Differential contributions of dopaminergic D1- and D2-like receptors to cognitive function in rhesus monkeys

Abstract

Rationale: Dopaminergic neurotransmission is critically involved in many aspects of complex behavior and cognition beyond reward/reinforcement and motor function. Mental and behavioral disorders associated with major disruptions of dopamine neurotransmission, including schizophrenia, attention deficit/hyperactivity disorder, Parkinson's disease, Huntington's disease, and substance abuse produce constellations of neuropsychological deficits in learning, memory, and attention in addition to other defining symptoms.

Objective: To delineate the role dopaminergic D1- and D2-like receptor subtypes play in complex brain functions.

Materials and methods: Monkeys (N = 6) were trained on cognitive tests adapted from a human neuropsychological assessment battery (CAmbridge Neuropsychological Test Automated Battery). The battery included tests of spatial working memory (self-ordered spatial search task), visuo-spatial associative memory and learning (visuo-spatial paired associates learning task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function (bimanual motor skill task, BMS; rotating turntable task, RTT) were also included. The effects of the dopamine D2-like antagonist raclopride (10-56 microg/kg, i.m.) and the D1-like antagonist SCH23390 (SCH, 3.2-56 microg/kg, i.m.) on cognitive performance were then determined.

Results: Deficits on PR, RTT, and BMS performance were observed after both raclopride and SCH23390. Spatial working memory accuracy was reduced to a greater extent by raclopride than by SCH, which was unexpected, given prior reports on the involvement of D1 signaling for spatial working memory in monkeys. Deficits were observed on vsPAL performance after raclopride, but not after SCH23390.

Conclusions: The intriguing results suggest a greater contribution of D2- over D1-like receptors to both spatial working memory and object-location associative memory.

Figure 1. Session Schedule

The approximate timing for the three types of behavioral sessions run in rotation on successive test sessions is outlined. The effective pre-treatment intervals for each of the test compounds varied slightly depending on the behavioral task, as illustrated. The challenge studies for raclopride and SCH23390 were run sequentially with a minimum 3 week interval between studies. Preliminary analyses suggested the each compound lost significant behavioral activity after about 60 min, see Materials and methods for data treatment.

Figure 2. Progressive Ratio

The mean effect of acute doses of raclopride (N = 6; ± SEM) and SCH23390 (N = 5; ± SEM) on performance of the PR task is expressed in terms of the number of reinforcers acquired, the time of last response, the total number of responses and the response rate. A significant difference from the vehicle condition is indicated by *. Base indicates noninjection baseline sessions; Veh indicates vehicle injection sessions.

Figure 3. Bimanual Motor Skill and Rotating Turntable Tasks

The mean effect of acute doses of raclopride (N = 6; ± SEM) and SCH23390 (N = 5; ± SEM) on performance of the BMS and RTT tasks. Data are expressed as a proportion of individual baseline performance levels. A significant difference from the vehicle condition is indicated by * and Veh indicates vehicle injection sessions.

Figure 4. Self-Ordered Spatial Search

The mean effect of acute doses of raclopride (N = 6; ± SEM) and SCH23390 (N = 5; ± SEM) on performance of the SOSS task are presented in terms of the percentage of trials correctly completed and the response latency for correct trials. The data are presented separately for each of three trial difficulty levels. A significant pair-wise difference from the vehicle condition is indicated by * and complete analysis details are provided in the text. Base indicates noninjection baseline sessions; Veh indicates vehicle injection sessions.

Figure 5. visuo-spatial Paired Associates Learning

The mean effect of acute doses of raclopride (N = 6; ± SEM) and SCH23390 (N = 5; ± SEM) on performance of the 2-stimuli/2-locations vsPAL trials. The data presented in the top panel include the proportion of trials successfully completed on the initial attempt and the overall completion success. The lower panels present the response latency for sample and choice responses, the per-response choice accuracy on the first attempt at each trial, the total number of correct and incorrect responses and the percent of the task that was completed. A significant difference from the vehicle condition is indicated by *. Base indicates noninjection baseline sessions; Veh indicates vehicle injection sessions.