Michael S. Cousins

Anhedonia or anergia? Effects of haloperidol and nucleus accumbens dopamine depletion on instrumental response selection in a T-maze cost/benefit procedure.

Two experiments were conducted to study the role of dopamine in the performance of a novel cost/benefit procedure. Rats were trained on a T-maze task in which one arm contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). Different groups of rats were trained either with unobstructed access to both arms from the start area, or under a condition in which a large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the first experiment, rats trained under each procedure received injections of 0.1 mg/kg haloperidol and tartaric acid vehicle as a control procedure. Analysis of variance indicated that there was a significant effect of the barrier on maze arm choice, a significant effect of haloperidol, and a significant drug x barrier interaction. Haloperidol did not affect arm choice in rats tested without the barrier present, but this drug significantly reduced the number of selections of the arm with high reinforcement density when the barrier was present. In the second experiment, groups of rats were trained as described above, and then received intraaccumbens injections of 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions produced by 6-hydroxydopamine decreased the number of selections of the arm with high reinforcement density when the barrier was present, but had no effect on arm choice when the barrier was not present.(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task.

This experiment was conducted to study the role of nucleus accumbens dopamine in the performance of a novel T-maze cost/benefit procedure. Rats were trained on a T-maze task for food reinforcement. Under one of the test conditions, one arm of the maze contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). A large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the second test condition, a separate group of rats was trained in the same T-maze, in which there were 4 food pellets in the arm that was obstructed by the barrier, yet there were no food pellets in the unobstructed arm. After training rats received intra-accumbens of injections 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions substantially decreased the number of selections of the obstructed arm with the high reinforcement density when the unobstructed arm also contained 2 food pellets. Dopamine-depleted rats in this condition showed increased selection of the no-barrier arm as well as decreased entry into the arm that contained the barrier. These effects persisted throughout the 3 weeks of post-surgical testing. Nevertheless, when the unobstructed arm contained no food pellets, and the only way to obtain food was to climb the barrier, rats with nucleus accumbens dopamine depletions showed only a modest effect on selections of the obstructed arm, which recovered by the second week of testing. Dopamine-depleted rats that were tested with food in the unobstructed arm showed significantly fewer barrier crossings than dopamine-depleted rats that were tested with no food in the unobstructed arm. Thus, the present findings are not consistent with the notion that nucleus accumbens dopamine depletion rendered the animals unable to climb the barrier, or set an absolute ceiling on the number of barrier crossings the animals could perform. Instead, the present results indicate that nucleus accumbens dopamine depletions affected the relative allocation of barrier climbing responses if alternative food sources were available.

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)

Nucleus Accumbens Dopamine Depletions in Rats Affect Relative Response Allocation in a Novel Cost/Benefit Procedure

Rats were tested on days 1, 3, and 5 of a 5-day test week in an operant chamber in which they could either lever press on a fixed-ratio 5 (FR5) schedule to obtain food pellets (Bioserve) or approach and consume lab chow that was also available in the chamber (Teklad Premier). Rats typically pressed at high rates to obtain the food pellets and ate little of the lab chow. On days 2 and 4 of each week lab chow was not concurrently available, and rats could only lever press on the FR5 schedule for pellets to obtain food. Dopamine depletions produced by intraaccumbens injections of the neurotoxic agent 6-hydroxydopamine produced a dramatic decrease in lever pressing and increase in chow consumption on days when lab chow was available. Lever pressing was not significantly reduced in dopamine-depleted rats on days when chow was not available, although there was a significant correlation between lever pressing and accumbens dopamine levels. These results suggest that nucleus accumbens dopamine depletions do not produce a general deficit in food motivation. Moreover, accumbens dopamine depletions do not appear to produce severe deficits in fine motor control that impair the execution of individual motor acts involved in lever pressing. Rather, the present results are consistent with the notion that accumbens dopamine sets constraints upon which food-related response is selected in a particular situation, and that these depletions alter the relative allocation of food-related 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)

Pharmacological characterization of performance on a concurrent lever pressing/feeding choice procedure: effects of dopamine antagonist, cholinomimetic, sedative and stimulant drugs

This experiment was undertaken to provide a pharmacological characterization of performance on a task involving food-related instrumental and consummatory 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 approaching and consuming 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. Previous work has shown that injection of dopamine (DA) antagonists, or depletion of DA in the nucleus accumbens, caused a substantial shift in behavior such that lever pressing was reduced but chow consumption increased. In the present study it was shown that the DA antagonist haloperidol decreased lever pressing and increased chow consumption at doses of 0.1 and 0.15 mg/kg. The D1 antagonist SCH 23390 (0.05, 0.1 and 0.15 mg/kg) and the non-selective DA antagonistcis-flupenthixol (0.3 and 0.45 mg/kg) decreased lever pressing and produced substantial increases in chow consumption. The D2 antagonist sulpiride decreased lever pressing, but produced only slight increases in chow intake at the highest dose. Pentobarbital reduced lever pressing and increased chow consumption at 10.0 mg/kg. The muscarinic agonist pilocarpine produced dose-related decreases in lever pressing, but failed to increase chow consumption. Amphetamine produced dose-related decreases in both lever pressing and chow consumption. These results indicate that low/moderate doses of the DA antagonists haloperidol,cis-flupenthixol and SCH 23390 can suppress lever pressing in doses that leave the animal directed towards food acquisition and consumption.

The role of nucleus accumbens dopamine in responding on a continuous reinforcement operant schedule : a neurochemical and behavioral study

Two experiments were undertaken to investigate the role of nucleus accumbens dopamine (DA) in instrumental lever pressing on a continuous reinforcement (CRF) schedule. Rats trained to press a lever for food reinforcement on a CRF schedule, and food-deprived control rats, were implanted with dialysis probes in the nucleus accumbens. The day after implantation, rats were tested and dialysis samples were assayed for DA and the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). Performance of the lever-pressing task resulted in significant increases in extracellular levels of DA and DOPAC relative to control rats. The increases in extracellular DA were significantly correlated (r = 0.92) with the number of lever press responses committed. In the second 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. 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 in the session. This initial slowing of response rate was present across all 5 test days. These results indicate that DA release and metabolism increases in rats performing on a CRF schedule, and that DA depletion produces a slowing of initial response rate.

Tremulous jaw movements induced by the acetylcholinesterase inhibitor tacrine: effects of antiparkinsonian drugs

Several experiments were conducted to study the effects of established or potential antiparkinsonian drugs on the tremulous jaw movements induced by the anticholinesterase tacrine (9-amino-1,2,3,4-tetrahydroaminoacridine hydrochloride). In the first group of four experiments, separate groups of animals that received 2.5 or 5.0 mg/kg tacrine showed a dose-dependent decrease in tremulous jaw movements following co-administration of the non-selective dopamine receptor agonist apomorphine, the full dopamine D2 receptor agonist bromocriptine, and the full dopamine D1 receptor agonist APB (R(+)-6-bromo-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine). Co-administration of the partial dopamine D1 receptor agonist SKF 38393 (R(+)-2,3,4,5-tetrahydro-7,8-dihydroxy-l phenyl-1 H-benzazepine: 7.5-30.0 mg/kg) did not reduce tremulous jaw movements produced by 2.5 or 5.0 mg/kg tacrine. In animals treated with 2.5 mg/kg tacrine, co-administration of SKF 38393 resulted in a dose-related trend towards a potentiation of tremulous jaw movements. In the second group of experiments, all rats received 2.5 mg/kg tacrine. The dopamine precursor L-DOPA (L-3,4-dihydroxyphenylalanine), the dopamine and norepinephrine releasing agent amantadine, and the muscarinic receptor antagonist benztropine all reduced tremulous jaw movements induced by 2.5 mg/kg tacrine. Across all experiments, it was noted that apomorphine, bromocriptine and benztropine were more potent than amantadine and L-DOPA. These results are broadly consistent with the therapeutic doses of these agents noted in the clinical literature. The results of these experiments indicate that tremulous jaw movements in rats may be a useful model for evaluating potential antiparkinsonian agents.

Different behavioral effects of haloperidol, clozapine and thioridazine in a concurrent lever pressing and feeding procedure

Rats were tested using a lever pressing/feeding procedure in which a preferred food (Bioserve pellets) was available by pressing a lever on a fixed ratio 5 schedule, but a less preferred food (lab chow) was also available concurrently in the operant chamber. The effects of repeated (14 day) injections of haloperidol, clozapine and thioridazine were compared. Haloperidol (0.05–0.15 mg/kg) significantly reduced lever pressing and increased chow intake throughout the drug treatment period. Injections of clozapine (2.0–6.0 mg/kg) suppressed lever pressing but failed to produce substantial increases in chow intake. In the haloperidol experiment there was a significant inverse correlation between lever pressing and chow intake, but in the clozapine experiment there was not. Regression analysis indicated that rats treated with the high dose of clozapine showed some tolerance to the suppression of lever pressing. Tests of sedation also were conducted before and after the instrumental behavior sessions. Haloperidol produced little or no sedative effect in the dose range tested. Clozapine produced substantial sedation during the first 10 days of administration, but this effect, like the suppression of lever pressing, showed signs of tolerance. Thioridazine (3.0–9.0 mg/kg) produced some effects that resembled haloperidol, and other effects, including sedation, that resembled clozapine. These studies indicate that haloperidol suppresses lever pressing for food at low doses that do not produce severe motivational or sedative effects that disrupt food intake. In contrast, it appears as though the suppression of lever pressing produced by clozapine stems from a sedative effect that also serves to set limits on chow intake. These results indicate that haloperidol and clozapine suppress lever pressing through different mechanisms.

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.