of experimenter administered cocaine (10 mg/kg and 20 mg/kg) to reinstate lever pressing, whereas the priming effect of cocaine (10 mg/kg) was enhanced by SB242084. These results indicate distinct, and in some cases opposite, effects of a 5-HT(2A) compared with a 5-HT(2C) receptor antagonist on various cocaine-mediated behavioral effects.

Aminopyridines↗