Cognitive, Behavioral, and Systems NeuroscienceResearch PaperQuinpirole-induced sensitization to noisy/sparse periodic input: temporal synchronization as a component of obsessive-compulsive disorder
Research highlights
▶Rats are studied using a 40-s peak-interval timing procedure. ▶We examine changes in timing as a function of quinpirole administration. ▶Quinpirole-induced rhythmical behavior similar to the repetitive motor habits frequently observed in obsessive-compulsive disorder. ▶Observations are discussed in terms of excitation and inhibition of cortical-striatal circuits.
Section snippets
Subjects
Ten Sprague-Dawley male rats (Charles River VAF plus) approximately 4-months of age were housed in pairs in a temperature-controlled room, under a 12-h light/dark (L/D) cycle. Rats were provided free access to water in their home cages and were maintained at 85% of their ad lib weights by restricting access to food (Rodent Diet 5001, PMI Nutrition International, Inc., Brentwood, MO, USA). Experiments were conducted during the light portion of the L/D cycle in accordance with standard procedures
Drug administration and behavioral testing
For control rats given saline injections, during FI trials both the rate of lever pressing and food-cup entries gradually increased as a function of signal duration up until the time of reinforcement at 40 s after which lever presses abruptly decreased and food-cup entries abruptly increased. Following a 10–20-s period of food-cup checking, both responses were emitted randomly and at a low level for the remainder of the ITI (160-s min). In contrast, on unreinforced probe trials, lever pressing
Discussion
The present results demonstrated an unexpected level of rhythmical behavior in a secondary measure of responding (e.g. food-cup entries) that is a necessary action for the retrieval of the reward (e.g. food pellet), but not the instrumental response required to produce its delivery. As a consequence, this behavior is typically not recorded or analyzed during most timing experiments in which lever pressing is the reinforced response. The fact that it is a “secondary” response, and arguably more
Conclusion
In summary, our proposal is that there is an increased tendency to entrain to noisy and sparse periodic input as a result of reduced inhibitory control in cortico-striatal circuits following chronic QNP administration or in OCD patients. As a consequence, the repetitive motor habits frequently observed in OCD will have a tendency to be synchronized to specific temporal regularities in the environment that would normally be inhibited (Meck and Benson, 2002, Swerdlow, 2001). Moreover, it has been
Acknowledgments
This research was supported, in part, by a fellowship from the National Science Council of Taiwan to WHM. The authors would like to thank E. Crawford for assistance in training the rats.
References (84)
- et al.
Cross-species models of OCD spectrum disorders
Psychiatry Res
(2009) - et al.
Ketamine “unlocks” the reduced clock-speed effect of cocaine following extended training: evidence for dopamine—glutamate interactions in timing and time perception
Neurobiol Learn Mem
(2007) - et al.
Differential effects of cocaine and ketamine on time estimation: implications for neurobiological models of interval timing
Pharmacol Biochem Behav
(2006) - et al.
Endogenous oscillations in short-interval timing
Behav Processes
(2007) - et al.
Altered dopamine D2-like receptor binding in rats with behavioral sensitization to quinpirole: effects of pre-treatment with Ro 41-1049
Eur J Pharmacol
(2008) Temporal organization of the brain: neurocognitive mechanisms and clinical implications
Brain Cogn
(2004)- et al.
Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder
Biol Psychiatry
(2004) - et al.
Effects of dopamine antagonists on the timing of two intervals
Pharmacol Biochem Behav
(2003) - et al.
Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder
Behav Brain Res
(2006) - et al.
Rituals, stereotypy and compulsive behavior in animals and humans
Neurosci Biobehav Rev
(2006)
The transition from synchronization to continuation tapping
Hum Mov Sci
The importance of the reinforcer as a time marker
Behav Processes
Evidence for separate neural mechanisms for the timing of discrete and sustained responses
Brain Res
Neural bases of individual differences in beat perception
Neuroimage
Toward a neurobiology of obsessive-compulsive disorder
Neuron
Frontal-striatal circuitry activated by human peak-interval timing in the supra-seconds range
Cogn Brain Res
Effects of quinpirole on operant conditioning: perseveration of behavioral components
Behav Brain Res
Chronic treatment with haloperidol induces working memory deficits in feedback effects of interval timing
Brain Cogn
Systems-level integration of interval timing and reaction time
Neurosci Biobehav Rev
Interaction of raclopride and preparatory interval effects on simple reaction time performance
Behav Brain Res
Reinforcement-induced within-trial resetting of an internal clock
Behav Processes
Cortico-striatal circuits and interval timing: coincidence-detection of oscillatory processes
Cogn Brain Res
Affinity for the dopamine D2 receptor predicts neuroleptic potency in decreasing the speed of an internal clock
Pharmacol Biochem Behav
Neuroanatomical localization of an internal clock: a functional link between mesolimbic, nigrostriatal, and mesocortical dopaminergic systems
Brain Res
Dissecting the brain's internal clock: how frontal-striatal circuitry keeps time and shifts attention
Brain Cogn
Cortico-striatal representation of time in animals and humans
Curr Opin Neurobiol
Oscillations following periodic reinforcement
Behav Processes
Performance of spontaneously hypertensive rats in a peak-interval procedure with gaps
Behav Brain Res
Experimental evidence for synchronization to a musical beat in a nonhuman animal
Curr Biol
Temporal generalization accounts for response resurgence in the peak procedure
Behav Processes
Effects of the dopamine D2 agonist, quinpirole, on time and number processing in rats
Pharmacol Biochem Behav
Obsessive-compulsive disorder and tic syndromesAdvances in the pathophysiology and treatment of psychiatric disorders: implications for internal medicine
Med Clin North Am
Inactivation of dorsolateral striatum enhances sensitivity to changes in the action-outcome contingency in instrumental conditioning
Behav Brain Res
Timing and anticipation: conceptual and methodological approaches
Eur J Neurosci
Attenuation of the effects of d-amphetamine on interval timing behavior by central 5-hydroxytryptamine depletion
Psychopharmacology
Synchronization in networks of excitatory and inhibitory neurons with sparse, random connectivity
Neural Comput
Effects of noisy drive on rhythms in networks of excitatory and inhibitory neurons
Neural Comput
Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior
Psychopharmacology
What makes us tick?Functional and neural mechanisms of interval timing
Nat Rev Neurosci
Relativity theory and time perception: single or multiple clocks?
PLoS One
Synchronization of the neural response to noisy periodic synaptic input
Neural Comput
Habit formation and the loss of control of an internal clock: inverse relationship between the level of baseline training and the clock-speed enhancing effects of methamphetamine
Psychopharmacology
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