A Comparison of Repeated MDMA- and AMPH-Produced Centre and Periphery Activity and the Underlying Neuroadaptations

<p>The recreational use of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') is increasing in New Zealand. MDMA is a ring-substituted derivative of AMPH and, similar to AMPH, produces hyperactivity upon administration. However, the behavioural profile of hyperlocomotion produced by MDMA differs from that produced by AMPH, suggesting that different neural mechanisms underlie the behavioural response. The repeated administration of both MDMA and AMPH induces sensitised hyperactive responses that have recently been found to be different. In the present study, MDMA- and AMPH-induced centre and periphery hyperactivity were compared to investigate the neuroadaptations produced by repeated exposure to the two drugs. Rats were pre-treated with saline, MDMA, or AMPH and the acute response to MDMA, AMPH, or the D1 agonist, SKF-81297 was measured to determine whether cross-sensitisation was produced. Repeated administration of MDMA and AMPH produced similar behavioural profiles. However, cross-sensitisation between the two drugs was uni-directional, suggesting that the two produce different neuroadaptations. Repeated AMPH, but not MDMA, produced a sensitised response to the hyperlocomotor effects of SKF-81297, suggesting that D1 receptor mechanisms are one example of different neuroadaptations.</p>

A Comparison of Repeated MDMA- and AMPH-Produced Centre and Periphery Activity and the Underlying Neuroadaptations

<p>The recreational use of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') is increasing in New Zealand. MDMA is a ring-substituted derivative of AMPH and, similar to AMPH, produces hyperactivity upon administration. However, the behavioural profile of hyperlocomotion produced by MDMA differs from that produced by AMPH, suggesting that different neural mechanisms underlie the behavioural response. The repeated administration of both MDMA and AMPH induces sensitised hyperactive responses that have recently been found to be different. In the present study, MDMA- and AMPH-induced centre and periphery hyperactivity were compared to investigate the neuroadaptations produced by repeated exposure to the two drugs. Rats were pre-treated with saline, MDMA, or AMPH and the acute response to MDMA, AMPH, or the D1 agonist, SKF-81297 was measured to determine whether cross-sensitisation was produced. Repeated administration of MDMA and AMPH produced similar behavioural profiles. However, cross-sensitisation between the two drugs was uni-directional, suggesting that the two produce different neuroadaptations. Repeated AMPH, but not MDMA, produced a sensitised response to the hyperlocomotor effects of SKF-81297, suggesting that D1 receptor mechanisms are one example of different neuroadaptations.</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