The effects of pharmacological blockade of the 5-HT(6) receptor on formalin-evoked nociceptive behaviour, locomotor activity and hypothalamo-pituitary-adrenal axis activity in rats.

5-hydroxytryptamine (5-HT) mediates behavioural and neuroendocrine responses to noxious or stressful stimuli. 5-HT(6) receptors are expressed in brain regions involved in nociceptive processing, however, their role in nociception is unknown. Here we demonstrate that acute, systemic administration of the 5-HT(6) receptor antagonist, 5-chloro-N-(4-methoxy-3-benzothio-phenesulfonamide (SB-271046), reduces formalin-evoked nociceptive behaviour and increases plasma corticosterone. SB-271046 dose-dependently reduced pre-formalin distance moved, rearing, grooming and defecation. These data provide the first evidence for 5-HT(6) receptor-mediated regulation of nociception and hypothalamo-pituitary-adrenal axis activity in a model of persistent pain although effects on locomotor activity demand that the putative antinociceptive effect of SB-271046 be interpreted with some caution.

Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo.

Recent clinical evidence indicates that the broad spectrum anticonvulsant drug lamotrigine is effective against the depressive phase of bipolar illness and the difficult to treat rapid cycling form of the disorder. However, the molecular mechanism underlying this therapeutic action remains uncertain. Given that inhibition of the A-type of monoamine oxidase (MAO) is a proven antidepressant mechanism, we investigated the effects of lamotrigine on MAO activities in vitro and on monoamine disposition in vivo. In vitro, lamotrigine inhibited rat brain MAO activities with Ki values (MAO-A, 15 microM; MAO-B, 18 microM) potentially within the therapeutic range for this drug. The effects of lamotrigine on the MAO-A activities of rat brain and human liver preparations were almost identical suggesting minimal species or tissue variation. In contrast, there was no (MAO-A) or minimal (MAO-B) reduction in brain MAO activities when assayed ex vivo following the administration of lamotrigine to rats. In vivo brain microdialysis failed to detect meaningful alterations in extracellular hippocampal or frontal cortex monoamine concentrations. Furthermore, lamotrigine did not modulate oral tyramine-induced hypertension in rats or 5-hydroxytryptophan-induced head shaking in mice, providing strong evidence that the drug does not perturb monoamine metabolism in vivo. The absence of observable effects of lamotrigine on monoamine disposition in vivo may be explained by the competitive and highly reversible nature of the interaction of lamotrigine with MAO isoforms. Thus, altered monoamine metabolism in vivo is unlikely to account for the antidepressant action of the drug in bipolar depression.

Cannabinoids modulate ultrasound-induced aversive responses in rats.

RATIONALE: Mechanisms and brain substrates mediating cannabinoid-induced modulation of behaviour towards aversive stimuli are poorly understood. OBJECTIVES: To investigate the effects of systemic and intra-dorsal periaqueductal grey (PAG) administration of the cannabinoid receptor agonist HU210 on behaviour and plasma corticosterone levels in rats exposed to ultrasound and determine the contribution of CB(1) receptors. METHODS: In experiment 1, rats received vehicle or CB(1) receptor antagonist SR141716A (3 mg/kg, IP) 30 min prior to a second injection of vehicle or HU210 (5, 20 or 80 microg/kg, IP). In experiment 2, rats received intra-dorsal PAG vehicle or SR141716A (30 microg/rat) 10 min prior to intra-dorsal PAG vehicle or HU210 (5 microg/rat). Following injections, rats were exposed to an aversive 20 kHz ultrasonic tone for 3 min. Behaviour, including hyperlocomotor activity and freezing, was monitored during and post-ultrasound. Plasma corticosterone levels 10 min post-ultrasound were measured. RESULTS: Ultrasound induced explosive running and freezing behaviour. Systemic administration of HU210 attenuated the expression of ultrasound-induced hyperlocomotor activity and increased freezing. The HU210-induced attenuation of hyperlocomotor activity was blocked by SR141716A. Intra-PAG administration of HU210 reduced the expression of ultrasound-induced hyperlocomotor activity, an effect not blocked by SR141716A. Systemic and intra-PAG administration of HU210 increased plasma corticosterone levels, an effect not blocked by SR141716A. CONCLUSIONS: The cannabinoid receptor agonist HU210 modulates behaviour towards an aversive ultrasound stimulus in rats, an effect accompanied by increased HPA axis activity. These effects may be mediated, at least in part, by the dorsal PAG but cannot be explained solely by an action at CB(1) receptors.

The role of the central nucleus of the amygdala in nociception and aversion.

The role of the central nucleus of the amygdala in nociception--conditioned and unconditioned aversion--was studied. Rats received microinjection of vehicle or the N-type Ca2+ channel blocker omega-conotoxin GVIA (0.2 microg/250 nl) into the central amygdaloid nucleus prior to intra-plantar injection of formalin, ultrasound exposure or immediately prior to the acquisition phase of an aversive conditioning trial. Intra-amygdala omega-conotoxin GVIA resulted in an earlier onset of nociceptive response to formalin and increased nociceptive behaviour during the first 5 min. Omega-conotoxin GVIA significantly reduced conditioned freezing behaviour with no effect on ultrasound-induced unconditioned aversive behaviour. These data indicate that N-type Ca2+ channels in the central amygdaloid nucleus play a role in mediating behavioural responses to nociceptive and conditioned aversive stimuli.

Long-term changes in social interaction and reward following repeated MDMA administration to adolescent rats without accompanying serotonergic neurotoxicity.

RATIONALE: MDMA is a popular drug of abuse in adolescents which causes serotonergic neurotoxicity in adult but not young rodents. However, few studies have examined the long-term behavioural consequence of MDMA and it is unclear whether such changes occur in the absence of neurotoxicity. OBJECTIVES: The present study examined whether treatment of young rats with MDMA produced long-term behavioural alterations without accompanying serotonergic neurotoxicity. METHOD: Male Lister hooded rats ( n=36, postnatal day (PND) 39) received MDMA (7.5 mg/kg i.p., twice daily for 3 days) or saline (l ml/kg i.p.) and the acute effect on open field behaviour and body temperature was monitored. Following drug withdrawal, social interaction in pre-treatment- and weight-matched rat pairs, cortical [(3)H]paroxetine binding and hippocampal and frontal cortical serotonin and dopamine levels (PND 53, n=12) and conditioned place preference (PND 70, n=24) to cocaine (5 mg/kg IP) were analysed. RESULTS: MDMA elicited the expected immediate serotonin syndrome with significant hyperlocomotion, decreased rearing and hypothermia. Twelve to 29 days after the last MDMA injection social interaction was significantly attenuated (by 41%) and the sub-threshold conditioned place preference to cocaine was significantly enhanced compared with that in saline controls, although no significant side preference to cocaine occurred in the latter. MDMA pre-treatment did not alter 5-HT levels or cortical [(3)H]paroxetine binding. CONCLUSION: MDMA administration to adolescent rats reduced social interaction and enhanced the sub-threshold rewarding effect of cocaine at adulthood, despite an absence of accompanying serotonergic and dopaminergic neurotoxicity.