Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps

Abstract

Previous research indicates that dopamine controls both the speed of an internal clock (Maricq and Church, 1983) and sharing of resources between the timer and other cognitive processes (Buhusi, 2003). For example, dopamine agonist methamphetamine increases the speed of an internal clock and resets timing after a gap, while dopamine antagonist haloperidol decreases the speed of an internal clock and stops timing during a gap (Buhusi and Meck, 2002a). Using a 20-s peak-interval procedure with gaps we examined the acute effects of clozapine (2.0 mg/kg i.p.), which exerts differential effects on dopamine and serotonin in the cortex and striatum, two brain areas involved in interval timing and working memory. Relative to saline, clozapine injections shifted the response functions leftward both in trials with and without gaps, suggesting that clozapine increased the speed of an internal clock and facilitated the maintenance of the pre-gap interval in working memory. These results suggest that clozapine exerts effects in different brain areas in a manner that allows for the pharmacological separation of clock speed and working memory as a function of peak trials without and with gaps.

Intelligence and Variability in a Simple Timing Task Share Neural Substrates in the Prefrontal White Matter

“…Large bodies of literature show that dopaminergic neurotransmission is involved in both prefrontal functions related to cognition (Miller and Cohen, 2001;Nieoullon, 2002;Bäckman et al, 2006;Cropley et al, 2006) and timing (Rammsayer, 1997;Buhusi and Meck, 2005;Lewis and Miall, 2006;Meck, 2006). Administration of dopaminergic drugs has been shown to simultaneously affect timing and working memory (Buhusi and Meck, 2007).…”

Clock Speed as a Window into Dopaminergic Control of Emotion and Time Perception

“…Several decades of work has described patients with schizophrenia also suffer from disrupted perceptual timing (Ciullo et al, 2016;Ward et al, 2012). As in Parkinson's disease, several drugs that are effective for schizophrenia (including haloperidol) act on dopaminergic receptors, with some potently blocking striatal D2 signaling and others such as clozapine, risperidone, and aripiprazole with partial action on dopamine receptors in addition to serotonin and norepinephrine receptors (e.g., Buhusi & Meck, 2007;Heilbronner & Meck, 2014;MacDonald & Meck, 2005).…”

Altered time-perception performance in individuals with high schizotypy levels

“…Multiple brain regions 1 and neurotransmitters [2][3][4] are implicated in schizophrenia. For example, it has long been hypothesized that dopamine overactivity is related to schizophrenia [5][6][7] , and an important brain region where neurotransmitter activity contributes to schizophrenic symptoms is the striatum 3,8,9 , which is known to be involved in the control of timing 10,11 .…”

“…For example, it has long been hypothesized that dopamine overactivity is related to schizophrenia [5][6][7] , and an important brain region where neurotransmitter activity contributes to schizophrenic symptoms is the striatum 3,8,9 , which is known to be involved in the control of timing 10,11 . Changes in dopamine activity also influences performance in timing tasks 9,12 ; increased dopamine activity in the striatum slows subjective time-perception, making subjects over-estimate the passage of time 13,14 .…”