Neural mechanisms of MK-801 induced sensitisation

Abstract

Behavioural sensitisation describes the progressive and enduring augmentation of a drug-induced response that develops with repeated exposure. Sensitisation is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitisation has been described for several different drug classes. The neural mechanisms underpinning behavioural sensitisation to most drugs of abuse share similarities, such as NMDA receptor (NMDAR) activation, although not all use the same mechanism of action.The NMDAR antagonist MK-801 can inhibit sensitisation to other drugs of abuse. However, MK-801 also produces behavioural sensitisation to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitisation has a distinctive mechanism of action.The overall aim of my thesis was to investigate the neural mechanisms of behavioural sensitisation to MK-801 in rats. First, I established the effect of drug dose, environmental context, length of withdrawal period and rat strain on the ability of repeated intermittent MK-801 administration to induce behavioural sensitisation. MK-801-induced sensitisation was shown to be dependent on the dose of MK-801, length of withdrawal period and the rat strain. Sensitisation however was not modulated by the environmental context in which MK-801 administration occurred.In the established sensitisation paradigm, a functional and molecular analysis of the nucleus accumbens of rats sensitised to MK-801 was undertaken. Ex vivo slice electrophysiology revealed a decrease in the excitatory synaptic strength in the nucleus accumbens of rats sensitised to MK-801. An LC-MS/MS proteomics approach demonstrated that proteins altered by MK-801 sensitisationwere predominately related to functions including calcium signalling and mitochondrial dysfunction.I also probed the role of corticosterone signalling using a pharmacological and physiological approach. Pharmacological antagonism of the glucocorticoid receptor with RU486 was found to facilitate behavioural sensitisation to MK-801, potentially through its augmenting effect on MK-801 induced corticosterone levels. Following on from this experiment, I showed that pharmacological antagonism of the stress-related kappa opioid receptor with nor-Binaltorphimine did not have the same effect as RU486. Lastly, I also used LY354740, a pharmacological agonist of the metabotropic glutamate receptors, as a preliminary investigation into the role of glutamatergic transmission. Stimulation of these receptors however was without effect on MK-801 sensitisation.ii Using a range of approaches I have elucidated some of the neural mechanisms and adaptations associated with behavioural sensitisation to MK-801. These results predominately show that sensitisation to MK-801 differs from the mechanism of sensitisation to other drugs of abuse. This model could prove useful for studying the role of NMDARs in the pathophysiology of drug addiction and schizophrenia.iii

Effect of intermittent subchronic MK‐801 administration on dopamine synthesis capacity and responsiveness in the prefrontal cortex

“…Hence, we opted for a method that at least demonstrates the behavioral effects of repeated administration because the behavioral effect of MK‐801 displays an inverted U dose response, and the behavior may not be involved in the dopamine release in the mPFC. 20 , 23 …”

“…MK‐801 was administered to the rats using a previously described method. 20 MK‐801 (Sigma‐Aldrich, St. Louis, Missouri, USA) was dissolved in saline (0.3 mg/mL) and intraperitoneally injected for 10 days at a dose of 0.3 mg/kg BW/day. This dose was selected because it was previously shown to induce a peak level of MK‐801 on locomotor activity.…”

“…This dose was selected because it was previously shown to induce a peak level of MK‐801 on locomotor activity. 20 The rats in the control group were administered an equivalent volume of saline.…”

“…This dose was selected because it was previously shown to induce a peak level of MK-801 on locomotor activity. 20 The rats in the control group were administered an equivalent volume of saline. Rats were injected intraperitoneally with MK-801 or saline, and the locomotor distance was monitored for 2 h to record their responses.…”

“…Hence, we opted for a method that at least demonstrates the behavioral effects of repeated administration because the behavioral effect of MK-801 displays an inverted U dose response, and the behavior may not be involved in the dopamine release in the mPFC. 20,23 Currently, the molecular mechanisms that mediate the effect of ketamine on behavior and regional brain metabolic activity remain unclear. Most of the differences in potency of each NMDAR antagonist could be accounted for by differences in the reverse rate constants, which were approximately 0.2, 0.03, and 0.003 s −1 for ketamine, PCP, and MK-801, respectively.…”