Rebound Hypersomnolence, Stimulant Abuse, and DAT-Mediated Dopamine Release

NOT MUCH ATTENTION HAS BEEN PAID TO THE INVOLVEMENT OF THE DOPAMINERGIC SYSTEM IN THE REGULATION OF SLEEP-WAKE CYCLE, IN CONTRAST to those of other monoamines such as norepinephrine (NE), serotonin, and histamine. This is mostly due to the fact that dopaminergic neurons in the ventral tegmental area or substantia nigra, the midbrain dopaminergic nuclei that project to forebrain, do not change their firing rates across sleep cycles, yet there are changes in their firing patterns.¹ Pharmacological studies however, consistently reported that modes of action of most currently available wake-promoting agents such as amphetamines and modafinil are mediated by stimulation of dopaminergic neurotransmission.²

The major molecular target of the dopaminergic wake-promoting compounds is the dopamine transporter (DAT), an integral membrane protein located in the dopaminergic nerve terminals that binds DA in the synaptic cleft with Na+ and Cl− ion dependent mechanisms. DAT provides the primary mechanism through which DA is removed from synapses, by transporting DA into a dopaminergic neuron (i.e., reuptake of DA). The driving force for DAT-mediated DA reuptake is the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase.

The DAT reuptake inhibitors, such as GBR-12909 and bupropion, bind DAT and compete with the binding of DA, resulting in increases in DA concentration in the synaptic cleft and consequently enhancing the dopaminergic neurotransmission. Amphetamines act on DAT and inhibit the reuptake of DA. Amphetamine also enhances the release of DA through DAT-mediated mechanisms, a process called “exchange diffusion”.^3,4 Amphetamine (phenylisopropylamine) has a simple chemical structure resembling endogenous catecholamines, namely DA and NE. Due to the structural similarity, DAT bound amphetamine would be taken up, while DAT uptake inhibitors simply immobilize the DAT function. This amphetamine transportation causes inward current, and intracellular sodium ions become more available facilitating the binding of cytoplasmic DA to DAT. This results in reverse transportation of DA to the synaptic cleft.^3,4 Therefore, amphetamine has dual functions on the DAT to facilitate dopaminergic neurotransmission.

Since amphetamine also binds to the NE transporter (NET), amphetamine enhances NE neurotransmission with an analogous NET-mediated mechanism. Amphetamine enhances serotonin release to a lesser degree. However, a series of experimental reports have suggested the critical roles of the dopaminergic system as the pharmacological target for amphetamine and other wake-promoting compounds.^5–7

The modes of action of amphetamine are more complex; high doses of amphetamine inhibit monoamine oxidase (MAO) and prevent monoamine metabolism. Amphetamine also interacts with the vascular monoamine transporter 2 (VMAT2), serving as a physiological VMAT2 antagonist that releases the vascular DA into the cytoplasm. All of these effects contribute to the enhancement of dopaminergic neurotransmission and to the exhibition of the potent stimulant effect.

Amphetamine-like compounds, such as phentermine, methylphenidate, pemoline, and fencamfamin are structurally similar to amphetamines (and thus to endogenous catecholamines); all compounds include a benzene core with an ethylamine group side chain and are classified as phenethylamine derivatives, and some of these compounds may share amphetamine's pharmacological properties.

It is well known that amphetamine induces significant rebound hypersomnolence (RHS: increased sleep following increased wake). The RHS of amphetamine is sudden and intolerable, and therefore often referred to as a “crash.” This effect significantly hampers therapeutic effects of amphetamine especially when amphetamine is used for the treatment of excessive daytime sleepiness. It is also known that some other wake-promoting compounds, such as modafinil or caffeine do not induce RHS. Occurrences of RHS after intake of wake-promoting compounds cannot be explained solely by the difference in pharmacokinetics of the compounds, and the basic mechanisms of the stimulant-induced RHS are not fully understood.

In this issue of SLEEP, Gruner and colleagues⁸ address several important questions related to dopaminergic agents that induce RHS. The authors tested 3 DA-releasing and 6 DAT-inhibiting agents in rats and monitored sleep/wake activity, especially RHS, after administrations of equal wake-promoting dose of the compounds. The study was well designed and extensive, using many compounds with in vivo and in vitro evaluations. Three DA-releasing (amphetamine, methamphetamine, phentermine) and 3 DAT-inhibiting agents (cocaine, bupropion, and methylphenidate) produced significant RHS during the first few hours after the onset of sleep recovery. However, other DAT- inhibiting agents (mazindol, nomifensine, GBR-12909, and GBR-12935) did not produce RHS.

The authors demonstrated that motor stimulatory effects of the DA agents did not correlate with RHS, indicating that RHS was not simply a result of excessive motor activation preventing animals from going to sleep or leading to exhaustion and rapid sleep recovery.

From these results, the authors concluded that amphetamine-like DA release appears sufficient for inducing RHS, but additional properties (pharmacologic and/or pharmacokinetic) evidently underlie RHS of some DAT inhibitors.

The second major result of the study is that nomifensine (a DAT inhibiting agent) was shown to potentiate the wake-promoting effects of amphetamine, but eliminated amphetamine-induced RHS. These results suggest unique pharmacological interactions between DAT-inhibiting agents and amphetamine relative to wake promotion and RHS.

The conclusions of Gruner and colleagues⁸ appear to be valid, but some other comments are also needed. The designation of the class of DA compounds is based on the systematic comparison of effects of each compound on spontaneous DA release in rat synaptosome preparations (i.e., DA releasing effects) as well as those on amphetamine-induced DA release (i.e., DAT inhibition). All non-DA-releasing compounds inhibited amphetamine-induced DA release, validating the designation of the pharmacological classes.

It should be noted, however, that each compound should have its own pharmacological characteristic even if the compounds belong to the same designated class. For example, despite the fact that cocaine is often classified as a DAT inhibitor, the pharmacological profile of cocaine is very different from other DAT inhibiting agents. Some DAT inhibitors, such as GBR12909 or JHW007, do not display a cocaine-like behavioral profile, but rather attenuate cocaine-induced behaviors such as locomotor activity and discriminative stimulus effects.^9,10 Cocaine is also reported to enhance DA release in vivo.¹¹ These results suggest that cocaine may interact on DAT differently from the modes by which other DAT-inhibiting agents interact with DAT. Cocaine also has relatively high affinity to the serotonin transporters.

As stated above, amphetamine-like compounds have multiple functions and have effects on multiple monoaminergic systems, and each compound has a different potency on each system. For example, d-methamphetamine and d-amphetamine potently enhance DA release, and l-methamphetamine has little effect on DA release, while all three compounds equally enhance NE release.^4,7

Mazinzol and nomifensine have relatively high affinity to NET,⁶ though these are classified as DAT-inhibiting agents. Therefore, the designated class does not simply indicate the mode of action of the compound. Nevertheless, the study⁸ clearly showed that DA release is one of the most critical factors that contribute to the RHS of DA wake-promoting compounds, and the following hypothesis for the mechanisms underlying the stimulant-induced RHS can be made: If DA release is supraphysiologically enhanced by these compounds, rapid desensitization of the postsynaptic DA receptors likely occurs. DA releasing agents would also temporarily deplete the cytoplasmic DA. These effects may explain the occurrence of RHS. In contrast, pure DAT inhibiting agents are unlikely to affect presynaptic DA sources. If these compounds produce a more physiological and mild increase in DA in the synaptic cleft, an alternation in synaptic homeostatic mechanisms may be subtle and the sleep amount may still be under physiological control even after the drug-induced prolonged wakefulness.

Of note, potent DA releasing agents, such as amphetamine and methamphetamine cause stimulant abuse. Beside these compounds, the study indicated a tendency for drugs that produce larger RHS (e.g., cocaine and methylphenidate) to have higher abuse potential than those that produce smaller RHS (mazindol and nomifensine). Since it is reported that rate and magnitude of change in synaptic DA concentration has also been related to the abuse potential of dopaminergic psychostimulants,¹² this pharmacological property may contribute to the abuse potency of the compounds. Further research is needed in this area.

In this regard, the result of coadministration of amphetamine and nomifensine is interesting. Although it is still not conclusive why nomifensine enhances the wake-promoting effect of amphetamine, the major factors that contributed to this phenomenon included a metabolic interaction or pharmacokinetic effects, and the study showed that the plasma and brain concentrations and half-lives of amphetamine increased in the presence of nomifensine.⁸

More importantly, the result that nomifensine attenuates the RHS after the amphetamine administration should be emphasized, since this finding may provide useful clues about the mechanisms of RHS and drug abuse. Nomifensine is likely to compete with amphetamine to bind DAT, thus inhibiting the exchange diffusion and DA release, as has been shown in the in vitro synaptosome experiments. Therefore, this result is also consistent with the importance of DA release for the underlying mechanisms of RHS. If these hypotheses are correct, selective DA uptake inhibitors can be used for the treatment of amphetamine abuse and/or amphetamine withdrawal. Along this line, several researchers proposed possible clinical applications of some DAT inhibiting agents for the treatment of cocaine abuse, and experiments are in progress.^12,13

Although some of the mechanisms discussed here are hypothetical, the results reported by Gruner et al.⁸ emphasize novel links among stimulant induced RHS, abuse potency, and DAT-mediated functions. Additional experiments to establish whether RHS could be functionally related to drug abuse liability appear warranted.

DISCLOSURE STATEMENT

Dr. Nishino has indicated no financial conflicts of interest.