Abstract
To identify basal ganglia circuit dysfunctions that might produce repetitive behaviors known as motor stereotypies, we applied psychomotor stimulants and a direct dopamine receptor agonist to induce different levels of stereotypy in rats. We then used a gene induction assay to measure the functional activation of neurons in the neurochemically distinct compartments of the striatum, the striosomes and the extrastriosomal matrix. The amount by which activation in the striosomes exceeded activation in the matrix predicted the degree of motor stereotypy induced by the drug treatments. These results suggest that imbalance between compartmentally organized basal ganglia circuits may represent a neural correlate of motor stereotypy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ridley, R. M. The psychology of perseverative and stereotyped behaviour. Prog. Neurobiol. 44, 221–231 (1994).
Manschreck, T. C. in Handbook of Schizophrenia Vol. 1. The Neurology of Schizophrenia (eds. Nasrallah, H. A. & Weinberger, D. R.) 65–96 (Elsevier, Amsterdam, 1986).
Antony, M. M., Downie, F. & Swinson, R. P. in Obsessive-compulsive Disorder: Theory, Research and Treatment (eds. Swinson, R. P., Antony, M. M., Rachman, S. & Richter, M. A.) 3–32 (Guildford, Oxford, 1988).
Randrup, A. & Munkvad, I. Influence of amphetamines on animal behaviour: stereotypy, functional impairment and possible animal-human correlations. Psychiatr. Neurol. Neurochir. 75, 193–202 (1972).
Gold, L. H., Geyer, M. A. & Koob, G. F. Neurochemical mechanisms involved in behavioral effects of amphetamines and related designer drugs. NIDA Res. Monogr. 94, 101–126 (1989).
Fog, R. On stereotypy and catalepsy: studies on the effect of amphetamines and neuroleptics in rats. Acta Neurol. Scand. Suppl. 50, 3–66 (1972).
Costall, B. & Naylor, R. J. Dissociation of stereotyped biting responses and oro-bucco-lingual dyskinesias. Eur. J. Pharmacol. 36, 423–429 (1976).
Creese, I. & Iversen, S. D. Amphetamine response in rat after dopamine neurone destruction. Nat. New Biol. 238, 247–248 (1972).
Fibiger, H. C., Fibiger, H. P. & Zis, A. P. Attenuation of amphetamine-induced motor stimulation and stereotypy by 6-hydroxydopamine in the rat. Br. J. Pharmacol. 47, 683–692 (1973).
Arnt, J. Antistereotypic effects of dopamine D-1 and D-2 antagonists after intrastriatal injection in rats. Pharmacological and regional specificity. Naunyn Schmiedebergs Arch. Pharmacol. 330, 97–104 (1985).
Cummings, J. L. Anatomic and behavioral aspects of frontal-subcortical circuits. Ann. NY Acad. Sci. 769, 1–13 (1995).
Rosenberg, D. R., Dick, E. L., O'Hearn, K. M. & Sweeney, J. A. Response-inhibition deficits in obsessive-compulsive disorder: an indicator of dysfunction in frontostriatal circuits. J. Psychiatry Neurosci. 22, 29–38 (1997).
Graybiel, A. M. The basal ganglia and cognitive pattern generators. Schizophr. Bull. 23, 459–469 (1997).
Graybiel, A. M., Moratalla, R. & Robertson, H. A. Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc. Natl. Acad. Sci. USA 87, 6912–6916 (1990).
Curran, T. & Morgan, J. I. Fos: an immediate-early transcription factor in neurons. J. Neurobiol. 26, 403–412 (1995).
Sharp, F. R., Sagar, S. M. & Swanson, R. A. Metabolic mapping with cellular resolution: c-fos vs. 2–deoxyglucose. Crit. Rev. Neurobiol. 7, 205–228 (1993).
Pierce, R. C. & Kalivas, P. W. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res. Brain Res. Rev. 25, 192–216 (1997).
Segal, D. S., Weinberger, S. B., Cahill, J. & McCunney, S. J. Multiple daily amphetamine administration: behavioral and neurochemical alterations. Science 207, 905–907 (1980).
Hope, B. T. et al. Induction of long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244 (1994).
Rosen, J. B., Chuang, E. & Iadarola, M. J. Differential induction of Fos protein and a Fos-related antigen following acute and repeated cocaine administration. Mol. Brain Res. 25, 168–172 (1994).
Moratalla, R., Elibol, B., Vallejo, M. & Graybiel, A. M. Network-level changes in expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal. Neuron 17, 147–156 (1996).
Scheel-Kruger, J. Behavioural and biochemical comparison of amphetamine derivatives, cocaine, benztropine and tricyclic anti-depressant drugs. Eur. J. Pharmacol. 18, 63–73 (1972).
Bhat, R. V., Cole, A. J. & Baraban, J. M. Role of monoamine systems in activation of zif268 by cocaine. J. Psychiatry Neurosci. 17, 94–102 (1992).
Ramamoorthy, S. & Blakely, R. D. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285, 763–766 (1999).
Steiner, H. & Gerfen, C. R. Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior. Exp. Brain Res. 123, 60–76 (1998).
Wang, J. Q., Daunais, J. B. & McGinty, J. F. NMDA receptors mediate amphetamine-induced upregulation of zif/268 and preprodynorphin mRNA expression in rat striatum. Synapse 18, 343–353 (1994).
Aosaki, T., Kimura, M. & Graybiel, A. M. Temporal and spatial characteristics of tonically active neurons of the primate's striatum. J. Neurophysiol. 73, 1234–1252 (1995).
Calabresi, P. et al. A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression. J. Neurosci. 19, 2489–2499 (1999).
Wang, J. Q. & McGinty, J. F. Alterations in striatal zif/268, preprodynorphin and preproenkephalin mRNA expression induced by repeated amphetamine administration in rats. Brain Res. 673, 262–274 (1995).
Konradi, C., Leveque, J.-C. & Hyman, S. E. Amphetamine and dopamine-induced immediate early gene expression in striatal neurons depends on postsynaptic NMDA receptors and calcium. J. Neurosci. 16, 4231–4239 (1996).
Torres, G. & Rivier, C. Cocaine-induced expression of striatal c-fos in the rat is inhibited by NMDA receptor antagonists. Brain Res. Bull. 30, 173–176 (1993).
Bito, H., Deisseroth, K. & Tsien, R. W. CREB phosphorylation and dephosphorylation: a Ca2+- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87, 1203–1214 (1996).
Liu, F.-C. & Graybiel, A. M. Spatiotemporal dynamics of CREB phosphorylation: Transient versus sustained phosphorylation in the developing striatum. Neuron 17, 1133–1144 (1996).
Dragunow, M. A role for immediate-early transcription factors in learning and memory. Behav. Genet. 26, 293–299 (1996).
Mello, C. V. & Clayton, D. F. Song-induced ZENK gene expression in auditory pathways of songbird brain and its relation to the song control system. J. Neurosci. 14, 6652–6666 (1994).
Graybiel, A. M. Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci. 13, 244–254 (1990).
Gerfen, C. R. The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci. 15, 133–139 (1992).
Volkow, N. D., Fowler, J. S., Wolf, A. P. & Gillespie, H. Metabolic studies of drugs of abuse. NIDA Res. Monogr. 105, 47–53 (1991).
Robbins, T. Stereotypies: addictions or fragmented actions? Bull. Br. Psychol. Soc. 35, 297–300 (1982).
Lyon, M. & Robbins, T. W. in Current Developments in Psychopharmacology (eds. Essmann, W. B. & Valzelli, L.) 80–163 (Spectrum, New York, 1975).
LaHoste, G. J. & Marshall, J. F. The role of dopamine in the maintenance and breakdown of D1/D2 synergism. Brain Res. 611, 108–116 (1993).
Paul, M. L., Graybiel, A. M., David, J.-C. & Robertson, H. A. D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease. J. Neurosci. 12, 3729–3742 (1992).
Wirtshafter, D. & Asin, K. E. Interactive effects of stimulation of D1 and D2 dopamine receptors on fos-like immunoreactivity in the normosensitive rat striatum. Brain Res. Bull. 35, 85–91 (1994).
Xu, M. et al. Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice. Cell 79, 945–955 (1994).
Xu, M. et al. Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell 79, 729–742 (1994).
Arnt, J. Antistereotypic effects of dopamine D-1 and D-2 antagonists after intrastriatal injection in rats. Pharmacological and regional specificity. Naunyn Schmiedebergs Arch. Pharmacol. 330, 97–104 (1985).
Hiroi, N. & Graybiel, A. M. Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum. J. Comp. Neurol. 374, 70–83 (1996).
Hughes, P. & Dragunow, M. Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacol. Rev. 47, 133–178 (1995).
Albin, R. L., Young, A. B. & Penney, J. B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375 (1989).
Wichmann, T. & DeLong, M. R. Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg. Clin. N. Am. 9
Acknowledgements
This work was funded by NIDA R01 DA08037, the National Parkinson Foundation, the Stanley Foundation and the Grayce B. Kerr Fund. We thank Patricia Harlan for technical assistance, Henry Hall for the photography, Joel Ventura and Paul Di Zio for advice on statistics and R. Bravo, R. P. Elde, M. Iadarola and S. Watson for their gifts of antisera.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Canales, J., Graybiel, A. A measure of striatal function predicts motor stereotypy. Nat Neurosci 3, 377–383 (2000). https://doi.org/10.1038/73949
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/73949
This article is cited by
-
Persistent enhancement of basolateral amygdala-dorsomedial striatum synapses causes compulsive-like behaviors in mice
Nature Communications (2024)
-
Co-morbid tics and stereotypies: a systematic literature review
Neurological Sciences (2024)
-
Chronic treatment with D2-antagonist haloperidol leads to inhibitory/excitatory imbalance in striatal D1-neurons
Translational Psychiatry (2023)
-
Optogenetic stimulation of striatal patches modifies habit formation and inhibits dopamine release
Scientific Reports (2021)
-
Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
Molecular Psychiatry (2021)