MDMA attenuates phase shifts of the circadian clock to the GABAB agonist baclofen

Blance, Rognvald Niall (2004) MDMA attenuates phase shifts of the circadian clock to the GABAB agonist baclofen. MLitt(R) thesis, University of Glasgow.

Abstract

The mammalian suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a circadian pacemaker that drives many rhythms of behaviour and physiology. The pacemaker displays a period of approximately 24 hours and can be entrained to external conditions by a variety of environmental cues. The principle entraining cue is the daily light-dark cycle but other non-photic stimuli can also reset the phase. In rodents, the pacemaker is sensitive to photic influences during the night while non-photic stimuli are only effective in resetting the pacemaker during the day. One afferent pathway to the SCN originating in the median raphe nucleus contains serotonin (5-HT) and has been implicated in the mediation of non-photic phase shifting of the pacemaker. Disruption of this pathway by neurotoxins can result in alteration of several parameters of circadian rhythmicity. Application of 5-HT or its receptor agonists during the day results in phase advances of pacemaker period. A role for the neurotransmitter -amino butyric acid (GABA) in circadian rhythmicity has also been shown. The GABAB receptor agonist baclofen has been shown to phase advance the pacemaker during the day in a manner similar to 5-HT. Baclofen has also been shown to result in an increase in the release of newly synthesised 5-HT within the SCN area during the day. The substituted amphetamine, 3,4-methylenedioxymethamphetamine (MDMA) is a common drug of misuse as well as being a selective 5-HT neurotoxin. At neurotoxic doses it is known to result in degeneration of 5-HT terminal areas. In this study, the magnitude of phase shifts due to daytime injection of baclofen to Syrian hamsters maintained in constant darkness was compared before and after administration of a neurotoxic dose of MDMA. Immunohistochemical techniques were employed to quantify neurotoxic damage to the 5-HTergic terminal field within the SCN and cell bodies within the raphe nuclei. It was found that the magnitude of baclofen induced phase advances during the day were significantly greater than phase shifts induced by control injections of saline at the same time. There was a significant difference between the magnitude of phase advances to baclofen before and after treatment with MDMA. The difference in density of immunohistochemical staining for 5-HT was also different between MDMA treated animals and untreated controls. These results imply there may be interaction between the GABAergic and 5-HTergic systems within the circadian system for mediation of non-photic phase shifting of the pacemaker during the day in rodents.

• Item Type: Thesis (MLitt(R))
• Qualification Level: Masters
• Additional Information: Adviser: Stephaney Biello
• Keywords: Neurosciences
• Date of Award: 2004
• Depositing User: Enlighten Team
• Unique ID: glathesis:2004-74046
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Sep 2019 15:33
• Last Modified: 23 Sep 2019 15:33
• URI: https://theses.gla.ac.uk/id/eprint/74046