ABSTRACT
Transgenic mice carrying human A30P mutated alpha-synuclein demonstrate hypolocomotion and dysfunction of the presynaptic machinery of dopamine overflow, induced by reducing capacity of the dopamine storage pool. We suggested that overexpression of alpha-synuclein may change sensitivity of these mice to L-DOPA. Current study assessed behavioural and neurochemical responses in A30P mice to L-DOPA using automated activity monitoring and voltammetry. We confirmed decreased locomotion and rearing of A30P transgenic mice compared to wild-type controls. L-DOPA (10-200mg/kg, i.p.) dose-dependently lowered locomotor activity, including stereotypy, in both genotypes, but the effects were larger in A30P mice. The effects of drug on stimulated dopamine overflow were investigated in the nucleus accumbens shell. L-DOPA at the dose of 30mg/kg did not change peak dopamine overflow induced by 10Hz stimulation of the medial forebrain bundle in either genotype, but increased it at the higher (20-50Hz) frequencies of stimulation. At the higher frequencies of stimulation, L-DOPA elevated dopamine overflow significantly more in A30P mice than in the control animals. These data show that A30P transgenic mice are more sensitive to the effects of L-DOPA at both behavioural and neurochemical level.
Subject(s)
Dopamine/metabolism , Levodopa/pharmacology , Motor Activity/drug effects , alpha-Synuclein/genetics , Animals , Dose-Response Relationship, Drug , Electric Wiring , Male , Mice , Mice, Transgenic , Nucleus Accumbens/metabolismABSTRACT
Alpha-synuclein has been implicated in the pathophysiology of Parkinson's disease. Recent studies revealed its role as a negative regulator of dopamine release in the nigrostriatal dopaminergic system. Alpha-synuclein may, however, play a more universal role in dopaminergic neurotransmission. It may represent an endogenous modulator in the mesolimbic dopaminergic system, and be involved in brain reward. We show here that the absence of alpha-synuclein resulting from spontaneous mutation in a subline of C57BL/6J mice greatly increased the rate of operant behavior during intracranial self-stimulation. The present work demonstrates that a lack of alpha-synuclein sensitized the brain reward system, implying that the levels of alpha-synuclein expression may predispose an individual to drug abuse or to a number of psychiatric diseases.
Subject(s)
Brain/physiology , Reward , Self Stimulation , alpha-Synuclein/deficiency , Animals , Corpus Striatum/physiology , Infrared Rays , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Substantia Nigra/physiology , alpha-Synuclein/genetics , alpha-Synuclein/physiologyABSTRACT
We have generated a transgenic mouse line overexpressing mutated human A30P alpha-synuclein under the control of the prion-related protein promoter. Immunohistology revealed mutated human A30P alpha-synuclein protein in numerous brain areas, but no gross morphological changes, Lewy bodies, or loss of dopaminergic cell bodies. The transgenic mice displayed decreased locomotion, impaired motor coordination, and balance. In vivo voltammetry showed that A30P mice responded to longer stimulation of the ascending dopaminergic pathways with less dopamine release in striatum and had a slower rate of dopamine decline after repeated stimulations or after alpha-methyl-p-tyrosine-HCl treatment. However, dopamine re-uptake or transporter levels were similar in transgenic and control mice. Our data provide evidence that overexpression of mutated human A30P alpha-synuclein in mice leads to a reduced size of the dopamine storage pool. This is in agreement with the previously postulated involvement of alpha-synuclein in the turnover of transmitter vesicles and may explain the observed motor deficits in A30P mice.
Subject(s)
Brain/metabolism , Dopamine/metabolism , Motor Activity/genetics , Parkinsonian Disorders/genetics , alpha-Synuclein/genetics , Animals , Brain/pathology , Brain/physiopathology , Disease Models, Animal , Dopamine Plasma Membrane Transport Proteins/drug effects , Dopamine Plasma Membrane Transport Proteins/metabolism , Electric Stimulation , Enzyme Inhibitors/pharmacology , Humans , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Mice, Transgenic , Mutation/genetics , Neural Pathways/metabolism , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Substantia Nigra/metabolism , Synaptic Transmission/genetics , Synaptic Vesicles/drug effects , Synaptic Vesicles/metabolism , alpha-Methyltyrosine/pharmacologyABSTRACT
The present work addresses the role of polyamines in learning and general behavior by subjecting transgenic mice overexpressing polyamine catabolic enzyme, spermidine/spermine N(1)-acetyltransferase (SSAT) and their syngenic littermates to neurobehavioral profiling assessment (SHIRPA) and to radial eight-arm maze. The general health and physiological conditions as well as the entire behavioral battery comprising of 34 parameters were recorded. The eight-arm radial maze (8-RAM) task included an initial acquisition task for 9 days followed by a 2-day retention test after a 2-week break. In addition, blood samples were taken for hormone analysis. Transgenic mice, which showed reduced motor activity, aggression and muscle tone, spent more time in the radial maze during initial acquisition and retention tasks as compared with syngenic mice. Moreover, the learning performance of transgenic females was significantly inferior to syngenic females. Interestingly, the levels of several hormones were significantly altered in SSAT transgenic mice; circulating adrenocorticotropic hormone (ACTH) and corticosterone levels were markedly increased while testosterone and thyroidal hormone levels were decreased. These changes may be related to the dramatic increase in brain putrescine levels in SSAT-overexpressing (SSAT-OE) mice, but it is likewise possible that the behavioral changes and learning impairment are attributable to more peripheral mechanisms (such as alterations in steroid hormone metabolism), which in turn, could be a consequence of the disturbed polyamine homeostasis.
