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The possible role of L-serine as an allosteric modulator of anandamide (AEA) action on cannabinoid receptors has been investigated along with the studying the actions of AEA metabolite, ethanolamine.  Dorsal root ganglia (DRG) neurons from neonate Sprague Dawley rats were used in primary culture. L-serine was found to modulate anandamide actions on overall neuronal excitability, voltage-activated K⁺ and Ca²⁺ currents and intracellular Ca²⁺ flux.  These modulations were suggested to be mediated via allosteric modulation of AEA actions at CB1 receptors.  These observations strengthen previous data obtained from binding studies of L-serine at CB1 receptors.  Furthermore, these modulations were abolished by CB1 antagonist, SR141716A, while L-serine alone failed to activate CB1 receptors.  We found that L-serine modulations were AEA-dependent and CB1 mediated, while no modulatory effects for L-serine were reported on TRPV1 or GPR55 receptors.  Similar modulations were reported from the CB1 allosteric modulator, Org-27569. Ethanolamine was fond to enhance the intracellular Ca²⁺ level via influencing thapsigargicin- and caffeine-sensitive calcium stores.  Ethanolamine actions were not abolished in PTX-treated DRG neurones or in the presence of CB1 antagonist, SR141716A indicating that these actions were conducted independently from CB1 receptors and inhibitory G-proteins. Additionally, ethanolamine modulated the voltage- activated potassium currents independently from its effect on intracellular Ca²⁺ level. In conclusion CB1 receptor modulation by ligands acting at an allosteric site may provide a novel approach to endocannabinoids-mediated therapies.

Thesis (doctoral)--University of Tartu, 2006. / Thesis based on six papers. Includes bibliographical references.

No description available.

Neurones in the superficial layers of the superior colliculus (SSC) respond to novel visual events. Cells in the SSC project via neurones in the deep layer of the superior colliculus to motor nuclei which generate appropriate behavioural and avoidance responses to novel sensory stimuli. Glutamate is a neurotransmitter at the retino-collicular and cortico-collicular synapse. Glutamate receptors can be classified as either ionotropic or metabotropic (mGluRs). At present, 8 mGluRs have been cloned (mGluRI - mGluR8), and these can be divided into 3 groups based on sequence homology, pharmacology and coupling to 2nd messenger pathways. There is evidence that metabotropic glutamate receptors may be present on SSC neurones and SSC afferents. This study examines how mGluRs may modulate the response properties of visually responsive cells in the SSC. Iontophoretic application of pharmacological agents including selective mGluR agonists and antagonists are used to probe the functional effects of mGluR manipulation in an in- Wvo preparation. All three groups of receptor appear to be activated by endogenous glutamate during visual synaptic transmission. Activation of Group I mGluRs (mGluRl and mGluR5) cause a depression of the visual response. Activation of both Group 11 (mGluR2 and mGluR3) and Group HI mGluRs (mGluR4, mGluR6, mGluR7 and mGIuR8) causes a facilitation or inhibition of the visual response in individual neurones. Neurones in the SSC detect novel visual stimuli by producing a decline in the response to repeated stimuli, this is called habituation. Group HI (but not Group I or Group H) mGluRs contribute to response habituation in the SSC and therefore have a functional role in detecting stimulus novelty. Activation of Group R receptors is dependent upon the intensity of the stimulus, probably due to their location away from the central region of the synapse. Immunohisto chemical data presented here details the distribution of selected mGluRs in the sub-cortical retinofugal pathway of the rat, ferret and cat. Analysis shows that the distribution in these three species is dissimilar. This suggests that mGluRs may have different functional roles in visual processing in different species.

Proefschrift Universiteit van Amsterdam. / Auteursnaam op omslag: Miriam Leenders. Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.