1.
Lindquist, Catarina
(författare)
Physiology and Pharmacology of GABAA receptors: The Brakes in the Brain
2005
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Inhibitory neurotransmission in the brain is mostly mediated by gamma-aminobutyric acid type A (GABAA) receptors. These receptors are involved in both phasic inhibition (point-to-point inhibition, synaptic transmission) and tonic inhibition (diffuse form of inhibition, brain homeostasis). In this thesis the functional and pharmacological properties of GABAA receptors expressed in brain slices or in Sf 9 cells were studied. GABAA receptors expressed extrasynaptically are believed to be involved in tonic inhibition. In hippocampal dentate gyrus granule cells we identified and characterized three types of extrasynaptic receptor types (GABARex) that varied in their affinity for GABA, maximal single-channel conductance and sensitivity to drugs. For the first time we showed how the GABA concentration determines the conductance of GABAA receptors in brain tissue. There is thus a direct link between the extracellular GABA concentration and the level of the tonic inhibition, providing dynamic control. It is only within the last ten years or so that the tonic inhibition was discovered and only recently has it gained widespread interest. One reason is that it has become quite clear that the first site of action and probably often the most important site of action of drugs are the extrasynaptic receptors. We found that a drug now in clinical trials (THIP) at the clinically relevant concentration activates these extrasynaptic receptors. It has been assumed that spontaneous openings of the receptors are only functionally significant in receptor complexes containing the epsilon-subunit or mutations. We show that alpha/beta and alpha/beta/gamma?receptors can open spontaneously and be modified by drugs. The capacity to open spontaneously may be vital for fast responses such as at synapses. This suggests that the functional properties of receptors located at synapses and outside of synapses (extrasynaptic receptors: GABARex) differ. Those at synapses open rapidly (ms) whereas those at extrasynaptic sites open after a delay of ten to hundreds of seconds. This functional difference is very important in terms of brain function as it ensures fast flow of information (synaptic transmission) but in a controlled way that is set by the gain and the time window for synaptic transmission integration via the tonic inhibition. By using the compound SR95531, we constructed a model that accounts for activation and inhibition of both phasic- and tonic-like currents in an expression system. This model can be used to calculate what concentrations of the inhibitor to use to specifically block certain GABARex receptors in brain tissue to study how a particular population of GABARex contributes to the tonic inhibition and how it affects both excitatory and inhibitory synaptic transmission.
2.
3.
Collin, Mattias, et al.
(författare)
Monitor – biology
2005
Ingår i: Drug Discovery Today. - 1878-5832. ; 10:15, s. 1073-1073
Tidskriftsartikel (refereegranskat)
4.
Collin, Mattias, et al.
(författare)
Monitor – biology
2005
Ingår i: Drug Discovery Today. - 1878-5832. ; 10:1, s. 75-77
Tidskriftsartikel (refereegranskat)
5.
Collin, Mattias, et al.
(författare)
Monitor – biology
2005
Ingår i: Drug Discovery Today. - 1878-5832. ; 10:7, s. 530-531
Tidskriftsartikel (refereegranskat)
6.
Collin, Mattias, et al.
(författare)
Monitor – biology
2005
Ingår i: Drug Discovery Today. - 1878-5832. ; 10:17, s. 1201-1203
Tidskriftsartikel (refereegranskat)
7.
Körner, Anna, et al.
(författare)
Molecular Information on the Dissolution of Polydisperse Polymers: Mixtures of Long and Short Poly(ethylene oxide).
2005
Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 109:23, s. 11530-11537
Tidskriftsartikel (refereegranskat) abstract
Abstract:A systematic study of the dissolution of dry, polydisperse poly(ethylene oxide) (PEO) samples, obtained from mixtures of low-molecular-weight and high-molecular-weight PEO, was made. During the dissolution process, the individual release of the low- and high-molecular-weight fractions was monitored. The high-molecular-weight/low-molecular-weight ratio controls the release rate, and the fraction of high-molecular-weight polymers dominates the effect on the overall release rate in mixed PEO tablets. Both fractions are released at the same rate during the main part of the dissolution process; however, during the initial dissolution period a fractionation occurs. The release rate is not a unique function of the average molecular weight of the polymer, but also depends on the polydispersity. By contrast, the average dimension of a polymer coil, as given by the intrinsic viscosity, gives a good prediction of the release rate irrespective of the polydispersity or details of the molecular weight distribution.
8.
Körner, Anna, et al.
(författare)
Tuning the polymer release from hydrophilic matrix tablets by mixing short and long matrix polymers
2005
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1520-6017 .- 0022-3549. ; 94:4, s. 759-769
Tidskriftsartikel (refereegranskat) abstract
In this work a rotating disc method was developed for studying the dissolution process of bimodal polymer tablets, whose dissolution rates have been tuned by mixing low-molecular weight and high-molecular weight samples of poly(ethylene oxide) in various proportions. The tablets were prepared along different routes, by mixing the polymer fractions as powders or by mixing on a molecular level so that the effect of tablet heterogeneity could be assessed, but also by purifying the original powders so the effect of additives could be determined. When the mixed tablet was dominated by the low-molecular weight fraction, a faster dissolution was observed for the tablet mixed at the powder level. In those cases small gel pieces were released from the tablet during the whole dissolution process. As long as no gel piece erosion was observed, it did not matter if the two polymer fractions were blended on the molecular level or on the powder level, the steady-state dissolution rate was the same. The presence of small amounts of additives in the nonpurified commercial samples had no significant effect on the tablet dissolution within the uncertainty of the experiment.
9.
