desmethoxyfallypride and Huntington-Disease

In Huntington's disease (HD) cognitive deficits co-exist with motor impairments, both contributing to the overall disease symptomology. Despite short-term and working memory impairments, learning and other non-motoric behavioral deficits arising from the damage to frontostriatal loop being common in HD patients, most of the experimental work with transgenic animals focuses on motor symptoms. The transgenic rat model (tgHD) recapitulates many hallmark HD-like symptoms, such as huntingtin aggregates, cellular loss and dysfunction, and motor, and some cognitive deficits. In the current study we tested tgHD rats in two different cognitive, water maze competition paradigms to learn more about the impact of the transgene on learning and memory processing using hippocampal- and striatal-based memory systems. The tgHD rats had early and robust cognitive deficits in learning and memory function in both paradigms. Specifically, the transgenic animals were impaired in task acquisition and committed more procedural errors with the strongest phenotype amongst the homozygote tgHD. Although the transgenic animals were capable of using both procedural and declarative memory, their response patterns were distinct from wild-type animals. Wide spread huntingtin aggregates were observed at 13 months, but neither PET nor autoradiography indicated neuronal loss or dysfunction in striatal dopamine receptor population. In summary, the homozygote tgHD showed a robust learning and memory impairment prior to any clear motor deficits, or striatal dysfunction. However, the data were not conclusive regarding how the memory systems were compromised and the precise nature and underlying mechanism of the cognitive deficit in the tgHD model requires further investigation.

Topics: Animals; Blood Glucose; Body Weight; Corpus Striatum; Disease Models, Animal; Female; Fluorine Radioisotopes; Functional Neuroimaging; Huntingtin Protein; Huntington Disease; Male; Maze Learning; Memory Disorders; Motor Activity; Nerve Tissue Proteins; Nuclear Proteins; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, Dopamine D2; Salicylamides

[(18)F]desmethoxyfallypride ([(18)F]DMFP) is a promising tracer for longitudinal assessment of striatal dopamine D2/D3-receptor (D2R) availability by positron emission tomography (PET) in small animal models. We explored the feasibility of [(18)F]DMFP-PET to image D2R availability in rat models of Huntington's (HD) and Parkinson's disease (PD).. Animals received either unilateral intrastriatal quinolinic acid lesions or medial forebrain bundle injections of 6-OHDA to produce the loss of striatal projection neurones or deplete the striatal dopamine, corresponding to established animal models for HD and PD, respectively. Three weeks after lesioning, PET scans were acquired on a microPET Focus 120 system following the tail vein injection of [(18)F]DMFP.. [(18)F]DMFP-PET clearly visualized lesion induced decreases and increases of D2R availability. In vivo estimates of D2R binding and changes thereof gained by pharmacokinetic analyses correlated significantly with D2R density and its change provided by in vitro [(3)H]raclopride-autoradiography.. In conclusion, [(18)F]DMFP-PET is a suitable method for in vivo D2R-assessment in preclinical research, e.g for monitoring cell-based therapies.

Topics: Animals; Disease Models, Animal; Huntington Disease; Parkinson Disease; Positron-Emission Tomography; Raclopride; Radioactive Tracers; Rats; Receptors, Dopamine D2; Receptors, Dopamine D3; Salicylamides