Diane C. Hoffman

Receptor subtype-specific dopaminergic agents and conditioned behavior

Dopaminergic neurotransmission has been implicated in reward-related learning. With the advent of pharmacological agents that are relatively specific for D1 and D2 dopamine receptors, it has become possible to assess the role of these receptor subtypes in this form of learning. Antagonist studies have shown that either D1 or D2 receptor blockers produced extinction-like effects on operant responding for food, water or brain stimulation reward and in drug self-administration paradigms. They also blocked place preference learning based on amphetamine. Agonist studies showed that D2, but not D1 agonists were self-administered, produced place preferences and enhanced responding for conditioned reward. It may be that the dopaminergic signal at the D1 receptor is important for the establishment and maintenance of reward-related learning. From this point of view the effects of D1 antagonists can be understood. D2 antagonists may produce extinction-like effects because they lead to increased dopamine release and, therefore, indirectly mask the dopamine signal at the D1 receptor. D1 agonists may fail to produce reward effects because they, unlike D2 agonists, directly mask the dopaminergic signal at the D1 receptor.

The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801

The amplitude of the acoustic startle response in rats is decreased if the startle stimulus is preceded by a nonstartle-eliciting auditory stimulus. This sensory gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the noncompetitive glutamate antagonist MK-801 disrupts prepulse inhibition. The present study examined whether the disruption by MK-801 is reversible in rats pretreated with the classical antipsychotic haloperidol or the atypical antipsychotic clozapine. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB tones presented alone or preceded by a 70 dB tone. Rats treated with 0.1 mg/kg MK-801 demonstrated a significant disruption of prepulse inhibition. Haloperidol (0.1 and 0.5 mg/kg) and clozapine (1.0 and 5.0 mg/kg) each consistently failed to antagonize the MK-801-induced blockade of prepulse inhibition. The effects of haloperidol and clozapine on prepulse inhibition were also examined in saline-treated rats. Clozapine and, to some extent, haloperidol produced a dose-related facilitation of prepulse inhibition. Although preliminary, this finding raises the possibility that the enhancement of prepulse inhibition by antipsychotics might provide a useful rodent model for screening potential antipsychotic drugs.

The effects of selective dopamine D1 or D2 receptor antagonists on the establishment of agonist-induced place conditioning in rats

The ability of the dopamine D1 antagonist, SCH 23390 (0.01, 0.1, 1.0, 2.0 mg/kg) or the D2 antagonist, metoclopramide (1.0, 10.0, 20.0 mg/kg), to block the establishment of place conditioning with either the nonselective dopamine agonist, amphetamine (2.0 mg/kg), the D1 agonist, SKF 38393 (10.0 mg/kg), or the D2 agonist, quinpirole (1.0 mg/kg), was evaluated in rats. The experimental protocol consisted of three phases. During the preexposure phase, rats explored two distinctive compartments joined by a small tunnel. During the 8-day conditioning phase, rats were pretreated with either saline, SCH 23390 or metoclopramide; 1 hr later the animals were treated with an agonist and confined to one compartment for 30 min. On alternate days, rats received saline and were placed in the opposite compartment. Test days occurred over the remaining 3 days during which drug-free animals were allowed access to both compartments. A significant increase or decrease in the amount of time spent in the drug-paired environment was indicative of a place preference or aversion, respectively. SCH 23390 and metoclopramide were effective in blocking amphetamine-induced place preference and SKF 38393-induced place aversion. At lower doses, the D1 and D2 antagonist blocked the place preference induced by quinpirole, however, higher doses were not effective. In general, these data suggest that both receptor subtypes participate in the establishment of place conditioning with amphetamine, SKF 38393 or quinpirole.

Effects of extinction, pimozide, SCH 23390, and metoclopramide on food-rewarded operant responding of rats

The similarity in the pattern of responding produced by extinction and dopamine (DA) receptor blockers has led to the suggestion that DA neurons may participate in the usual effects of reward on behaviour. The purpose of the present study was to evaluate the effect of receptor-subtype specific DA antagonists on food-rewarded operant responding. Rats were trained to lever press for food on a variable interval 30-s schedule. They then received one of the following treatments prior to testing on the next 5 days: saline, nonreinforcement, the DA receptor blocker pimozide (0.5 or 1.0 mg/kg), the D1 receptor blocker SCH 23390 (0.01, 0.05, 0.1 mg/kg), and the D2 receptor blocker metoclopramide (1.0, 5.0, 10.0 mg/kg). Nonreinforcement resulted in both intra- and intersession declines in responding. The drugs produced dose-dependent decreases in overall responding. Additionally, both doses of pimozide and the higher doses of SCH 23390 and metoclopramide altered intrasession patterns of responding when compared to saline, with their greatest effect being in the latter portion of the session. Intersession declines were seen with the highest doses of SCH 23390 and metoclopramide and control studies showed that these declines could not be attributed to a buildup of the drug with repeated dosing. It was concluded that both D1 and D2 receptors participate in the control of behaviour by reward.

The D1 Dopamine Receptor Antagonist, SCH 23390 Reduces Locomotor Activity and Rearing in Rats

Dopamine receptors have been found to be of at least two types, and interest has focused on the possible differential role played by each in the control of behavior. The recent finding that SCH 23390 selectively blocks D1 receptors has provided a new tool. To examine the contribution of D1 receptors to locomotor activity and rearing, rats were injected SC with doses of 0.01, 0.1 and 1.0 mg/kg and monitored for 3 hr in photocell cages. SCH 23390 suppressed both behaviors in a dose-dependent fashion. These results suggest that D1 receptors participate in dopamines control of locomotor activity and rearing.

Selective D1 and D2 dopamine agonists produce opposing effects in place conditioning but not in conditioned taste aversion learning

The neurotransmitter, dopamine (DA), has been implicated in place conditioning but the role of D1 and D2 receptors has not been investigated. In Experiment 1, the effects of SKF 38393 (0, 0.01, 0.1, 1.0, 10.0 mg/kg) and quinpirole (0, 0.01, 0.1, 1.0, 2.0, 4.0 mg/kg), preferential D1 and D2 receptor agonists, respectively, were evaluated and compared to (+)-amphetamine (0, 0.01, 0.1, 1.0, 2.0, 4.0 mg/kg). The experiment consisted of three phases. During the preexposure phase, rats explored two distinctive end compartments adjoined by a small tunnel. The time spent in each compartment was recorded. During the 8-day conditioning phase, rats were treated with drug and confined to one compartment for 30 min. On alternate days, rats received saline and were placed in the opposite compartment. Test days occurred over the remaining three days during which drug-free animals explored both compartments. Rats conditioned with (+)-amphetamine demonstrated a dose-dependent increase in time spent in the drug-paired environment from preexposure to test indicating the establishment of a conditioned place preference. Treatment with quinpirole also resulted in a conditioned place preference, however, only an intermediate dose was effective. In contrast, SKF 38393 produced a dose-dependent decrease in time spent on the drug-paired side suggesting the establishment of a place aversion. The idea that D1 receptors may be exclusively involved in mediating the aversive properties of psychomotor stimulants was tested in Experiment 2 employing a conditioned taste aversion paradigm. The results did not support this notion; it was found that both quinpirole and SKF 38393 produced a conditioned taste aversion.(ABSTRACT TRUNCATED AT 250 WORDS)

D1 and D2 dopamine receptor antagonists reverse prepulse inhibition deficits in an animal model of schizophrenia.

The amplitude of the acoustic startle response is decreased if the startle stimulus is preceded by a nonstartle eliciting stimulus. This sensorimotor gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the dopamine agonist apomorphine disrupts prepulse inhibition and this disruption is reversed by classical and atypical antipsychotics. Furthermore, the ability of antipsychotics to reverse the apomorphine disruption is correlated with clinical potency and D2 receptor affinity. In the present study, the role of the D1 receptor in prepulse inhibition of the acoustic startle response was studied; the effects of the D1 receptor antagonist SCH 23390 were examined and compared to the effects of the D2 receptor antagonist eticlopride. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB noise bursts presented alone or preceded by a 75 dB noise burst. Trials consisting of no stimulus and the 75 dB prepulse stimulus alone were also included. These six trial types (ten each) were randomly presented within a 35-min session. Rats treated with 2.0 mg/kg apomorphine (SC) demonstrated a significant disruption of prepulse inhibition compared to vehicle controls. Pretreatment with the D1 antagonist SCH 23390 (0.01, 0.05, 0.1 mg/kg SC) or the D2 antagonist eticlopride (0.01, 0.05, 0.1 mg/kg SC) attenuated the disruptive effects of apomorphine. These results indicate that selective blockade of either the D1 or D2 receptor subtype is sufficient in reversing the sensorimotor gating deficits produced by apomorphine. The effects of eticlopride and SCH 23390 on prepulse inhibition in saline-treated rats were also examined. Each antagonist produced a dose-related facilitation of prepulse inhibition, suggesting that endogenous DA acting at either receptor subtype plays a role in the tonic modulation of sensorimotor gating.

The dopamine D2 receptor agonists, quinpirole and bromocriptine produce conditioned place preferences

1. The conditioned place preference paradigm was used to examine the role of the D2 receptor in mediating the reinforcing effects of dopamine (DA) agonists. 2. During the 3-day pre-exposure phase, rats explored two distinctive end compartments which were adjoined by a small tunnel. During the 8-day conditioning phase, groups of rats were treated with the selective D2 receptor agonists, quinpirole (0.01, 0.025, 0.05, 0.10, 0.25, 1.0 and 5.0 mg/kg IP) or bromocriptine (0, 0.01, 0.1, 0.5, 1.0, 5.0 and 10.0 mg/kg IP) and confined to one compartment for 30 min. On alternate days, rats received vehicle injections and were placed in the opposite compartment. Test days occurred over the remaining 3 days during which untreated animals explored both compartments. 3. Rats conditioned with quinpirole or bromocriptine showed significant increases in time spent in the drug-paired environment from pre-exposure to test indicating the establishment of conditioned place preferences. 4. This suggests a functional role for the D2 receptor in mediating the rewarding effects of DA agonists.

The noncompetitive NMDA antagonist MK-801 fails to block amphetamine-induced place conditioning in rats

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevents the development of sensitization to the locomotor-activating effects of amphetamine. In the present study, the possibility that the NMDA receptor might also play a role in the rewarding effects of amphetamine (as measured in the conditioned place preference paradigm) was investigated. Male Sprague-Dawley rats received amphetamine (2.0 mg/kg IP) paired with one side of a two-compartment box and saline paired with the other side. During these pairings locomotor activity was measured. On the test day, the amount of time drug-free rats spent in each compartment was determined. Rats trained with amphetamine alone showed a significant increase in time spent on the drug-paired side from pre- to postconditioning, indicating a place preference. When rats were injected with MK-801 (0.03, 0.1, or 0.3 mg/kg SC) prior to amphetamine, no significant effects on amphetamine place conditioning were observed. Rats treated with MK-801 alone showed significant place conditioning, but only at the intermediate dose. On conditioning days, MK-801 produced a dose-dependent enhancement of amphetamine-induced locomotor activity; however, MK-801 alone caused a similar increase in activity. The preferential D2 dopamine receptor antagonist eticlopride (0.01, 0.05, or 0.1 mg/kg SC) significantly reduced amphetamine locomotor activity, and the highest dose blocked place conditioning. These data suggest that the NMDA receptor is not involved in either the rewarding or locomotor-activating effects of amphetamine.

Indoline and piperazine containing derivatives as a novel class of mixed D2/D4 receptor antagonists. Part 2: Asymmetric synthesis and biological evaluation

A series of chiral benzylpiperazinyl-1-(2,3-dihydro-indol-1-yl)ethanone derivatives were prepared and examined for their affinity at dopamine D(2) and D(4) receptors. Three compounds having D(2)/D(4) affinity ratios approximating that found for the atypical neuroleptic clozapine were further evaluated in behavioral tests of antipsychotic efficacy and motor side effects.