Dopaminergic control of sleep-wake statesCitation: Dzirasa K, Ribeiro S, Costa R, Santos LM, Lin SC, Grosmark A, Sotnikova TD, Gainetdinov RR, Caron MG, Nicolelis MA. Dopaminergic control of sleep-wake states.
J Neurosci. 2006; 26(41):10577-89.
Link
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17035544&query_hl=8&itool=pubmed_docsum
Background
During REM sleep brain levels of dopamine increase. Patients who suffer from disorders of dopamine function such as Parkinson’s disease, schizophrenia and attention deficient disorder also present with abnormal sleep patterns and excess daytime sleepiness. In the brain dopamine function depends upon the amount of dopamine produced, the function of dopamine transporters, and activation of neurons by binding to specific receptors (D1 and D2). To investigate the role of dopamine in sleep in animals, genetic models in which specific receptors or transporters are knocked out or pharmacological manipulations are used. Inhibiting transporters that transport dopamine from the synaptic cleft depletes presynaptic neuronal stores of dopamine while increasing the level of extracellular dopamine producing a hyperdopaminerigic state. This can be accomplished in mice by knocking out the dopamine transporter (DAT-KO) or administration of amphetamine to normal mice. Moreover, inhibiting dopamine synthesis by blocking the rate limiting enzyme, tyrosine hydroxylase (TH), creates a moderate hypodopaminergic state in the wildtype mice and a markedly hypodopaminergic state in the DAT-KO mice.
Hypothesis
The purpose of the study was to investigate the role of dopamine on sleep and wake states in mice.
Methods
- Adult DAT-KO and wild type littermates backcrossed to a C57B/6J background were studied.
- Mice underwent surgery to implant EMG electrodes into the trapezius muscle and an array of electrodes was placed into the dorsal hippocampus to record local field potentials. Both electrode systems were used to evaluate sleep-wake stages. Experiments were conducted one week after recovery.
- Studies were conducted in mice in their home cage or placed into a novel environment consisting of an empty cage whose bottom was divided into six equal rectangles to evaluate locomotion. The cage also contained two food pellets, a small piece of paper and a suspended water bottle. Studies were conducted during the light cycle when mice typically sleep.
- Electronic and behavioral recordings were compared shortly after the mouse had been placed into the novel environment and during a 2 hour period in the last 4 hours or a 12 hour session during which the mouse exhibited 10 minutes of waking and 2 minutes of REM. A wake REM index was calculated by taking the sum values of the differences in the peak power theta distributions during wakefulness and REM in each mouse. Power spectra from the hippocampal and EMG were used to evaluate the awake state, slow wave sleep (SWS) and REM sleep. Power clusters were determined to evaluate if these stages were according at similar or different spectra.
- To evaluate the effects of depleting dopamine, mice received the TH inhibitor α-methyl-p-tyrosine. Other agents used were L-DOPA which stimulates dopaminergic receptors and can override the effects of TH inhibition, the D2 receptor agonist quinpirole, the D2 receptor antagonist haloperidol, and the D1 agonist SK-81297.
- Statistical analysis consisted of the Mann Whitney test to compare results of 2 groups and the Kruskal- Wallis test when more than 2 groups were compared followed by the Mann Whitney test. Significance was accepted at P<0.05.
Results
- In the novel environment DAT-KO mice relative to the wild type mice exhibited increased locomotion. DAT-KO mice exhibited an overlap between REM and awake that the authors called a REM-like awake state. SWS was similar between the DAT-KO and wildtype mice. The overlap between the REM and wake state was no longer present during the last 4 hours of recordings.
- Treatment of DAT-KO mice with haloperidol suppressed the novelty-induced overlap of REM-like wake state and gamma oscillations in the hippocampus. Treatment of wild type mice with amphetamine increased gamma oscillations in the hippocampus and REM-like wake states. These changes were not due to hyperlocomotion that accompanied treatment of wild type mice with amphetamine.
- Treatment of wildtype and DAT-KO with the TH inhibitor α-methyl-p-tyrosine (or DDD mice) resulted in decrease in REM total time in wild type mice, eliminating REM in the DDD mice, preventing sleep, and creating an akinesia and rigidity similar to that seen in late stage Parkinson’s disease.
- In DDD mice A low dose of L-DOPA restored some REM, but did not increase mobility. Treatment of DDD mice with the D2, but not the D1 receptor agonist restored REM sleep and mobility.
Discussion and Clinical significance
This study indicated that elevated dopamine brain levels in mice result in the production of a REM-like state during wakefulness and an increase in gamma hippocampal oscillations. When dopamine levels are depleted, REM states disappear as do the gamma oscillations. This study also demonstrated that REM sleep requires activation of D2 receptor pathways. Thus, antipsychotic agents like haloperidol affect wake sleep cycles by suppressing the REM-like hippocampal oscillations in the wake state. Moreover, Parkinson’s patients who loss large numbers of dopaminergic neurons exhibit sever sleep disturbances such as excessive daytime sleepiness and REM sleep behavior disorder. These sleep disturbances may occur prior to motor deficits, findings similar to what was noted in the DAT-KO in a novel environment.
References
- Comella CL. Sleep disturbances and excessive daytime sleepiness in Parkinson disease: an overview. J Neural Transm Suppl. 2006; 70:349-355.
- Costa e Silva JA. Sleep disorders in psychiatry. Metabolism. 2006 ;55(10 Suppl 2):S40-4.
- Crochet S, Sakai K. Dopaminergic modulation of behavioral states in mesopontine tegmentum: a reverse microdialysis study in freely moving cats. Sleep. 2003;26(7):801-6.
- Lauer CJ, Schreiber W, Pollmacher T, Holsboer F, Krieg JC. Sleep in schizophrenia: a polysomnographic study on drug-naive patients.
- Neuropsychopharmacology. 1997 ;16(1):51-60.
- Eisensehr I, Linke R, Noachtar S, Schwarz J, Gildehaus FJ, Tatsch K. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson's disease and controls. Brain. 2000 ;123 ( Pt 6):1155-60.
| 
