Elsevier

Brain Research

Volume 608, Issue 2, 16 April 1993, Pages 247-258
Brain Research

Specificity of behavioral and neurochemical dysfunction in the chakragati mouse: a novel genetic model of a movement disorder

https://doi.org/10.1016/0006-8993(93)91465-5Get rights and content

Abstract

Thechakragati (ckr) mouse is a transgenic insertional mutant that displays lateralized circling behavior, locomotor hyperactivity, hyperexcitability as well as body weight deficits. The mutation is autosomal and recessive. We have previously found thatckr mice have bilateral asymmetric elevations in striatal dopamine (DA) D2-like (D2, D3 and/or D4), but not D1-like (D1 and/or D5) receptors. Predictably, these mice increase turning in response to the D2-like agonist quinpirole and spontaneously rotate contralateral to the striatal side with the higher D2-lik3 receptors. The overall objective of the present study was to assess the neurochemical specificity of the mutation inckr mouse, particularly since motor behaviors can be elicited by a multitude of brain regions and neurotransmitter systems within the basal ganglia. Using quantitative receptor autoradiography, we examined the regional distribution of DA uptake sites and 5-HT1A, 5-HT1B/1D, GABAA and μ opioid receptors. Also, we wanted to determine whether increased behavioral laterality as seen in rotation is evident with another test of laterality, such as lateral paw preference. Theckr mice showed greater paw preferences than normal mice; however, neither the degree nor direction of these preferences correlated with rotational behavior. Theckr mice showed moderate decreases in the density of DA uptakes sites in all subregions of the striatum, but not in the nucleus accumbens or olfactory tubercle. Interestingly, these decreases inckr mice were not accompanied by a reduction in striatal tissue DA content. 5-HT1 and μ opiate receptor populations were normal inckr mice. However, GABAA sites in the mediodorsal thalamus and superior colliculus were bilaterally and asymmetrically elevated inckr mice. These data are consistent with the idea that the motor phenotypes of theckr mouse result from specific 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 hyperkinetic motor syndromes in humans involving reduced basal ganglia outflow.

References (67)

  • FleisherL.N. et al.

    A telecephalic lesion site ford-amphetamine-induced contralateral rotation in rats

    Brain Res.

    (1975)
  • GrahamW.C. et al.

    Autoradiographic studies in animal models of hemiparkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. I. 6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat

    Brain Res.

    (1990)
  • GreenA.R.

    5-HT-mediated behaviour. Animal studies

    Neuropharmacology

    (1984)
  • GreensteinS. et al.

    Improved automated apparatus for recording rotation (circling behavior) in rats or mice

    Pharmacol. Biochem. Behav.

    (1975)
  • GroenewegenH.J.

    Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography

    Neuroscience

    (1988)
  • ImperatoA. et al.

    Behavioral effects of GABA agonists and antagonists infused in the mesencephalic reticular formation and deep layers of the superior colliculus

    Brain Res.

    (1981)
  • JoyceJ.N.

    Differential response of striatal dopamine and muscarinic cholinergic receptor subtypes to the loss of dopamine. I. Effects of intranigral or intracerebroventricular 6-hydroxydopamine lesions of the mesostriatal dopamine system

    Exp. Neurol.

    (1991)
  • KilpatrickI.C. et al.

    Evidence for the participation of nigrotectal γ-aminobutyrate-containing neurones in striatal and nigra-derived circling in the rat

    Neuroscience

    (1982)
  • LeonardC.M.

    The prefrontal cortex of the rat. I. Cortical projection of the mediodorsal nucleus. II. Efferent projections

    Brain Res.

    (1969)
  • MansourA. et al.

    Pharmacological and anatomical evidence of selective mu, delta and kappa opioid binding in rat brain

    Brain Res.

    (1986)
  • MarshallJ.F. et al.

    Dopamine high-affinity transport site topography in rat brain: major differences between dorsal and ventral striatum

    Neuroscience

    (1990)
  • MeansL.W. et al.

    Effects of dorsomedial thalamic lesions on spatial discrimination reversal in the rat

    Physiol. Behav.

    (1975)
  • MillerR. et al.

    On the interpretation of asymmetries of posture and locomotion produced with dopamine agonists in animals with unilateral depletion of striatal dopamine

    Prog. Neurobiol.

    (1991)
  • O'DellS.J. et al.

    Transport of [3H]mazindol binding sites in mesostriatal dopamine axons

    Brain Res.

    (1988)
  • PazosA. et al.

    Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors

    Brain Res.

    (1985)
  • PrzedborskiS. et al.

    Regional changes in brain 5-HT1A serotonin receptors in the rat model of persistent spasmodic dyskinesias induced by iminodipropionitrile

    Brain Res.

    (1989)
  • RattyA.K. et al.

    Circling behavior exhibited by a transgenic insertional mutant

    Mol. Brain Res.

    (1990)
  • Rydelek-FitzgeraldL. et al.

    NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors

    Brain Res.

    (1990)
  • SavastaM. et al.

    Denervation supersensitivity of striatal D2 dopamine receptors is restrcted to the ventro- and dorsolateral regions of the striatum

    Neurosci. Lett.

    (1987)
  • StarrM.S. et al.

    Multifocal brain sites for apomorphine-induced circling and other stereotyped motor behavior in the 6-hydroxydopamine-lesioned rat

    Neurosci. Lett.

    (1982)
  • StarrM.S. et al.

    Role of the ventromedial nucleus of the thalamus in motor behavior - II. Effects of lesions

    Neuroscience

    (1983)
  • VivesF. et al.

    Electrophysiological evidence that the mediodorsal nucleus of the thalamus is a relay between the ventral pallidum and medial prefrontal cortex in the rat

    Brain Res.

    (1985)
  • WaeberC. et al.

    Visualization of a novel serotonin recognition site (5-HT1D) in the human brain by autoradiography

    Neurosci. Lett.

    (1988)
  • Cited by (29)

    • Gender differences in locomotor and stereotypic behavior associated with l-carnitine treatment in mice

      2011, Gender Medicine
      Citation Excerpt :

      In addition, when the gender of rats or mice was specified, it was always male. This is somewhat surprising, considering the literature on the anatomical and biochemical sexual dimorphism of the brain and the carnitine system.20–40 Gonadal steroids are implicated in the development of sexually dimorphic structures in the central nervous system, in the control of physiological behaviors, and via rapid nongenomic actions, in the modulation of neuronal excitability.24

    • Magnetic resonance imaging and spectroscopy in a mouse model of schizophrenia

      2008, Brain Research Bulletin
      Citation Excerpt :

      For instance, the mouse mutant shows behavioral abnormalities, including novelty-driven hyperactivity that is manifested as increased circling activity in the open field [20,24,25]. Further, ckr mice show asymmetric elevations of dopamine (DA) D2-like receptors in basal ganglia circuitry [9], and high-resolution magnetic resonance imaging (MRI) of these mutants indicates selective enlargement of the lateral ventricles [24]. As these abnormalities are often diagnosed in patients with schizophrenia, genetically mutant ckr mice might be relevant for understanding or pinpointing psychoses-causing mechanisms.

    View all citing articles on Scopus
    *

    Formerly spelled Titeler.

    View full text