Antagonism of D1, but not D2, dopamine receptors inhibits cued sucrose seeking by decreasing arousal

Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis, a novel synthesis that accounts both for our findings and many previous results that have drawn disparate and conflicting conclusions.

A Three-Way Drug Discrimination Study: A Role for DA-Mediated Effects in MDMA's Discriminative Cue Properties

<p>While 3,4-methylenedioxymethamphetamine (MDMA) shares many similarities with amphetamine, previous two choice drug discrimination procedures have shown that substitution between the two substances is inconsistent. Three choice drug discrimination procedures have revealed that MDMA can be discriminated from amphetamine, due to MDMA’s primary influence in releasing 5-HT. Neurochemical evidence had previously suggested that at doses >3.0mg/kg MDMA-induced dopamine (DA) release will increase significantly. In the current study rats were trained to discriminate MDMA from amphetamine and saline. As the dose of MDMA increased beyond the training dose (>1.5mg/kg) MDMA-appropriate responding decreased, while the proportion of amphetamine lever responding increased and eventually surpassed MDMA-appropriate responding at the highest dose (4.5mg/kg). This would indicate an important role for DA mediated influences in MDMA’s discriminative cue properties. Further evidence for this conclusion comes from tests with the D1 antagonist SCH23390 and the D2 antagonist eticlopride which attenuated this effect and also led to a nonsignificant increase in the proportion of saline lever responding. Subsequent tests with the 5-HT2c antagonist RS102221resulted in no significant dose dependent changes, but appeared to reduce MDMA-appropriate responding especially at the training dose. The current findings would suggest that low doses of MDMA are discriminable from amphetamine, however with increasing doses MDMA will be perceived as more “amphetamine-like”. These findings could suggest that at relatively high doses MDMA produces effects that are typically associated with dopamine-releasing drugs, such as high abuse potential.</p>

A Three-Way Drug Discrimination Study: A Role for DA-Mediated Effects in MDMA's Discriminative Cue Properties

<p>While 3,4-methylenedioxymethamphetamine (MDMA) shares many similarities with amphetamine, previous two choice drug discrimination procedures have shown that substitution between the two substances is inconsistent. Three choice drug discrimination procedures have revealed that MDMA can be discriminated from amphetamine, due to MDMA’s primary influence in releasing 5-HT. Neurochemical evidence had previously suggested that at doses >3.0mg/kg MDMA-induced dopamine (DA) release will increase significantly. In the current study rats were trained to discriminate MDMA from amphetamine and saline. As the dose of MDMA increased beyond the training dose (>1.5mg/kg) MDMA-appropriate responding decreased, while the proportion of amphetamine lever responding increased and eventually surpassed MDMA-appropriate responding at the highest dose (4.5mg/kg). This would indicate an important role for DA mediated influences in MDMA’s discriminative cue properties. Further evidence for this conclusion comes from tests with the D1 antagonist SCH23390 and the D2 antagonist eticlopride which attenuated this effect and also led to a nonsignificant increase in the proportion of saline lever responding. Subsequent tests with the 5-HT2c antagonist RS102221resulted in no significant dose dependent changes, but appeared to reduce MDMA-appropriate responding especially at the training dose. The current findings would suggest that low doses of MDMA are discriminable from amphetamine, however with increasing doses MDMA will be perceived as more “amphetamine-like”. These findings could suggest that at relatively high doses MDMA produces effects that are typically associated with dopamine-releasing drugs, such as high abuse potential.</p>

Where and how does d-amphetamine act to reveal antipsychotic-induced dopamine supersensitivity in rats?

ABSTRACTAntipsychotic treatment can produce a dopamine supersensitive state. In both schizophrenia patients and rodents, this is linked to antipsychotic treatment failure. In rodents, dopamine supersensitivity is often confirmed by an exaggerated behavioural response to the indirect monoamine agonist, d-amphetamine, after discontinuation of antipsychotic treatment. Here we investigated where and how d-amphetamine acts to trigger behavioural expression of dopamine supersensitivity, as this could uncover pathophysiological mechanisms underlying this supersensitivity. First, we examined the contributions of a central increase in dopamine/monoamine activity. Haloperidol-treated rats showed a potentiated psychomotor response to systemic d-amphetamine, confirming dopamine supersensitivity. However, they showed a normal psychomotor response to an increase in ventral midbrain dopamine impulse flow or to intracerebroventricular injection of d-amphetamine. This suggests that d-amphetamine’s peripheral effects are required for a supersensitive response. Second, we determined the specific contributions of dopamine neurotransmission. The D2 agonist quinpirole, but not the D1 agonist SKF38393 or the dopamine reuptake blocker GBR12783 produced a supersensitive psychomotor response in haloperidol-treated rats. In these rats, the D1 antagonist SCH39166 decreased d-amphetamine-induced psychomotor activity, whereas the D2 antagonist sulpiride enhanced it. Thus, when d-amphetamine triggers a supersensitive response, this involves both D1- and D2-mediated transmission. Finally, we measured d-amphetamine-induced changes in D1- and D2-mediated intracellular signalling pathways in the striatum. In haloperidol-treated rats, a supersensitive response to d-amphetamine was linked to enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens, suggesting increased D2-mediated signalling. These findings provide new insights into the neurobiology of antipsychotic-evoked dopamine supersensitivity.

Role of dopaminergic system in oxytocin analgesia: The missing part in a puzzle

Purpose: To investigate the analgesic effects of oxytocin (OT) and elucidate the role of dopaminergic system in its mechanisms.Methods: In this study, 72 male (n=6 for each group) 230-250 gr Wistar Albino rats were used. Firstly, dose studies were performed with 100 μg/kg, 200 μg/kg and 400 μg/kg to determine the optimal analgesic effect of oxytocin. Optimal dose was found at 200 μg/kg, and then animals were divided into nine groups: Saline, D1 agonist (SKF 38393; 0.1 mg/kg), D1 antagonist (SCH-23390; 0.1 mg/kg), D1 agonist + oxytocin, D1 antagonist + oxytocin, D2 agonist (Cabergoline; 0,5 mg/kg), D2 antagonist (Sulpride; 10 mg/kg), D2 agonist + oxytocin and D2 antagonist + oxytocin. Serum physiologic saline was given to the saline group and other drugs were administered intraperitoneally at the indicated doses. Tail-flick and hot-plate tests were used to measure analgesic effects. Analgesic tests were measured in 30 min-intervals (at 30th, 60th, 90th, and 120th min) and recorded in seconds. To evaluate maximum antinociceptive effect (% MPE), the tail-flick and hot-plate latencies were converted to the antinociceptive effectivenessResults: The results show that D1 antagonist SCH-23390 (0.1 mg/kg) and D2 agonist cabergoline (0.5 mg/kg) created strong analgesia while the D1 agonist SKF 38393 (0.1 mg/kg) and D2 antagonist sulpiride (10 mg/kg) did not have any analgesic effect. However, only D2 antagonist sulpiride blocked the analgesic effect produced by OTConclusion: OT may be one of the primary agents participating in spinal analgesia, and the dopaminergic system is one of the central mechanisms of action for this important molecule. The dopaminergic system may also be one of the targets for ‘descending’ analgesic system. Keywords: Oxytocin, Tail flick, Hot plate, Dopaminergic, Analgesic, Antagonist, Agonist