Dopaminergic Lesions of the Dorsolateral Striatum in Rats Increase Delay Discounting in an Impulsive Choice Task

Abstract

Dysregulated dopamine transmission in striatal circuitry is associated with impulsivity. The current study evaluated the influence of dopaminergic inputs to the dorsolateral striatum on impulsive choice, one aspect of impulsive behavior. We implemented an operant task that measures impulsive choice in rats via delay discounting wherein intracranial self-stimulation (ICSS) was used as the positive reinforcer. To do so, rats were anesthetized to allow implanting of a stimulating electrode within the lateral hypothalamus of one hemisphere and bilateral dorsal striatal injections of the dopaminergic toxin, 6-OHDA (lesioned) or its vehicle (sham). Following recovery, rats were trained in a delay discounting task wherein they selected between a small ICSS current presented immediately after lever pressing, and a large ICSS current presented following a 0 to 15s delay upon pressing the alternate lever. Task acquisition and reinforcer discrimination were similar for lesioned and sham rats. All rats exhibited an initial preference for the large reinforcer, and as the delay was increased, preference for the large reinforcer was decreased indicating that the subjective value of the large reinforcer was discounted as a function of delay time. However, this discounting effect was significantly enhanced in lesioned rats for the longer delays. These data reveal a contribution of dopaminergic inputs to the dorsolateral striatum on impulsive choice behavior, and provide new insights into neural substrates underlying discounting behaviors.

Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease

“…6OHDA (7μg) was bilaterally infused (0.2μL/min for 10min) into the DLS (from Bregma: +1.0mm AP, ±3.4mm ML; −4.7mm DV from skull). We previously verified that this protocol depletes tyrosine hydroxylase (TH) consistently confined to the DLS [10,13,34], and retrogradely reduces the number of TH + neurons within the lateral aspect of the substantia nigra pars compacta by 50% [13]. This 6OHDA-induced lesion profile results in a predictable, severe forelimb akinesia in all rats which persists for at least 3 months post-injection [13].…”

“…As Dopamine agonists are frequently used to treat early stage PD, we employed this lesion profile for the current study. Following our published protocols [10,13], desipramine (Sigma-Aldrich), a norepinephrine reuptake inhibitor, was administered (25mg/kg subcutaneously (sc)) to enhance dopaminergic selectivity of 6OHDA. Rats were anesthetized with isoflurane and secured in a stereotaxic frame.…”

“…We previously verified that this protocol depletes tyrosine hydroxylase (TH) consistently confined to the DLS [10,13,34], and retrogradely reduces the number of TH + neurons within the lateral aspect of the substantia nigra pars compacta by 50% [13]. This 6OHDA-induced lesion profile results in a predictable, severe forelimb akinesia in all rats which persists for at least 3 months post-injection [13]. After the 6OHDA injection, a bipolar stimulating electrode (MS303/3-B/SPC; Plastics One, Roanoke, VA) was lowered to the lateral hypothalamus (LH) for ICSS (from Bregma: −2.6mm AP; −1.8mm ML; −8.4mm DV from skull), and the electrode plug was held in place with dental acrylic affixed to stainless steel screws secured in the skull.…”

“…Thus, we utilized this task as motor index of the 6OHDA-induced lesion and PPX treatment efficacy, per our previously published procedures [10,13]. In brief, the experimenter gently restrained the rat’s rear legs and one forelimb, and ‘dragged’ the rat on the unrestrained forepaw 0.9m for 5s in the abduction direction.…”

“…Discounting tasks also have been implemented in rats, using food [9] or intracranial self-stimulation (ICSS) [10–13] as positive reinforcers. We demonstrated that ICSS protocols allow for repeated testing without changing feeding status, and we have implemented this procedure in a rat model of PD (i.e., rats with 6-hydroxydopamine (6OHDA)-induced lesions of the dorsolateral striatum (DLS)) [8,10,11].…”