Dose- and Rate-Dependent Effects of Cocaine on Striatal Firing Related to Licking

Abstract

To examine the role of striatal mechanisms in cocaine-induced stereotyped licking, we investigated the acute effects of cocaine on striatal neurons in awake, freely moving rats before and after cocaine administration (0, 5, 10, or 20 mg/kg). Stereotyped licking was induced only by the high dose. Relative to control (saline), cocaine reduced lick duration and concurrently increased interlick interval, particularly at the high dose, but it did not affect licking rhythm. Firing rates of striatal neurons phasically related to licking movements were compared between matched licks before and after injection, minimizing any influence of sensorimotor variables on changes in firing. Both increases and decreases in average firing rate of striatal neurons were observed after cocaine injection, and these changes exhibited a dose-dependent pattern that strongly depended on predrug firing rate. At the middle and high doses relative to the saline group, the average firing rates of slow firing neurons were increased by cocaine, resulting from a general elevation of movement-related firing rates. In contrast, fast firing neurons showed decreased average firing rates only in the high-dose group, with reduced firing rates across the entire range for these neurons. Our findings suggest that at the high dose, increased phasic activity of slow firing striatal neurons and simultaneously reduced phasic activity of fast firing striatal neurons may contribute, respectively, to the continual initiation of stereotypic movements and the absence of longer movements.

Acute Effects of Cocaine on Movement-Related Firing of Dorsolateral Striatal Neurons Depend on Predrug Firing Rate and Dose

“…The elevation of movement-related FR of lateral striatal neurons by behaviorally relevant, acute doses of cocaine (see Tang et al, 2008) is consistent with recent suggestions of medial-to-lateral functional partitioning in striatum (Ikemoto et al, 2005) and our own observations of medial-tolateral transitions in MSN activity. Neurons in the accumbens core, compared with neurons in the more medial shell, exhibit stronger relations to instrumental responses, less responsiveness to auditory discriminative stimuli, and greater prevalence of elevated FR during cocaine self-administration (Ghitza et al, 2006).…”

“…Striatal variations in FR likely reflect differing degrees of excitatory corticostriatal synaptic input (Stern et al, 1997), as recognized by hypotheses that DA transmission suppresses weak and enhances strong excitatory striatal inputs (Nicola et al, 2000;O'Donnell, 2003). Inconsistent with these hypotheses, all three doses elevated average FR of slow-firing neurons, and the high dose suppressed average FR of faster-firing neurons (see Tang et al, 2008). Moreover, within individual neurons, cocaine dose dependently enhanced low and reduced high T1FR, which likely reflects a given neuron's responses to weak versus strong synaptic inputs, respectively.…”

“…Neurons in the accumbens core, compared with neurons in the more medial shell, exhibit stronger relations to instrumental responses, less responsiveness to auditory discriminative stimuli, and greater prevalence of elevated FR during cocaine self-administration (Ghitza et al, 2006). Further laterally than the core, in the lateral or sensorimotor striatum, MSNs exhibit robust, unconditioned relations to activity of body parts (Carelli and West, 1991), little responsiveness to visual (Kimura, 1990) or auditory (Carelli et al, 1997) discriminative stimuli, and only elevations of FR in the presence of low to moderate levels of cocaine (Tang et al, 2008;present study). How these functional differences fit with the laterally spiraling connections of striatal structures via mesencephalic and thalamocortical loops (Haber et al, 2000) will be important in understanding basal ganglia function in health and disease.…”

“…Previous reports from this laboratory (Pederson et al, 1997;Prokopenko et al, 2004;Tang et al, 2008) have revealed variability between neurons in drug-induced FR changes. Therefore, an analysis of the variability of the standardized measure of change in FR was carried out.…”

“…The method anticipates cocaine-induced movements, such as head bobbing or oral behaviors, so that comparisons of firing between cocaine and precocaine periods eliminate differences in sensorimotor behavior. We reinforced vertical head movements and selected only DLS neurons correlated specifically with vertical head movement (note that studying other neuronal types requires matching of the movements to which they are related) (Tang et al, 2008). Conditioning the correlated movement enabled the collection of thousands of different head movements, and thus numerous independent observations of each neuron's FR under behavioral and environmental conditions that were similar in both precocaine and cocaine periods.…”