Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat

Abstract

The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025-2.0 mg/kg) and bromocriptine (0.25-6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05-0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects. The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of mesolimbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhibitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists.

Essential Role of Dopamine D2Receptor in the Maintenance of Wakefulness, But Not in Homeostatic Regulation of Sleep, in Mice

“…First, the use of D 2 R agonist drugs has been found in patients with Parkinson's disease to cause sudden sleep attacks, but in humans these are mainly during the active (light) phase (Tan, 2003). Of course D 2 R agonists are a two-edged sword, because they activate postsynaptic D 2 R, but also reduce dopamine release via presynaptic D 2 R (Monti et al, 1988;Ongini et al, 1993;Sebban et al, 1999), and thus may actually decrease dopamine availability at D 1 R. Second, the flipflop switch model of sleep regulation predicts that when either side of the sleep-arousal circuit is weakened (Saper et al, 2005;Lu et al, 2006), there should be an increase in the instability in both states (i.e., that we would see an increase in both wake to NREM transitions, but also in NREM to wake transition, a result that is counter-intuitive if one thinks of the D 2 R effect as only being to promote arousal). Our results not only support that model, but also suggest that the dopamine system is an important part of the arousal side of the wake-sleep flip-flop switch.…”

“…To clarify the roles of D 2 R in sleep-wake regulation, researchers have often used the pharmacological approach. Systemic administration of a D 2 R antagonist increases NREM sleep and the electroencephalogram (EEG) power density in the low-frequency bands (Monti et al, 1988;Ongini et al, 1993;Sebban et al, 1999). Under conditions of low arousal, the D 2 R agonist quinpirole promotes wakefulness after an intracerebroventricular administration (Isaac and Berridge, 2003).…”

“…Under conditions of low arousal, the D 2 R agonist quinpirole promotes wakefulness after an intracerebroventricular administration (Isaac and Berridge, 2003). However, the systemic injection of a D 2 R agonist induces biphasic effects, such that low doses reduce wakefulness, whereas large doses have the opposite effect (Monti et al, 1988). Therefore, pharmacological tools used to determine the role of D 2 R in sleep-wake regulation show limited selectivity and/or incomplete blockade.…”

Dose‐dependent effects of the 5‐HT1A receptor agonist 8‐OH‐DPAT on sleep and wakefulness in the rat

“…Ten days after surgery the animals were habituated for four days to a dimly lit, soundproofed chamber fitted with slip-rings and cable connectors and were then administered either a control solution or the drug(s) to be tested. The electrographic activity in 50 s periods was analysed and assigned to the following categories based in the waveform: wakefulness, light sleep, slow-wave sleep and REM sleep (Monti et al 1988). In addition, slow-wave sleep and REM sleep latencies were determined.…”

Научный Диалог: Вопросы Медицины

“…Увеличение синтеза дофамина в полосатом теле связано с прогрессированием положительных симптомов, тогда как снижение его секреции в дорсолатеральной перифронтальной коре связан с усилением негативной симптоматики [12,13]. В эксперименте агонисты дофаминовых рецепторов усиливают бодрствование и снижают сон [14]. Нарушение обмена серотонина проявляется в виде повышенной секреции 5-гидроксииндолуксусной кислоты, основного метаболита серотонина в ЦНС.…”