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.

Download Full-text

Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine

BMJ Case Reports ◽

10.1136/bcr-2021-242495 ◽

2021 ◽

Vol 14 (4) ◽

pp. e242495

Author(s):

Nagara Takao ◽

Toshiya Murai ◽

Hironobu Fujiwara

Keyword(s):

Animal Studies ◽

Significant Proportion ◽

Antipsychotic Treatment ◽

High Dose ◽

Receptor Density ◽

Treatment Resistant ◽

Psychomotor Activity ◽

Receptor Blockers ◽

Dopamine Supersensitivity

Dopamine supersensitivity psychosis (DSP) frequently arises with long-term antipsychotic treatment and accounts for a significant proportion of treatment-resistant schizophrenia. The mechanism underlying DSP is thought to be a compensatory increase in dopamine receptor density in the striatum caused by long-term antipsychotic treatment. Previous animal studies have reported that antipsychotics increase serotonin 5-HT2A receptor density in the striatum and that 5-HT2A receptor blockers suppress dopamine-sensitive psychomotor activity, which may be linked to the pathophysiology of DSP. In this paper, we describe a patient who was hospitalised with treatment-resistant schizophrenia. Following treatment with high-dose antipsychotic polypharmacy for 10 weeks, the patient experienced worsening of psychotic and extrapyramidal symptoms. The patient was then started on second-generation antipsychotic asenapine while other antipsychotics were tapered off, resulting in improvement of these symptoms. Retrospectively, we presumed that the high-dose antipsychotic polypharmacy caused DSP, which was effectively treated by the potent 5-HT2A receptor antagonism of asenapine.

Download Full-text

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

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i5.26 ◽

2020 ◽

Vol 19 (5) ◽

pp. 1087-1092

Author(s):

Yaşar Taştemur ◽

Ahmet Şevki Taşkıran ◽

Ahmet Altun ◽

Ahmet Kemal Filiz ◽

Kader Gülmez ◽

...

Keyword(s):

Analgesic Effect ◽

Dopaminergic System ◽

Sch 23390 ◽

Tail Flick ◽

Hot Plate ◽

Analgesic Effects ◽

D2 Agonist ◽

D1 Agonist ◽

D2 Antagonist

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

Download Full-text

Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function

Neuropharmacology ◽

10.1016/j.neuropharm.2015.03.012 ◽

2015 ◽

Vol 99 ◽

pp. 715-725 ◽

Cited By ~ 12

Author(s):

Cynthia El Hage ◽

Anne-Marie Bédard ◽

Anne-Noël Samaha

Keyword(s):

Nucleus Accumbens ◽

Antipsychotic Treatment ◽

Dopamine Supersensitivity

Download Full-text

Circadian regulation of retinomotor movements. I. Interaction of melatonin and dopamine in the control of cone length.

The Journal of General Physiology ◽

10.1085/jgp.86.5.671 ◽

1985 ◽

Vol 86 (5) ◽

pp. 671-689 ◽

Cited By ~ 206

Author(s):

M E Pierce ◽

J C Besharse

Keyword(s):

Adrenergic Receptor ◽

Dopaminergic System ◽

Light Signal ◽

Dopamine Antagonist ◽

D2 Agonist ◽

Lighting Conditions ◽

Lower Vertebrates ◽

D1 Agonist ◽

Dark Signal

In lower vertebrates, cone retinomotor movements occur in response to changes in lighting conditions and to an endogenous circadian clock. In the light, cone myoids contract, while in the dark, they elongate. In order to test the hypothesis that melatonin and dopamine may be involved in the regulation of cone movement, we have used an in vitro eyecup preparation from Xenopus laevis that sustains light- and dark-adaptive cone retinomotor movement. Melatonin mimics darkness by causing cone elongation. Dark- and melatonin-induced cone elongation are blocked by dopamine. Dopamine also stimulates cone contraction in dark-adapted eyecups. The effect of dopamine appears to be mediated specifically by a dopamine receptor, possibly of the D2 type. The dopamine agonist apomorphine and the putative D2 agonist LY171555 induced cone contraction. In contrast, the putative D1 agonist SKF38393-A and specific alpha 1-, alpha 2-, and beta-adrenergic receptor agonists were without effect. Furthermore, the dopamine antagonist spiroperidol not only blocked light-induced cone contraction, but also stimulated cone elongation in the light. These results suggest that dopamine is part of the light signal for cone contraction, and that its suppression is part of the dark signal for cone elongation. Melatonin may affect cone movement indirectly through its influence on the dopaminergic system.

Download Full-text

Successful rechallenge with paliperidone after clozapine treatment for a patient with dopamine supersensitivity psychosis

SAGE Open Medical Case Reports ◽

10.1177/2050313x20929561 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2092956

Author(s):

Remiko Kobayashi ◽

Yasunori Oda ◽

Ryunosuke Hayatsu ◽

Nozomi Ohki ◽

Misa Akutsu ◽

...

Keyword(s):

Symptomatic Relief ◽

Psychotic Symptoms ◽

Psychotic Episode ◽

Antipsychotic Treatment ◽

Treatment Resistant ◽

Clozapine Treatment ◽

Clozapine Dose ◽

Japanese Male ◽

Old Japanese ◽

Dopamine Supersensitivity

We describe the case of a 49-year-old Japanese male patient successfully treated with a paliperidone rechallenge following 2-year treatment with clozapine for treatment-resistant schizophrenia. He had responded well to conventional antipsychotic treatment for the initial psychotic episode but gradually developed dopamine supersensitivity; even treatment with paliperidone and another antipsychotic medication (a total up to 1700 mg in chlorpromazine-equivalent dose) had not improved his psychotic symptoms. Clozapine treatment produced temporary symptomatic relief, but the clozapine dose could not be increased to > 150 mg due to the patient’s intolerance. Following low-dose clozapine treatment for 2 years, a rechallenge with paliperidone monotherapy ameliorated his psychotic symptoms. This suggests that clozapine may have the potential to release the dopamine supersensitivity state. Our patient’s case indicates that for patients with dopamine supersensitivity psychosis, a rechallenge with a previously ineffective antipsychotic after clozapine treatment may be successful.

Download Full-text

The antipsychotic potential of l-stepholidine—a naturally occurring dopamine receptor D1 agonist and D2 antagonist

Psychopharmacology ◽

10.1007/s00213-008-1172-1 ◽

2008 ◽

Vol 199 (2) ◽

pp. 275-289 ◽

Cited By ~ 40

Author(s):

Sridhar Natesan ◽

Greg E. Reckless ◽

Karen B. L. Barlow ◽

John Odontiadis ◽

José N. Nobrega ◽

...

Keyword(s):

Dopamine Receptor ◽

Naturally Occurring ◽

D1 Agonist ◽

D2 Antagonist

Download Full-text

Plasma monoamines change under dopamine supersensitivity psychosis in patients with schizophrenia: A comparison with first-episode psychosis

Journal of Psychopharmacology ◽

10.1177/0269881119900982 ◽

2020 ◽

Vol 34 (5) ◽

pp. 540-547

Author(s):

Masayuki Takase ◽

Hisoshi Kimura ◽

Nobuhisa Kanahara ◽

Yusuke Nakata ◽

Masaomi Iyo

Keyword(s):

Homovanillic Acid ◽

Chronic Schizophrenia ◽

First Episode Psychosis ◽

First Episode ◽

Antipsychotic Treatment ◽

Blood Concentrations ◽

Dopamine D2 ◽

Schizophrenia Group ◽

Episode Psychosis ◽

Dopamine Supersensitivity

Background: Patients with first-episode psychosis respond well to initial antipsychotic treatment, but among patients experiencing a relapse of psychosis, the response rate falls to approximately 30%. The mechanism of this discrepancy has not been clarified, but the development of dopamine supersensitivity psychosis with the underlying up-regulation of post-synaptic dopamine D2 receptors could be involved in this lesser response. It is uncertain whether elevated dopamine synthesis and release occurs in patients with dopamine supersensitivity psychosis, in contrast to those with first-episode psychosis. Patients and methods: We examined a first-episode psychosis group ( n=6) and a chronic schizophrenia group, i.e. patients experiencing relapse ( n=23) including those who relapsed due to dopamine supersensitivity psychosis ( n=18). Following the initiation of treatment, we measured the patients’ blood concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol at two weeks and four weeks after the baseline measurements. Results: The first-episode psychosis group tended to show decreased homovanillic acid, accompanied by an improvement of symptoms. The chronic schizophrenia group showed no alteration of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol over the treatment period. These results were the same in the dopamine supersensitivity psychosis patients alone. Conclusions: Our findings suggest that unlike first-episode psychosis, the release of dopamine from presynaptic neurons did not increase in relapse episodes in the patients with dopamine supersensitivity psychosis. This indirectly indicates that the development of supersensitivity of post-synapse dopamine D2 receptor is involved in relapse in dopamine supersensitivity psychosis patients.

Download Full-text