Assessment of recovery in the hemiparkinson rat: drug-induced rotation is inadequate.
Recovery from apomorphine-induced rotational behavior was compared to sensorimotor and motor function in hemiparkinsonian rats receiving intrastriatal grafts of astrocytes expressing recombinant tyrosine hydroxylase (TH) or control beta-galactosidase (beta-gal). Rats received unilateral intranigral infusions of 6-hydroxydopamine (6-OHDA). Animals with large lesions, as determined by apomorphine-induced rotation, received grafts of astrocytes into the denervated striatum. Behavioral recovery was assessed on days 14-16 post-transplantation using apomorphine-induced rotation, somatosensory neglect, and reaching for pellets using the Montoya staircase method. Rats that received transplants of TH-transfected astrocytes showed a 34% decrease in rotational behavior, but no consistent recovery of somatosensory neglect or skilled reaching. Post-mortem histological analyses revealed survival of grafted astrocytes in host striatum and expression of TH at 17 days post-transplantation. We suggest that TH-expressing astrocytes may reverse post-synaptic dopamine (DA) receptor supersensitivity; however, sensorimotor and motor abilities are not restored due to a failure by TH-expressing astrocytes to reestablish dopaminergic circuitry. The present results demonstrate the need to utilize a variety of sensory and motor behavioral tests that cohesively provide greater interpretability than a single behavioral measure used in isolation, such as drug-induced rotational behavior, to assess the efficacy of experimental gene therapies.
Castañeda
Eddie
E
Molecular and Structural Neurobiology and Gene Therapy Program, Department of Psychology, Arizona State University, Tempe, Arizona 85287-1104, United States. eddie.c@asu.edu
Fleming
Sheila
S
Paquette
Melanie A
MA
Boat
Kim
K
Moffett
John
J
Stachowiak
Ewa K
EK
Bloom
David C
DC
Stachowiak
Michal K
MK
D000818:Animals; D001058:Apomorphine; D001253:Astrocytes / Q000378:metabolism / Q000637:transplantation; D035841:Behavioral Research / Q000379:methods; D016380:Brain Tissue Transplantation / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D003714:Denervation; D004298:Dopamine / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009048:Motor Skills / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology* / Q000601:surgery*; D010468:Perceptual Disorders / Q000601:surgery* / Q000628:therapy; D051381:Rats; D011916:Rats, Inbred F344; D020127:Recovery of Function / Q000502:physiology*; D012399:Rotation; D013239:Stereotyped Behavior; D013378:Substantia Nigra / Q000187:drug effects; D016896:Treatment Outcome
D016627:Oxidopamine; D001058:Apomorphine; D004298:Dopamine