ABSTRACT
Dystonia is a disabling neurological syndrome characterized by abnormal movements and postures that result from intermittent or sustained involuntary muscle contractions; mutations of DYT1/TOR1A are the most common cause of childhood-onset, generalized, inherited dystonia. Patient and mouse model data strongly support dysregulation of the nigrostriatal dopamine neurotransmission circuit in the presence of the DYT1-causing mutation. To determine striatal medium spiny neuron (MSN) cell-autonomous and non-cell autonomous effects relevant to dopamine transmission, we created a transgenic mouse in which expression of mutant torsinA in forebrain is restricted to MSNs. We assayed electrically evoked and cocaine-enhanced dopamine release and locomotor activity, dopamine uptake, gene expression of dopamine-associated neuropeptides and receptors, and response to the muscarinic cholinergic antagonist, trihexyphenidyl. We found that over-expression of mutant torsinA in MSNs produces complex cell-autonomous and non-cell autonomous alterations in nigrostriatal dopaminergic and intrastriatal cholinergic function, similar to that found in pan-cellular DYT1 mouse models. These data introduce targets for future studies to identify which are causative and which are compensatory in DYT1 dystonia, and thereby aid in defining appropriate therapies.
Subject(s)
Corpus Striatum/metabolism , Disease Models, Animal , Molecular Chaperones/biosynthesis , Molecular Chaperones/physiology , Motor Skills/physiology , Substantia Nigra/metabolism , Animals , Cocaine/pharmacology , Dopamine/metabolism , Dystonia/genetics , Dystonia/metabolism , Electric Stimulation , Female , Gene Expression/drug effects , Male , Mice , Mice, Transgenic , Molecular Chaperones/genetics , Mutation , Neural Pathways/metabolism , Neurons/metabolism , Trihexyphenidyl/antagonists & inhibitors , Trihexyphenidyl/pharmacologySubject(s)
Aminobutyrates/physiology , Diazepam/pharmacology , Motor Activity/drug effects , Parasympatholytics/antagonists & inhibitors , gamma-Aminobutyric Acid/physiology , Animals , Atropine/antagonists & inhibitors , Atropine/pharmacology , Benztropine/antagonists & inhibitors , Benztropine/pharmacology , Diazepam/antagonists & inhibitors , Male , Mice , Mice, Inbred Strains , Picrotoxin/pharmacology , Scopolamine/antagonists & inhibitors , Scopolamine/pharmacology , Semicarbazides/pharmacology , Strychnine/pharmacology , Trihexyphenidyl/antagonists & inhibitors , Trihexyphenidyl/pharmacologyABSTRACT
Experiments were carried out in mice to investigate the influence of diazepam (DZP) on dexamphetamine, parachloro-N-methylamphetamine (pCMA), cocaine, morphine, trihexyphenidyl or (in MAOIs pretreated) reserpine induced motor hyperactivity. The interaction of DZP with these hyperactivities in which probably different biochemical central mechanisms are involved allows to construct a profile of action of DZP and to approach its mechanism of action. The locomotor hyperactivities induced by dexamphetamine, pCMA, morphine, cocaine were not reduced by DZP even by doses which decrease spontaneous locomotor activity; low doses of DZP enhance the hyperactivity induced by these compounds. Those induced by trihexyphenidyle or by reserpine (after MAOI) were reduced by DZP at doses which produce no decrease in spontaneous motor activity. Inasmuch as DZP at low doses potentiates the effects of 4 different substances, the results can hardly be satisfactorily explained neither by an interference of the benzodiazepine on the metabolism of the drugs or by a depression of the anxiogenic action of dexamphetamine. Even though it may be difficult to relate the antagonism of DZP on trihexyphenidyl- or on reserpine- (after MAOI) induced motor hyperactivity to the suggested anticholinergic and dopaminergic actions of DZP, these effects may partly be involved in the increase in locomotor hyperactivity induced by dexamphetamine, morphine, or cocaine. The observed effect of DZP on pCMA induced locomotor hyperactivity does not support a possible antiserotonine action often suggested to explain the effects of benzodiazepines in conflict situations.
