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

Abstract

To investigate striatal mechanisms underlying the acute effects of stimulants on motor behavior, firing rates (FRs) of striatal neurons related specifically to vertical head movement were studied exclusively during vertical head movements. Precocaine FRs were recorded after intraperitoneal saline injection (time 1; T1), and rats performed conditioned vertical head movements (Ͼ10,000) similar to those induced by stimulants. After cocaine injection (0, 5, 10, or 20 mg/kg; T2), animals continued in the task. The proportion of long head movements was increased by low doses but decreased by the high dose, which induced stereotypic head movements. Comparing each neuron's FR during movements that were matched between T1 and T2 (e.g., regarding direction, distance), cocaine's effects depended on predrug FR and dose. Plots regressing T2FR on T1FR showed dose-dependent, "clockwise" rotations of regression lines in plots of all the neurons' average FRs and of individual neurons' FRs during different movements. All three doses elevated normally low FRs; the high dose also suppressed many higher FRs. Enhancement of a neuron's FR associated with weak and suppression of FR associated with strong corticostriatal inputs contradict several current theories of dopamine (DA) function. Induction of stereotypy by a single, high-dose injection suggests that this cocaine level exceeded that in other studies using cocaine self-administration, in which stereotypy develops only after several sessions. Suppressive effects observed only at the high dose and in numerous electrophysiological studies of DA agonist effects may be unrepresentative of uniform elevations in lateral striatal firing related to movement observed at lower cocaine levels.Effects of psychostimulants include increased rates of grooming, social activity, rearing, and locomotion at low doses; increased rates of locomotion and rearing at the expense of feeding, grooming, and social activity at moderate doses; whereas complex movements are replaced by short, repetitive, apparently purposeless movements, termed stereotypy, such as head bobbing at high doses (Lyon and Robbins, 1975). Dopamine (DA) transmission in the lateral striatum plays a key role in psychostimulant-induced stereotypy (Creese and Iversen, 1974;Kelly et al., 1975), more so than non-DA monoamines (Fog and Pakkenberg, 1971;Creese and Iversen, 1974). DA agonists in the lateral, but not medial, striatum cause stereotypy (Kelley and Delfs, 1994). DA antagonists or 6-hydroxydopamine lesions of striatal DA attenuate psychostimulant-induced stereotypy (Kelly et al., 1975).Glutamatergic projections from somatic sensorimotor cortices converge in dorsolateral striatum (DLS) (Kü nzle, 1975;McGeorge and Faull, 1989). Striatal medium spiny neurons (MSNs) fire in relation to sensorimotor activity of particular body parts (Crutcher and DeLong, 1984;Carelli and West, 1991) and project via pallidum and substantia nigra pars reticulata to thalamocortical premotor areas (Parent and Hazrati, 1995). The convergence onto M...

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