Jonathan D. Sokolowski

Different effects of nucleus accumbens and ventrolateral striatal dopamine depletions on instrumental response selection in the rat

This experiment was undertaken to investigate dopaminergic involvement in food-related instrumental behavior. Rats were tested in an operant chamber in which there was a choice between pressing a lever to receive a preferred food (Bioserve pellets) or feeding upon a less preferred food (lab chow). The lever-pressing schedule was a fixed ratio 5 (FR5). Rats usually pressed the lever at high rates to obtain the preferred food, and typically ate little of the lab chow even though it was freely available in the chamber concurrently with the lever-pressing schedule. The neurotoxic agent 6-hydroxydopamine was injected directly into the nucleus accumbens, medial striatum, or ventrolateral striatum to determine the effects of dopamine depletion on the performance of this task. Depletion of dopamine in the nucleus accumbens led to a dramatic shift in behavior in which there was a significant decrease in lever pressing but a significant increase in consumption of lab chow. The shift away from lever pressing and towards chow consumption in rats with accumbens DA depletions was significantly correlated with a decrease in spontaneous locomotor activity. Dopamine depletions in the medial striatum did not significantly affect lever pressing or chow consumption. Ventrolateral striatal dopamine depletions decreased lever pressing but also tended to reduce consumption of lab chow. Rats with ventrolateral striatal dopamine depletions also showed profound deficits in home-cage feeding, and these rats had to receive wet mash or tube feeding to maintain body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

A neurochemical and behavioral investigation of the involvement of nucleus accumbens dopamine in instrumental avoidance

Two experiments were conducted to investigate the role of nucleus accumbens dopamine in the performance of a lever press avoidance task in the rat. In this task, 0.5 mA shock was presented for 5 s every 30 s, but the rat could escape shock presentation, or avoid the shock for 30 s, by pressing a lever. In the first experiment, dialysis probes were implanted into the nucleus accumbens of rats previously trained on the avoidance procedure, and also two groups of untrained rats. On the day after dialysis probe implantation, rats trained to press a lever to avoid shock (n = 10) were exposed to a 45 min avoidance test session. Untrained rats were either exposed to periodic shock (n = 9) or the control procedure in which lights were dimmed but no shock was presented (n = 8). Performance of the avoidance task led to significant increases in extracellular dopamine and dopamine metabolites. There was a significant positive correlation between increases in extracellular dopamine and the number of avoidance responses emitted. In the second experiment, groups of rats were trained on the lever press avoidance procedure. After training, rats received intra-accumbens injections of the neurotoxic agent 6-hydroxydopamine or ascorbic acid vehicle. Dopamine depletion produced by 6-hydroxydopamine injection led to a substantial decrease in lever pressing to avoid or escape shock. These results indicate that dopamine in nucleus accumbens is important for operant avoidance responding, and that the involvement of accumbens dopamine in instrumental behavior is not unique to positively reinforced responses.

The role of brain dopamine in response initiation : effects of haloperidol and regionally specific dopamine depletions on the local rate of instrumental responding

Two experiments were undertaken to investigate dopaminergic involvement in the local rate of responding on a fixed ratio 5 (FR5) instrumental lever pressing schedule. Rats were trained to press a lever for food reinforcement on a FR5 schedule, and a computer program was used to record the interresponse time (IRT) for each response. The IRT is the time between each lever pressing response, which is equal to the reciprocal of the local response rate. After several weeks of training, rats received i.p. injections of the dopamine antagonist haloperidol (HP; 0.1, 0.2 and 0.4 mg/kg). HP produced a dose-related decline in overall response number. In addition, HP dramatically altered the IRT distribution. HP-treated rats showed a dose-related reduction in the proportion of IRTs with low time values (high local rates of responding), and a corresponding increase in the relative number of IRTs with high time values (low local rates of responding). In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the nucleus accumbens, medial neostriatum or ventrolateral neostriatum in order to determine the effects of DA depletion on lever pressing performance. Dopamine depletion in all regions significantly reduced lever pressing, and dopamine-depleted rats had substantial changes in their IRT distributions. Rats with dopamine depletions showed significant reductions in the proportion of IRTs with low time values, and increases in the relative number of IRTs with high time values. The greatest reductions in response number and the most pronounced alterations of the IRT distribution were shown by rats with ventrolateral neostriatal dopamine depletions.(ABSTRACT TRUNCATED AT 250 WORDS)

The Role of Accumbens Dopamine in Lever Pressing and Response Allocation: Effects of 6-OHDA Injected into Core and Dorsomedial Shell

Three experiments investigated the behavioral effects of injections of the neurotoxic agent 6-hydroxydopamine (6-OHDA) into the core or shell of the nucleus accumbens. In the first experiment, it was observed that injections of 6-OHDA into either core or shell had no significant effect on variable interval 30-s responding. In Experiment 2, responding on a fixed ratio 5 (FR5) schedule was impaired by 6-OHDA injections in the core, but not the shell. Rats with core injections of 6-OHDA showed significant alterations in the relative distribution of interresponse times, which were indicative of reductions in the maximal rate of responding and increases in the number of pauses. In the third experiment, rats were tested using a lever-pressing/chow-feeding procedure, in which a preferred food (Bioserve pellets) was available by pressing a lever on a FR5 schedule, but a less preferred food (lab chow) was also available concurrently in the test chamber. Untreated rats usually pressed the lever at high rates to obtain the food pellets and ate little of the lab chow. After training, dopamine depletions were produced by injections of 6-OHDA directly into the core or dorsomedial shell subregions. Injections of 6-OHDA into the core significantly decreased lever pressing for food pellets, increased lab chow consumption, and decreased the relative amount of food obtained by lever pressing. Dorsomedial shell injections of 6-OHDA had no significant effects on either lever pressing or lab chow consumption. Neurochemical results indicate that injections of 6-OHDA in the shell produced substantial depletions in the shell that were somewhat selective; however, injections of 6-OHDA into the core tended to deplete both core and shell. Correlational analyses revealed that decreases in FR5 lever pressing were associated with dopamine levels in the core, but not the shell. The present results indicate that substantial depletions of dopamine in the dorsomedial shell are not sufficient for suppressing reinforced lever pressing, and indicate that dopamine depletions must include the core area to impair performance on these tasks. The lack of effect of accumbens dopamine depletions on VI30 responding are consistent with the notion that accumbens dopamine depletions affect responding on schedules that generate a high rate of responding (FR5), but not those that generate a moderate rate of responding (e.g., VI30 s). The results of the concurrent FR5/chow-feeding experiment indicate that rats with accumbens dopamine depletions remain directed towards the acquisition and consumption of food. These results suggest that dopamine in the core region of accumbens sets constraints upon the selection of food-related behaviors, and that core dopamine depletions alter the relative allocation of food-related responses.

Effects of dopamine depletions in the medial prefrontal cortex on DRL performance and motor activity in the rat

Two experiments assessed the behavioral effects of dopamine depletions in the medial prefrontal cortex that were produced by injection of the neurotoxic agent 6-hydroxydopamine. In the first experiment, rats were trained to respond on a differential reinforcement of low rates of responding-30 second (DRL30) schedule. On this schedule, rats were only reinforced if they withheld responding for 30 s. Rats with prefrontal dopamine depletions were found to be impaired in the DRL task. These animals responded more than controls, received fewer reinforcers, and were less efficient in their responses. Moreover, an analysis of interresponse times (IRTs) revealed that rats with medial prefrontal dopamine depletions made more responses with short-duration IRTs, and fewer responses with long-duration IRTs. In the second experiment, rats were tested on open field activity, amphetamine-induced locomotor activity and stereotypy. No increase in spontaneous locomotor activity was found following surgery; however, increases in amphetamine-induced locomotor activity and stereotypy were observed. These results are consistent with hypothesized role for the prefrontal cortex in behavioral inhibition, and indicates that prefrontal cortical dopamine is an integral part of the system.

A microdialysis study of nucleus accumbens core and shell dopamine during operant responding in the rat

This investigation examined dopamine release and metabolism in nucleus accumbens core and shell during three operant tasks in the rat. Rats were trained to lever press on a fixed-ratio 5, variable-interval 30 s, or a tandem variable interval 30/fixed-ratio 5 schedules; these three schedules were chosen because they generate a wide range of response and reinforcement rates. After several weeks of training, dialysis probes were implanted into nucleus accumbens core or shell subregions. A single 30 min behavioural session was conducted during the dialysis test session. Rats lever pressing on each of the three operant schedules showed a significant increase in extracellular dopamine relative to the food-deprived control group during the behavioural session. In addition, increases in dopamine in nucleus accumbens shell were found to be significantly greater than in the core during the lever pressing period. Across all three schedules, extracellular dopamine in the nucleus accumbens was significantly correlated with the number of lever presses performed, but was not correlated with the number of food pellets delivered. Analysis of covariance, which used amount of food consumed as the covariate, showed an overall group difference, indicating that dopamine levels increased in lever pressing animals even if one corrected for the amount of food consumed. These results indicate that dopamine release was more responsive in the nucleus accumbens shell than in the core during operant responding, and that increases in extracellular dopamine in nucleus accumbens are related to response rate rather than reinforcement magnitude.

The effects of haloperidol and clozapine on PCP- and amphetamine-induced suppression of social behavior in the rat.

Previous work has shown that phencyclidine (PCP) and amphetamine decrease social behavior in rats. The purpose of the present study was to determine the effects of the dopamine antagonists clozapine and haloperidol on PCP- and amphetamine-induced changes in rat social behavior. An intruder paradigm was used, in which rats were injected with drug and placed into a stable home colony of three other rats. Social behaviors were recorded for 30 min. Both amphetamine (4.0 mg/kg) and PCP (4.0 mg/kg) substantially reduced social behavior. Haloperidol and clozapine did not produce a general reversal of the effects of amphetamine or PCP on the total number of social behaviors. Nevertheless, 0.025 mg/kg haloperidol did reverse the effects of PCP and amphetamine on some of the specific social behaviors observed (side threats, mounting, crawling under). Clozapine had no effect on reversing the actions of amphetamine on social behavior, but 2.0 mg/kg clozapine did reverse the effect of PCP on side threats and mounting. These results indicate that DA antagonists do not restore normal social behavior in animals treated with PCP or amphetamine, but can reverse some of the effects of PCP or amphetamine on specific social behaviors.

The effects of nucleus accumbens dopamine depletions on continuously reinforced operant responding: Contrasts with the effects of extinction

Two experiments were undertaken to study the role of nucleus accumbens dopamine (DA) in instrumental lever pressing on a continuous reinforcement schedule (CRF). In the first experiment, the neurotoxic agent 6-hydroxydopamine was infused directly into the nucleus accumbens to investigate the effects of DA depletion on lever pressing performance. DA depletion had only a modest effect on the total number of lever presses, and there was a significant effect on total lever presses only on the first test day (third day postsurgery). Analyses also were performed on responding across the 45-min session by breaking down the session into three 15-min periods. During the test session on day 3 postsurgery, there was a significant group x time interaction, with DA-depleted rats showing a significant reduction in the numbers of responses in the first 15-min period, but no significant effects over the second or third 15-min period within the session. Although control rats showed a within-session decline in responding, the DA-depleted rats did not. In addition, analysis of interresponse times (IRTs) indicated that accumbens DA depletions produced a slowing of the local rate of responding as indicated by a significant decrease in high rate (i.e., short-duration IRT) responses and an increase in low rate (i.e., long-duration IRT) responses. In a second experiment, the effects of extinction on CRF performance were investigated. Unlike the effects of nucleus accumbens DA depletion, extinction produced lower levels of responding throughout the entire test session.(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleus accumbens dopamine and rate of responding: Neurochemical and behavioral studies

It has been suggested that accumbens dopamine (DA) is involved in the process of enabling organisms to expend energy in various situations, including foraging, maze running, and leverpressing. Although accumbens DA depletions impair stimulant self-administration, the effects of these depletions on various food-reinforced operant schedules are highly variable. Accumbens DA depletions have little or no effect on total response output in rats responding on the simplest schedule of food reinforcement (i.e., the fixed ratio 1). In addition, it has been shown clearly that the effects of accumbens DA depletions do not resemble the effects of extinction or prefeeding to reduce food motivation. Over the last several years, our laboratory has investigated the effects of accumbens DA depletions on several schedules, including fixed ratio 1, variable interval 30 sec, fixed interval 30 sec, progressive ratio, and fixed ratio 4, 5, 16, and 64. These schedules generate very different rates of responding, ranging from 300 to 3,000 responses per 30 min. Regression analyses of all these studies indicates a significant linear relation between control rates of responding and the degree of suppression of responding produced by accumbens DA depletions. Schedules that generate relatively low response rates, such as fixed ratio 1 or variable interval 30 sec, are little affected by accumbens DA depletions, yet schedules that generate high response rates (e.g., fixed ratio 64) are severely disrupted. Prefeeding shows different patterns of suppression as a function of response rate. Microanalysis of the temporal characteristics of lever-pressing has shown that accumbens DA depletions produce a response slowing, as measured by the interresponse time; extinction and prefeeding produce a different pattern of effects. These results indicate that accumbens DA depletions do not blunt the reinforcing effects of food, but do suppress responding in a rate-dependent manner. In addition, microdialysis studies have shown that accumbens DA release is positively correlated with leverpressing response rate. Accumbens DA appears to be involved in energy expenditure, behavioral activation, or maintenance of high local rates of responding, which are functions that represent an area of overlap between motor and motivational processes.

Effects of dopamine depletions in the medial prefrontal cortex on active avoidance and escape in the rat

Dopamine systems have been implicated in the performance of avoidance behavior, and the dopaminergic innervation of medial prefrontal cortex is known to be responsive to stressful stimuli. In the present investigation, injections of 6-hydroxydopamine were used to produce moderate depletions of dopamine in the medial prefrontal cortex of rats trained to perform an active avoidance/escape task. In this task, 0.5 mA shock was presented for 5 s every 30 s, and the rat could escape shock presentation, or avoid the shock for 30 s, by pressing a lever. Depletion of dopamine in the medial prefrontal cortex did not affect total number of responses, and did not impair avoidance responding (i.e. responding when the shock was off), and in fact dopamine-depleted animals tended to make slightly more avoidance responses than control animals. Prefrontal dopamine depletions did result in a significant decrease in the number of escape responses (i.e. responding to terminate shock when the shock was on). Moreover, dopamine depletions significantly decreased response efficiency, which is an index of the reduction of shock time produced per lever pressing response. Previous work has indicated that dopamine antagonists and accumbens dopamine depletions have dramatic effects on avoidance behavior; thus, the present results indicate that prefrontal cortex dopamine depletions do not mimic the effects of interference with subcortical dopamine systems. The selective effects of dopamine depletions on escape behavior in the present study suggest that rats with medial prefrontal dopamine depletions have an impairment in the ability to respond appropriately to the direct presentation of footshock.(ABSTRACT TRUNCATED AT 250 WORDS)