The results of this study establish that a dose of cocaine as low as 2.5 mg/kg can produce significant alterations in sleep patterns in the rat. Their REM sleep was significantly higher in the second and third hours following the administration of a 2.5 mg/kg dose. The administration of the 5 mg/kg dose produced a suppression of REM sleep for 2 h followed by an increase over control values in total REM sleep in the fourth hour. The injection of the 10 mg/kg dose of cocaine, on the other hand, eliminated REM sleep for the first 3 h. In addition to these effects on REM sleep, cocaine administration also reduced SWS and increased the percentage of time of wakefulness in a dose-dependent manner. Reductions in REM sleep and SWS, as well as increases in the time spent awake, have been previously shown to occur in the rat following the administration of either cocaine9,10
or other psychomotor stimulants such as d
The significant increase in REM sleep produced by the administration of low doses of cocaine in this study has not been previously reported, although a trend in this direction was detected in an earlier study.9
Cocaine was administered in the present study on what can be characterized as a subacute acute basis. Similar schedules of administration are used frequently in studies of the rewarding effects of cocaine.11
The administration of psychomotor stimulants other than cocaine, including amphetamine and methamphetamine, to rats may result in a rebound in both REM sleep and SWS several hours later during the day in which these drugs were administered.17,18
REM sleep, however, may not increase above control levels.19
After initially producing decreased SWS and REM sleep resulting in increased wakefulness, the chronic administration of high doses of cocaine to rats is followed by a rebound increase in REM sleep and SWS observed 12 h later, during the daily dark phase.10
In human cocaine users, rebound increases in REM sleep have been observed during periods of withdrawal from this drug,6,8
although this has not been a consistent finding.5
It is not yet clear whether the increases in REM sleep produced by low dose cocaine administration is mechanistically related to the rebound REM sleep that results from either amphetamine administration or chronic cocaine use. It should be noted, that in contrast to the effects of amphetamine, treatment with low dose cocaine resulted in increases in REM sleep that did not occur in association with concurrent changes in other sleep parameters.
After an intraperitoneal injection, cocaine serum levels peak very rapidly.20
The serum half-life of cocaine has been determined to be approximately 13 min. Thus, at the times at which REM sleep was found to increase following administration of low dose cocaine in the present study, blood concentrations of this drug would have dropped markedly from their initial levels. The possibility then exists that increases in REM sleep seen subsequent to cocaine administration are produced by some later response to cocaine exposure rather than to the direct actions of this stimulant, or they may reflect the actions of very low concentrations of this drug. However, we acknowledge that these possible explanations would have to be supported by future experiments.
Cocaine selectively blocks monoamine transporter proteins. In vitro
, the IC50s
for the cocaine-induced blockade of dopamine, serotonin and norepinephrine transporters are all within the same order of magnitude as each other.21,22
Amphetamine-induced arousal and waking may be mediated, in part, by the actions of norepinehprine.19,23
Some findings suggest that dopamine also may play a role in mediating the effects of psychomotor stimulants on wakefulness. The relative potencies of D-, L-, and methamphetamines in producing wakefulness in the dog correlate with their effects on dopamine efflux in the caudate nucleus.24
Furthermore, dopamine transporter knockout mice are unresponsive to the wakefulness-promoting effects of either methamphetamine or the selective dopamine reuptake blocking agent GBR 12909.25
It is not yet clear whether wakefulness is increased during psychomotor stimulant administration by the actions of dopamine on the neural mechanisms that regulate natural sleep or by a secondary processes that increases locomotor activity.
Serotonin released from the dorsal raphe nucleus and norepinephrine from the locus coeruleus can suppress the activity of brain stem neurons that are involved in the generation of REM sleep.26,27
Thus, the reductions in REM sleep that were produced by the administration of moderate doses of cocaine in the present study may have due to the inhibition of serotonin and/or norepinephrine reuptake by this drug.
What role, if any, elevations in brain monoamine levels produced by low doses of cocaine play in the increase in REM sleep exhibited after administration remains to be established. The acute administration of cocaine may produce feedback inhibition of serotonin and norepinephrine synthesis and turnover.28–31
Cocaine-induced inhibition of serotonin or norepinephrine synthesis could then be associated with the elevations in REM sleep observed after the administration of low dose cocaine. In one study, recovery from cocaine-induced suppression of serotonin synthesis was found to occur between 120 and 150 min after the administration of this drug in doses ranging between 3.0 and 18.2 mg/kg i.p.30
In the present study, however, cocaine induced-elevations in REM sleep produced by the 2.5 and 5 mg/kg doses of cocaine were found to persist for more than 3 h. Thus, the elevation of REM sleep seen following the administration of low dose cocaine appears to continue for several hours after the inhibition of serotonin synthesis by this agent has subsided.
In the present study, cocaine was found to have two different effects on REM sleep and/or wakefulness, depending on the dose administered. In two other studies, a similar pattern of responses was seen when glutamate was microinjected into the pedunculopontine tegmentum (PPT).32,33
Glutamate promoted REM sleep at low concentrations and wakefulness at higher concentrations. The similarity of the effects between glutamate and cocaine suggest that the possibility that the disparate alterations in sleep patterns observed post-administration of different doses of cocaine might involve a glutamatergic mechanism. This may involve the indirect actions of cocaine on pathways that influence the PPT.
In addition to its direct effects in the brainstem, cocaine could influence REM sleep through the extensive connections that exist between the PPT and the other brain regions that mediate the actions of this drug. These connections include cholinergic projections from the PPT to regions that are densely populated with dopaminergic neurons; notably the substantia nigra34
and the ventral tegmental area.35
In addition, afferents to the PPT originating from basal ganglia structures including the substantia nigra36
and several limbic structures, such as the bed nucleus of the stria terminalis and the central nucleus of the amygdale, may also have a role.37
Consistent with the results of previous studies, it has been shown here that the subacute administration of cocaine results in an increase in wakefulness and decrease in SWS. These effects occur in a dose-dependent manner. While the higher doses of cocaine used in this study were found to initially reduce REM sleep, this stage of sleep increased above control levels a few hours following the administration of lower doses of cocaine. The neuronal mechanism that produces this latter effect remains to be elucidated. The PPT, which plays a critical role in the generation of REM sleep, has been suggested to play a role in the reinforcing effects of cocaine, nicotine,38,39
Determination of the extent to which there is a functional overlap in the neuronal populations that regulate REM sleep and drug-induced reinforcement in the PPT might greatly help in understanding the processes that are associated with the development of drug dependence.