A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [11C]FLB 457 and [11C]WAY 100635

In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D2 dopamine and 5-HT1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a "gold standard". The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data. In conclusion, the wavelet-based approaches seem to provide the most valid and reliable estimates across regions with a wide range of receptor densities. Furthermore, the results support the use of receptor parametric imaging in applied studies in basic or clinical research.     

Activation of post-synaptic 5-HT(1A) receptors in the dorsal hippocampus prevents learned helplessness development

Activation of post-synaptic 5-HT(1A) receptors in the dorsal hippocampus is proposed to mediate stress adaptation. Chronic social stress and high corticosteroid levels would impair this coping mechanism, predisposing animals to learned helplessness. To test the hypothesis that increasing serotonin levels in the dorsal hippocampus would attenuate the development of learned helplessness, rats received inescapable foot-shock (pre-test session) and were tested in a shuttle box 24-h later. Pre-stressed animals showed impairment of escape responses. This effect was prevented by chronic (21 days) treatment with imipramine (15 mg/kg). Similar results were obtained when the animals received bilateral intra-hippocampal injections, immediately after pre-test, of zimelidine (100 nmol/0.5 microl), a serotonin reuptake blocker, or 8-OH-DPAT (10 nmol), a 5-HT(1A) receptor agonist. The zimelidine effect was prevented by pre-treatment with WAY-100635 (30 nmol), a 5-HT(1A) receptor antagonist. These data suggest that facilitation of serotonergic neurotransmission in the dorsal hippocampus mediates adaptation to severe inescapable stress, probably through the activation of post-synaptic 5-HT(1A) receptors.     

Reversal of visual attention dysfunction after AMPA lesions of the nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT<Subscript>1A</Subscript> receptor antagonist WAY 100635

Rationale. Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease (AD). In addition to memory dysfunction, attentional functions are also impaired in AD. Objective. We investigated the extent to which the cholinesterase inhibitor donepezil reversed the attentional performance deficit in nucleus basalis magnocellularis (NBM) lesioned rats. We also examined the effects of a selective and potent 5-HT_1A receptor antagonist, WAY 100635, on the attentional deficit of NBM lesioned rats. Methods. We injected α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the NBM to selectively destroy cholinergic neurons projecting to the neocortex. Attentional functions were examined using the 5-CSRT task, in which hungry rats were required to locate brief visual targets presented randomly in one of five locations in a specially designed chamber. Results. AMPA lesions of the NBM caused marked reductions in choline acetyltransferase activity (ChAT) ranging from 30 to 46% in medial areas of the cortex (medial-frontal and cingulate) and from 58 to 72% in more lateral areas (anterior-dorso-lateral and parietal). AMPA lesioned rats made fewer correct responses (choice accuracy), longer latency to correct response and an increase in the number of premature and perseverative responses. These impairments showed some recovery over the next 12 weeks. Reducing the duration of the visual stimulus reinstated the impairments in choice accuracy. The anticholinesterase inhibitor donepezil at 1.0 mg/kg but not 0.5 mg/kg reversed the impairments in choice accuracy and correct response latency. The premature and perseverative over-responding of AMPA lesioned rats remained unchanged. A dose of 0.1 mg/kg WAY 100635 to AMPA-lesioned rats improved their choice accuracy but did not shorten correct response latencies. The number of premature responses was reduced by WAY 100635 but perseverative over-responding was not affected. Conclusions. The attentional impairments induced due to cortical cholinergic dysfunction may be ameliorated by cholinergic treatments such as cholinesterase inhibitors. In addition, 5-HT_1A receptors and the cortical cholinergic system exert balanced opposition in regulating attentional performance in the rat. Blockade of 5-HT_1A receptors may be useful to treat some aspects of attentional dysfunction in AD. Electronic Publication     

The contribution of serotonin 1A receptors to kappa opioid immunosuppression

Activation of kappa opioid receptors (kappa-OR) with the selective agonist rimorphin (0.1 mg/kg) produced marked suppression of the immune response in CBA mice. This effect was not seen on administration of rimorphin on the background of a reduction in the activity of the serotoninergic (5-HTergic) system resulting from stimulation of presynaptic (8-OH-DPAT, 0.1 mg/kg) or blockade of postsynaptic (WAY-100635, 1.0 mg/kg) 5-HT_1A receptors. These data led to the conclusion that 5-HTergic mechanisms involving preand postsynaptic 5-HT_1A receptors have a role in kappa-opioid-mediated immunosuppression. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 7, pp. 807–813, July, 2008.