SPECIFICITY OF BEHAVIORAL AND NEUROCHEMICAL DYSFUNCTION IN THE CHAKRAGATI MOUSE - A NOVEL GENETIC MODEL OF A MOVEMENT DISORDER

The chakragati (ckr) mouse is a transgenic insertional mutant that dis plays lateralized circling behavior, locomotor hyperactivity, hyperexc itability as well as body weight deficits. The mutation is autosomal a nd recessive. We have previously found that ckr mice have bilateral as ymmetric elevations in striatal dopamine (DA) D2-like (D2, D3 and/or D 4), but not D1-like (D1 and/or D5) receptors. Predictably, these mice increase turning in response to the D2-like agonist quinpirole and spo ntaneously rotate contralateral to the striatal side with the higher D 2-like receptors. The overall objective of the present study was to as sess the neurochemical specificity of the mutation in ckr mouse, parti cularly since motor behaviors can be elicited by a multitude of brain regions and neurotransmitter systems within the basal ganglia. Using q uantitative receptor autoradiography, we examined the regional distrib ution of DA uptake sites and 5-HT1A, 5-HT1B/1D, GABA(A) and mu opioid receptors. Also, we wanted to determine whether increased behavioral l aterality as seen in rotation is evident with another test of laterali ty, such as lateral paw preference. The ckr mice showed greater paw pr eferences than normal mice; however, neither the degree nor direction of these preferences correlated with rotational behavior. The ckr mice showed moderate decreases in the density of DA uptake sites in all su bregions of the striatum, but not in the nucleus accumbens or olfactor y tubercle. Interestingly, these decreases in ckr mice were not accomp anied by a reduction in striatal tissue DA content. 5-HT1 and mu opiat e receptor populations were normal in ckr mice. However, GABA(A) sites in the mediodorsal thalamus and superior colliculus were bilaterally and asymmetrically elevated in ckr mice. These data are consistent wit h the idea that the motor phenotypes of the ckr mouse result from spec ific disturbances within nigro-striatal, striato-pallido-thalamic and striato-nigro-collicular circuitry. The implications of these and past findings are discussed in relation to current thinking about hyperkin etic motor syndromes in humans involving reduced basal ganglia outflow .