Willuhn I, Steiner H. Motor-skill learning in a novel running-wheel task is dependent on D1 dopamine receptors in the striatum. Neuroscience 153: 249-258

Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Neuroscience (Impact Factor: 3.36). 05/2008; 153(1):249-58. DOI: 10.1016/j.neuroscience.2008.01.041
Source: PubMed


Evidence indicates that dopamine receptors regulate processes of procedural learning in the sensorimotor striatum. Our previous studies revealed that the indirect dopamine receptor agonist cocaine alters motor-skill learning-associated gene regulation in the sensorimotor striatum. Cocaine-induced gene regulation in the striatum is principally mediated by D1 dopamine receptors. We investigated the effects of cocaine and striatal D1 receptor antagonism on motor-skill learning. Rats were trained on a running wheel (40-60 min, 2-5 days) to learn a new motor skill, that is, the ability to control the movement of the wheel. Immediately before each training session, the animals received an injection of vehicle or cocaine (25 mg/kg, i.p.), and/or the D1 receptor antagonist SCH-23390 (0, 3, 10 microg/kg, i.p., or 0, 0.3, 1 microg, intrastriatal via chronically implanted cannula). The animal's ability to control/balance the moving wheel (wheel skill) was tested before and repeatedly after the training. Normal wheel-skill memory lasted for at least 4 weeks. Cocaine administered before the training tended to attenuate skill learning. Systemic administration of SCH-23390 alone also impaired skill learning. However, cocaine given in conjunction with the lower SCH-23390 dose (3 microg/kg) reversed the inhibition of skill learning produced by the D1 receptor antagonist, enabling intact skill performance during the whole post-training period. In contrast, when cocaine was administered with the higher SCH-23390 dose (10 microg/kg), skill performance was normalized 1-6 days after the training, but these rats lost their improved wheel skill by day 18 after the training. Similar effects were produced by SCH-23390 (0.3-1 microg) infused into the striatum. Our results indicate that cocaine interferes with normal motor-skill learning, which seems to be dependent on optimal D1 receptor signaling. Furthermore, our findings demonstrate that D1 receptors in the striatum are critical for consolidation of long-term skill memory.

Download full-text


Available from: Ingo Willuhn,
  • Source
    • "Cocaine modulates the action of D1 dopamine receptors, associated with c-fos gene regulation in the striatum (Graybiel et al., 1990; Gerfen et al., 1995). Therefore, it has been suggested that cocaine encodes the transcription of motor skill learning (Willuhn and Steiner, 2008). Dopamine dysfunction or deficiency in the striatum is the major clinical observation in Parkinsonism (Khan et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The motor cortex and dorsal striatum (caudate nucleus and putamen) are key regions in motor processing but the interface between the cortex and striatum is not well understood. While dorsal striatum integrates information from multiple brain regions to shape motor learning and habit formation, the disruption of cortico-striatal circuits compromises the functionality of these circuits resulting in a multitude of neurologic disorders, including Parkinson's disease. To better understand the modulation of the cortico-striatal circuits we recorded simultaneously single neuron activity from four brain regions, primary motor, and sensory cortices, together with the rostral and caudal segments of the putamen in rhesus monkeys performing a visual motor task. Results show that spatial and temporal-task related firing relationships between these cortico-striatal circuit regions were modified by the independent administration of the two drugs (cocaine and baclofen). Spatial tuning and correlated firing of neurons from motor cortex and putamen were severely disrupted by cocaine and baclofen on correct trials, while the two drugs have dramatically decreased the functional connectivity of the motor cortical-striatal network. These findings provide insight into the modulation of cortical-striatal firing related to movement with implications for therapeutic approaches to Parkinson's disease and related disorders.
    Frontiers in Systems Neuroscience 03/2014; 8:27. DOI:10.3389/fnsys.2014.00027
  • Source
    • "Recent findings have suggested that the generation of aberrant procedural memories in striatal motor circuits could participate in the manifestation of abnormal motor responses associated with DRT (Calon et al., 2000; Pisani et al., 2005; Jenner, 2008; Simola et al., 2009; Frau et al., 2013). Thus, the striatum plays a major role in processes such as integration of motor signals, acquisition of motor habits, and execution of motor programs, which are all critically regulated by dopamine (Mink, 1996; Packard and Knowlton, 2002; Gerdeman et al., 2003; Tang et al., 2007; Willuhn and Steiner, 2008). Starting from these premises, it has been hypothesized that the dopamine-denervated striatum fails to properly process motor information, and that this may result in an overload of striatal motor circuits following the performance of movement stimulated by drugs that activate dopamine receptors (Picconi et al., 2005; Pisani et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal involuntary movements (AIMs) and dyskinesias elicited by drugs that stimulate dopamine receptors in the basal ganglia are a major issue in the management of Parkinson's disease (PD). Preclinical studies in dopamine-denervated animals have contributed to the modeling of these abnormal movements, but the precise neurochemical and functional mechanisms underlying these untoward effects are still elusive. It has recently been suggested that the performance of movement may itself promote the later emergence of drug-induced motor complications, by favoring the generation of aberrant motor memories in the dopamine-denervated basal ganglia. Our recent results from hemiparkinsonian rats subjected to the priming model of dopaminergic stimulation are in agreement with this. These results demonstrate that early performance of movement is crucial for the manifestation of sensitized rotational behavior, indicative of an abnormal motor response, and neurochemical modifications in selected striatal neurons following a dopaminergic challenge. Building on this evidence, this paper discusses the possible role of movement performance in drug-induced motor complications, with a look at the implications for PD management.
    Frontiers in Computational Neuroscience 10/2013; 7:142. DOI:10.3389/fncom.2013.00142 · 2.20 Impact Factor
  • Source
    • "Dopaminergic signals in the striatum and motor cortex play essential roles in the induction of synaptic plasticity and motor skill acquisition. Administration of a D1 receptor antagonist to the striatum previously resulted in impaired motor skill acquisition [12] [13], while 11C-raclopride positron emission tomography (PET) showed dopamine release in the striatum during new motor sequence learning [14]. The motor cortex is also associated with encoding elementary aspects of movement such as dynamic acceleration and force [15], [16], [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using (11)C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The (11)C-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that (11)C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition.
    PLoS ONE 02/2012; 7(2):e31728. DOI:10.1371/journal.pone.0031728 · 3.23 Impact Factor
Show more