The neurobiology of sleep and substance abuse interconnects, such that alterations
in one process have consequences for the other. Acute exposure to drugs of abuse disrupts
sleep by affecting sleep latency, duration, and quality [1]. With chronic administration,
sleep disruption becomes more severe, and during abstinence, insomnia with a negative
effect prevails, which drives drug craving and contributes to impulsivity and relapse.
Sleep impairments associated with drug abuse also contribute to cognitive dysfunction
in addicted individuals. Further, because sleep is important in memory consolidation
and the process of extinction, sleep dysfunction might interfere with the learning
of non-reinforced drug associations needed for recovery. Notably, current medication
therapies for opioid, alcohol, or nicotine addiction do not reverse sleep dysfunctions,
and this may be an obstacle to recovery [2, 3]. Whereas exposure to drugs of abuse
is causal to sleep dysfunctions that further promote chronic use, sleep disorders
in turn are risk factors for substance abuse and their severity can predict the prognosis
of substance use disorders (SUD) [4]. Sleep disruption results in a cumulation of
risk factors that drive drug abuse, including increasing the sensitivity to pain,
acting as a stressor, and biasing toward a negative effect. Recognizing and treating
sleep disorders may be an important preventive measure against future drug misuse
and SUD. Despite convergent evidence linking sleep and substance abuse, and the therapeutic
potential that can emerge from elucidating the biology underlying this link, this
has been a relatively neglected area of research. A first step in advancing this area
is to identify how the circuits and substrates that regulate sleep and arousal intersect
with those that mediate reward and also how they are targeted by drugs of abuse.
The locus coeruleus (LC)–norepinephrine (NE) system is a diffuse forebrain-projecting
system that is involved in arousal and also is a primary target of drugs of abuse,
including nicotine, stimulants, opioids, and cannabinoids. LC–NE neuronal activity
is positively correlated to the state of arousal, and LC neurons are most active during
waking and are off during REM sleep [5]. Selective LC activation is sufficient to
elicit cortical arousal, and conversely, selective LC inhibition prevents cortical
activation by stressors, indicating that this system is important in regulating cortical
arousal in response to stressors and other salient stimuli [6, 7]. The stress-related
neuropeptide, corticotropin-releasing factor (CRF), mediates stress-induced LC excitation,
and endogenous opioids that innervate the LC exert an opposing effect that may serve
to restrain excessive activation and promote recovery after stress termination [8].
Opioid tolerance would be expected to enhance stress-induced activation of this arousal
system, and promote a cycle of drug seeking to tone down the excessive response. LC
neurons are robustly activated during opioid withdrawal and this has implicated the
LC–NE system in opioid-withdrawal signs, including the hyperarousal and insomnia associated
with withdrawal [9]. Notably, α2-adrenergic antagonists (lofexidine and clonidine)
that inhibit LC discharge are clinically used for the attenuation of opioid and alcohol
withdrawal to reduce peripheral symptoms from sympathetic activation, such as tachycardia,
as well as central symptoms, such as insomnia, anxiety, and restlessness. Their utility
in suppressing symptoms during protracted abstinence, such as insomnia, along with
its associated adverse consequences (irritability, fatigue, dysphoria, and cognitive
impairments) remains unexplored.
Like LC–NE neurons, the raphe nuclei (including the dorsal raphe nucleus—DRN) serotonin
(5-HT) neurons modulate sleep and wakefulness through widespread forebrain projections.
The role of this system in sleep is complex. Raphe nucleus lesions trigger insomnia
[10, 11], and during the awake state, the cumulative 5-HT, released from the raphe
into the basal forebrain (including the nucleus basalis, which is the main cholinergic
input to the cortex, and regulates arousal), is believed to serve as a sleep-promoting
factor [11]. However, 5-HT neurons are active during waking, decrease their activity
during slow-wave sleep, and cease firing during REM sleep, as is the case for LC–NE
neurons [12, 13]. Notably, DRN-5-HT neurons are implicated in the arousal from sleep
in response to hypercapnia [14], which is impaired during opioid-induced overdoses,
and further work is required to assess how to target the serotonin system as a way
to prevent opioid-induced overdoses or to improve outcomes when naloxone cannot completely
reverse them (Table 1).
Table 1
Predominant effects of neurotransmitter targets of various drugs in sleep and arousal
and their typical effects during intoxication and withdrawal
Neurotransmitter
Drug
Intoxication
Abstinence
NE
Arousing
Stimulants
Opioids
Alcohol
Enhanced
Reduced
Reduced
Reduced during early stages of withdrawal
Hyperexcitable
Hyperexcitable
5-HT
Arousing/sedating
Stimulants
Ecstasy
Enhanced
Enhanced
Enhanced
Reduced
DA
Arousing
Stimulants
Opioids
Nicotine
Cannabis
Alcohol
All drugs enhance DA
D2R, DAT, and DA release are downregulated
Histamine
Arousing
Opioids
Alcohol
Enhanced
Reduced
Nicotine
Arousing
Nicotine
Enhanced
Tolerance
Orexin
Arousing
Cocaine
Opioids
Enhanced
Enhanced
Upregulated
Upregulated
Mu opioids
Sedating
Opioids
Nicotine
Alcohol
Enhanced
Enhanced
Enhanced
Tolerance of MOR
Adenosine
Sedating
Caffeine
Reduced
Tolerance
Cannabinoids
Sedating
Cannabis
Enhanced
Downregulation
Because the effects of a neurotransmitter on arousal and sleep may differ depending
on the brain region it targets, in some instances, the effects are mixed as is the
case for serotonin. Also, the effects can differ during early versus protracted withdrawal,
such as is the case for cocaine that leads to enhanced sedation that can last up to
3–4 weeks post withdrawal to then be followed by protracted insomnia
Like the LC–NE and DRN-5-HT systems, the histamine (HA) neurons of the tuberomammillary
nucleus form another diffusely projecting arousal system that is active during waking
only and these neurons are activated by opioids, which can further contribute to sleep
disruption associated with chronic opioid use. HA promotes arousal through activation
of cortical and basal forebrain neurons, effects that are primarily mediated by H1
receptors [15, 16]. Thus, the H1 receptor may be an alternate target for treating
sleep dysfunction associated with abstinence.
In contrast to the LC–NE and DRN-5-HT neurons, midbrain dopamine (DA) neurons were
not considered to be sleep-related, because they show little change in discharge rate
during the sleep/wake cycle other than bursting during paradoxical sleep. However,
the wake-promoting actions of drugs that enhance DA signaling are widely recognized
and used for clinical purposes [17, 18]. Transgenic modifications that enhance DA
neurotransmission in mice, such as deletion of the DA transporter gene, result in
increased wakefulness [19], whereas deletion of DA D2 receptors (D2R) decreases wakefulness
[20]. Further, recent optogenetic studies demonstrated that activation of DA neurons
in the ventral tegmental area (VTA) but not substantia nigra increases wakefulness
[21]. These arousal effects are mediated by VTA projections to the nucleus accumbens,
because optogenetic activation of DA terminals here, but not in other terminal regions,
also promoted wakefulness. Therefore, this specific DA circuit is a node that regulates
the rewarding effects of drugs of abuse and one that mediates arousal, including that
elicited by salient and rewarding stimuli.
The endogenous cannabinoid system (ECS) that signals through cannabinoid CB1 and CB2
receptors, which are targets of marijuana, is also involved in circadian rhythm and
the regulation of the sleep–wake cycle [22, 23]. Acutely, cannabis is sleep-promoting
and decreases latency, increases sleep time, increases slow-wave sleep, and decreases
REMs [1, 23]. Consistent with this, CB1 antagonists increase wakefulness and decrease
slow-wave sleep and REMs and conversely, the endogenous CB1 agonist, anandamide enhances
slow-wave sleep and REM [24]. The effects of CB1 signaling may be mediated through
the sleep-promoting molecule, adenosine because doses of anandamide that promote sleep
increase adenosine release in the basal forebrain [25]. Notably, adenosine is the
target of caffeine, which is an adenosine receptor antagonist that is widely used
to increase arousal. Another potential mechanism for the sleep-promoting effects of
endocannabinoids is through their opposing regulation of neuronal activity in the
lateral hypothalamus, inhibiting the activity of arousal-promoting orexin neurons
(see below), while increasing the activity of sleep-promoting melanin concentrating
hormone neurons [26].
With chronic use, tolerance occurs to the sleep-enhancing effects of cannabis, and
abstinence is characterized by unusual dreams and poor sleep quality that is predictive
of relapse [27]. ECS disruption with chronic marijuana use is likely to underlie the
long-lasting insomnia commonly observed during abstinence in cannabis abusers.
The orexin system that derives from the posterior lateral hypothalamus is like the
LC–NE, DRN-5-HT, and TMN–HA systems in that the cells only fire during waking and
are silent during sleep phases [28]. It is unique in being essential for sustaining
the waking state, as its disruption in patients with narcolepsy leads to periodic
and abrupt interruptions of the conscious state. The cluster of orexin neurons in
the hypothalamus is a node that links to the other arousal-related nuclei, including
basal forebrain cholinergic neurons, TMN–HA neurons, DRN-5-HT neurons, VTA–DA neurons,
lateral dorsal tegmental cholinergic neurons, and LC–NE neurons (Fig. 1). It is poised
to orchestrate a synchronous activation of multiple arousal systems. In addition to
its role in arousal, orexin has a role in the rewarding effects of drugs of abuse,
including those of opioids [29]. For example, narcoleptics that have low orexin levels
do not abuse opioids and mice with genetic deletion of orexin show decreased opioid-addiction
potential, implicating orexin in the initial rewarding effects of opioids [29]. Orexin
neurons are activated by reward and project to the DA neurons in VTA that innervate
the nucleus accumbens and mediate reward, which they also influence via their direct
projections to it. Chronic opioid exposure upregulates orexin in humans and rodents
[30]. Postmortem brains of heroin users showed increases in orexin neuron numbers
in the lateral hypothalamus and reverse translation studies verified that chronic
opioid administration in rodents also increased the number of orexin neurons in their
lateral hypothalamus. The upregulation of orexin would be expected to create a state
of hyperarousal and may underlie the insomnia observed both in treated and non-treated
opioid users. Preclinical studies, demonstrating that orexin microinjection into the
VTA increases cocaine self-administration and reinstates cocaine-conditioned place
preference, also implicate orexin in cocaine’s rewarding effects. It has been suggested
that orexin is specifically engaged in substance abuse during elevated motivational
states, such as when the effort to obtain the drug is high [29] or when animals are
stressed [31]. For example, orexin antagonists only affect self-administration under
conditions that require a relatively high effort, such as progressive ratio schedules,
or when drug seeking is triggered by cues or stress, suggesting that it may be particularly
active during relapse. This would be consistent with a state of heightened arousal
that accompanies craving. These findings provide a rationale for the evaluation of
orexin antagonists, such as suvorexant, a drug currently approved for use for insomnia,
as therapy for substance use disorders and for the development of new ones. These
agents may provide a two-fold benefit by preventing two distinct but interrelated
effects of orexin, potentiation of reward and arousal effects, which could help attenuate
drug reward and improve sleep disturbances.
Fig. 1
Schematic depicting efferent projections of lateral hypothalamic orexin neurons. The
orexin system is positioned to influence cognitive function, arousal, and reward.
Orexin neurons have broad forebrain projections. Cortical projections may modulate
cognitive aspects of substance use behavior such as decision-making. In addition,
they project to arousal-related nuclei, including the locus coeruleus (LC), which
expresses norepinephrine (NE), dorsal raphe nucleus (DRN), which expresses serotonin
(5-HT), lateral dorsotegmental nucleus (LDT), which expresses acetylcholine (ACh),
tuberomammillary nucleus (TMN), which expresses histamine (HA), and nucleus basalis
of Meynert (NBM), which expresses ACh. These nuclei in turn have diffuse projections
throughout the forebrain. Orexin neuronal projections to the ventral tegmental area
(VTA) and nucleus accumbens (NAc) are poised to modulate reward and to make rewarding
stimuli arousing
Although it is becoming well accepted that there are neurobiological links between
sleep dysfunction and substance abuse behavior that result in comorbidity, research
is still in its infancy. Earlier, we discussed a simplified anatomical framework that
identifies some of the relevant links for this comorbidity, but there are likely other
pathways and substrates, some of which still need to be discovered. The precise functional
interactions between these different regions and their involvement in the trajectory
of drug use has not been explored in any depth. Likewise, how the interaction between
sleep and substance use is shaped by genetics, life events, sex, and circadian rhythms
remains unknown. Further research to fill the knowledge gaps at the intersection of
sleep, drug reward, and addiction will help identify treatment targets that improve
the quality of life of individuals suffering from sleep and substance use disorders.
Funding and disclosure
This work was supported by the National Institute on Drug Abuse.