Serotonergic receptor subtypes in learning and memory : Focus on 5-HT1A, 5-HT1B and 5-HT2A receptors

The aim of this thesis was to study how serotonin (5-HT) receptor subtypes can influence hippocampus/amygdala-dependent teaming and memory using the water maze (WM) and the passive avoidance (PA) tasks in rodents, and to provide a cellular correlate to the behavioral results using histochemical methods. Glutamatergic neurons in the trisynaptic circuit of the hippocampus are believed to be important for spatial teaming and memory as well as synaptic plasticity. However, due to their widespread distribution in the CNS, blockade of glutamatergic NMDA receptors may result in behavioral/non-cognitive disturbances. The NMDA receptor antagonist MK-801 impaired acquisition and retention of a spatial teaming task in the rat and caused sensorimotor disturbances in the same dose range, indicating that the effects of global NMDA receptor blockade on spatial teaming in the WM task cannot be dissociated from sensorimotor disturbances. The presynaptic somatodendritic 5-HT1A receptor regulates the firing rate of serotonergic neurons in the raphe nuclei, while postsynaptic 5-HT1A receptors are located on a variety of target neurons involved in cognitive functions. The 5-HT1A receptor agonist 8-OH-DPAT impaired WM performance and displayed a biphasic effect in the PA; lower doses facilitating and higher doses impairing PA memory. NAD-299, a 5-HT1A receptor antagonist, facilitated PA memory, but failed to affect spatial teaming and memory. NAD-299 abolished impairments induced by 8-OH-DPAT. The muscarinic antagonist scopolamine was used to produce a memory deficit related to reduction of cholinergic transmission. NAD-299 blocked the scopolamine-induced impairment in the PA task, but not in the WM task, probably caused by a failure to attenuate the noncognitive effects of scopolamine. In addition, NAD-299 blocked the impairment produced by MK-901 in the PA. These results support the view that pre- and postsynaptic 5-HT1A receptors have opposite roles in teaming and memory. Moreover, 5-HT1A receptor blockade appears to enhance cholinergic and glutamatergic transmissions important for cognition. In the rat brain, 5-HT1A receptor mRNA and protein were shown to be codistributed and colocalized, respectively, with mRNAs and proteins used as markers for cholinergic and GABAergic septohippocampal neurons in the medial septum and diagonal band of Broca (MSDB). This indicates that 5-HT via the 5-HT1A receptor is an important modulator of major inputs to the hippocampal formation. Furthermore, 5-HT1A and 5HT2A receptor immunoreactivities were colocalized in neurons in the MSDB, suggesting that 5-HT can either stimulate or inhibit the same neuron in the MSDB, depending on the relative balance between these two receptors. In the septohippocampal circuit, 5-HT2A receptor protein was present in GABAergic and cholinergic neurons in the MSDB and glutamatergic principal neurons as well as the major types of GABAergic interneurons in the dorsal hippocampus. This indicates that 5-HT2A receptors can modulate septohippocampal functions via all major neuronal types in septohippocampal circuits. In the mouse, the same pattern of modulation of PA retention was shown for the 5-HT1A receptor ligands in combination with scopolamine and MK-801 as in the rat. Furthermore, anxiety-related behaviors and autonomic functions were not affected by treatment with NAD-299. 5-HT1A receptor mRNA was shown to be codistributed with mRNAs used as markers for cholinergic, GABAergic and putative glutamatergic septohippocampal neurons in the MSDB. These results provide evidence also in mice for an important role of 5-HT1A receptors in teaming and regulation of septohippocampal transmission. The terminal 5-HT1B receptor regulates the release of 5-HT. 5-HT1B receptor stimulation dose-dependently impaired performance in the WM and PA tasks, blocked by the 5-HT1B receptor antagonist NAS-181. NAS-181 facilitated PA memory retention, but did not affect WM performance. Moreover, NAS-181 did not prevent the impairment induced by scopolamine in the WM. However, a subthreshold dose of scopolamine blocked the facilitatory effect by NAS-181 on PA memory, indicating that serotonin through terminal 5-HT1B heteroreceptors can modulate cholinergic transmission. These results suggest important roles for serotonin in teaming and memory, acting through 5-HT1A, 5-HT1B and 5-HT2A receptors within septohippocampal circuits. This may have important implications for disorders associated with cognitive impairments, such as dementias

Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig mono-phasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to de-termine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixe