Dopamine (DA) and norepinephrine (NE) are monoaminergic neurotransmitters collectively known as catecholamines [1]. In DA neurons, synthesis begins with tyrosine from the blood that is first hydroxylated to dihydroxyphenylalanine (DOPA) and then decarboxylated to DA. The DA is bound into vesicles and if the vesicle fuses with the cell membrane it is released to the synapse [2]. DA can be catabolized intracellularly by monoamine oxidase (MAO) to 3,4-dihydroxy-phenylacetic acid (DOPAC) or extracellularly by catechol-O-methyltransferase (COMT) into homovanillic acid (see Fig. 7.1). DA neurons project to many brain areas via several tracts. The largest amount of DA projects via the nigrostriatal tract (from the substantia nigra to the striatum). The tuberoinfundibular tract runs from the hypothalamus’s arcuate nucleus to the pituitary stalk. The mesolimbic tract and the mesocortical tract connect ventral tegmentum to limbic areas and to prefrontal area, respectively. Many structures are involved, including hippocampus, amygdala, arcuate nucleus, periventricular hypothalamus, septum, thalamus, and frontal cortex [3]. In noradrenergic neurons, synthesis follows the same course as for dopamine but then in an extra reaction, dopamine beta hydroxylase converts DA to NE. Like DA, the NE is bound into vesicles that will release if fused with the cell membrane (see Fig. 7.2). MAO will catabolize NE to normetanephrine and COMT catabolism will result in homovanillic acid or 3-methoxy-4-hydromandelic acid [4]. NE synthesis occurs in several areas including the locus coeruleus (LC) which projects to the cerebral cortex, hypothalamus, thalamus, and hippocampus. There is a stepwise reduction in LC activity with the highest levels during wakefulness, reduced during NREM sleep, and nearly silent during REM sleep [5].

Pharmacological probes can be used to manipulate dopaminergic neurons to help elucidate the underlying mechanism. The precursor l-DOPA can increase chemical needed to synthesize DA. By contrast, reuptake into the presynaptic neuron can be inhibited by traditional stimulants (e.g., amphetamines) and cocaine. Postsynaptic receptors can be agonized by apomorphine, pergolide, bromocriptine, pramipexole, rotigotine, and ropinirole. These are G-bound receptors and agonist action differs between drugs. Receptor antagonism can be accomplished with pimozide and any of the traditional neuroleptics (e.g., chlorpromazine, haloperidol, or thioridazine). Intra- and intercellular catabolism can be diminished by monoamine oxidase inhibitors (e.g., phenelzine and tranylcypromine) [6].

NE containing neurons can be chemically probed with a wide variety of compounds. Alpha-methyl-p-tyrosine (AMPT) can retard the synthesis of DA and NE by blocking the conversion of tyrosine to DOPA. Disulfiram also inhibits NE synthesis by blocking the final step in which DA is converted to NE. Traditional stimulants (e.g., amphetamine) cause vesicles to rupture producing large-scale synaptic release in addition to blocking presynaptic reuptake, thereby greatly increasing synaptic catecholaminergic concentration. This produces excitation and diminishes sleep. Ultimately, the NE or DA that is trapped synaptically gets catabolized resulting in a net depletion of available DA and NE. This “crash” as it is dubbed by stimulant abusers is associated with very profound hypersomnolence. NE reuptake inhibition is also characteristic of tricyclic antidepressants (e.g., imipramine, protriptyline, nortriptyline, and amitriptyline) [7]. However, this property varies widely between compounds. More recently, more specific NE reuptake inhibitors have been developed (e.g., atomoxetine, reboxetine) [8].

Postsynaptically, the central nervous system includes α₁, α₂, and β NE receptors. These receptors can be agonized or antagonized by different pharmacological agents, including phenylephrine (α₁ agonist), prazosin (α₁ antagonist), clonidine (α₂ agonist), yohimbine (α₂ antagonist), and propranolol (β blocker) [9]. More agents are listed in Table 7.1.

Dopamine plays an important role in maintaining wakefulness. Consequently, it is not surprising that patients with Parkinson’s disease (and related DA deficits) commonly suffer from sleepiness. Some pharmacological agents that increase synaptic availability of NE and DA tend to raise arousal level and decrease REM sleep. This is markedly true of the traditional psychostimulants. These central nervous system stimulants increase arousal level by means of autonomic sympathetic activation (and thereby decrease drowsiness). For many years, these drugs were the mainstay of therapeutics for treating disorders of excessive sleepiness. The older amphetamines formulations of benzedrine, dexedrine, and desoxyn have largely been replaced by mixtures of amphetamine salts (e.g., Adderall^®), lysine bound lisdexamfetamine (e.g., Vyvanse^®), and the amphetamine congener, methylphenidate. Lisdexamfetamine is a prodrug and was developed in an attempt to decrease abuse potential [10]. Other, dopaminergics with stimulant properties have also been used to treat the sleepiness associated with narcolepsy and idiopathic hypersomnia, including selegiline, pemoline, and mazindol [11]. Pemoline is seldom used today because it was “black boxed” for provoking hepatic failure and jaundice and mazindol was never very popular due to its limited efficacy. Polysomnographic evaluation indicates that compounds in this class generally increase time spent awake and the number of awakenings. They also typically prolong both latency to sleep onset and latency to the first occurrence of REM sleep. In addition to decreasing total sleep time, traditional psychostimulants also suppress REM and slow wave sleep (see Table 7.2). Individuals seeking to extend the duration of their wakefulness period (whether for recreational or vocational purposes) are known to abuse these medications. Trismus (lockjaw), bruxism, and both sleep-related and awake teeth clenching are associated with amphetamine and amphetamine-like stimulants. Thus, teenagers and young adults abusing such substances during all-night dance parties (sometimes called raves) may accessorize their fashion statement with athletic mouth pieces designed to protect the teeth. Most of the formulations also produce significant euphoria, increasing further their potential for abuse. Abused substances include both pharmaceutical and black market products such as homemade methylamphetamine (speed), cocaine, and MDMA (3,4-methylenedioxy-N-methylamphetamine, commonly known as Ecstasy, X, or XTC). Methylamphetamine abuse is epidemic. In 2003, more than 10,000 small scale and 130 “superlabs” (capable of producing 10 lb per production cycle) were seized by law enforcement. Moreover, the Drug Enforcement Administration (DEA) has reported that in 2012, 11,210 laboratories producing methylamphetamine were seized.

Dopamine precursors and various DA receptor agonists (D2, D3, and D4), originally designed mainly for treating Parkinson’s Disease, are used to treat Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD). This class of drugs includes pramipexole, ropinirole, apomorphine, rotigotine, and bromocriptine. Currently, pramipexole and ropinirole appear to be the medications of choice for treating RLS [12] and both have been approved for this use by the U.S. Food and Drug Administration. At the doses prescribed, these medications are not stimulants. In fact, there have been reports of the opposite, that is, occurrence of sleep attacks. These drugs are also implicated in compulsive disorders (e.g., triggering excessive gambling, eating, and sexual urges). Recently, rotigotine has come into the market for treating RLS transdermally. With a side effect profile much like pramipexole and ropinirole, it provides an alternate route of administration [13]. With respect to RLS and PLMD, medications having the opposite effect, that is, worsening these conditions, include tricyclic antidepressants, selective serotonin reuptake inhibitors, some antiemetics (prochlorperazine and metoclopramide, lithium, some calcium channel blockers (verapamil, nifedipine, and diltiazem), antihistamines, and traditional neuroleptics [14].

Dopamine (D2 and D3) receptor antagonists in the form of traditional neuroleptics reliably produce sedation, increase sleep efficiency, increase slow wave sleep, and usually suppress REM sleep to some degree. This holds true for chlorpromazine, haloperidol, and thioridazine. The newer, non-D2, and non-D3 neuroleptics (clozapine, olanzapine, risperidone, ziprasidone) have variable effects on slow wave sleep with some producing decrease while other (e.g., risperidone, olanzapine, and ziprasidone) associated with an increase (perhaps related to its higher affinity 5-HT₂ receptors). These newer atypical antipsychotics do not universally produce sedation [15]. The amount of sedation produced appears to be determined by the combination of the drug’s relative potency and its affinity for the histamine-1 (H₁) receptor. For example, clozapine is very sedating and it has high H₁ affinity (32) and low potency (and consequently a need for large doses 50 mg), while olanzapine is less sedating even with an H₁ affinity of 1149 because with its high potency there is need for only a low dose (4 mg). Quetiapine also falls into the low potency (80 mg dose needed) and moderate H₁ affinity (5.2) category and thus is moderately sedating. Like traditional neuroleptics, these newer drugs can increase restless legs and periodic leg movement activity during sleep.

The tricyclic antidepressants (TCAs) comprise a wide range of compounds that share a similar three-ring chemical structure. This group of agents includes imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, trimipramine, doxepin, and protriptyline. Across the board, TCAs increase slow wave sleep (mildly to moderately) and suppress REM sleep (mildly to markedly). This can be seen in Table 7.2. TCAs are generally sedating (with a few exceptions, e.g., protriptyline). The range of sedation varies greatly and is most likely a function of antihistaminergic activity (see section on histamine). Imipramine, the prototypical compound in this class, is regarded as a non-selective NE reuptake inhibitor. In vitro acute biochemical activity studies reveal that it also produces serotonin reuptake inhibition, has high α₁ and muscarinic acetylcholinergic receptor affinity, and binds somewhat to histamine receptors. In sleep medicine, imipramine is best known for its REM suppressing properties and for decades was widely used as an anticataplectic agent for treating patients with narcolepsy. Imipramine’s slow wave sleep enhancing and REM sleep suppressing properties are illustrated in Fig. 7.3. In this patient, latency to the first REM sleep episode was almost 3 h, twice as long as normal. No REM sleep episode occurred at the usual 90–120 mins latency from sleep onset (the missing REM sleep episode). Additionally, REM sleep continued to be suppressed later in the night while slow wave sleep appeared to be above normal. The other popular TCA used in this manner is protriptyline. Protriptyline also has the advantage of being non-sedating; however, it can exacerbate erectile problems in men (that in turn can render therapeutic adherence problematic). The REM suppressing properties of TCAs appear to stem from a combination of aminergic (norepinephrine and serotonin) and anti-acetylcholinergic properties. The aminergic properties theoretically provide activation of REM-off systems, while the anticholinergic properties would inhibit REM-on systems. For example, clomipramine, the most REM suppressing TCA, strongly agonizes 5-HT by inhibiting reuptake of serotonin and also has moderate antimuscarinic properties. By contrast, the TCA amitriptyline, another strong REM suppressor, blocks acetylcholine with its very high muscarinic binding affinity but is a weaker serotonin reuptake inhibitor.

Monoamine oxidase inhibitors (MAOIs), as a class, are the strongest suppressors of REM sleep. They, of course, alter catabolism of all biogenic amine neurotransmitters (DA, NE, and serotonin) and like the TCAs; they can be used as antidepressants. It did not go unnoticed that until the atypical antidepressant bupropion was developed, all known antidepressant medications suppressed REM sleep. Furthermore, even instrumentally suppressing REM sleep by awakening sleepers in the laboratory whenever they entered REM sleep improved mood in patients diagnosed with depression [16]. Thus, it was posited that REM sleep promoted depression in some individuals and that REM sleep suppression was necessary and sufficient to achieve an antidepressant effect. The atypical antidepressants (e.g., venlafaxine and trazodone) suppress REM sleep (especially early in the night with some rebound toward morning). However, with the synthesis of bupropion (and afterward nefazodone), the axiom that REM suppression was necessary to achieve an antidepressant property was disproved; neither of these antidepressants suppress REM sleep. Nonetheless, while it may not be necessary to suppress REM sleep, REM suppression remains sufficient to produced antidepressant effects. Also noteworthy is that unlike the TCAs, the atypical antidepressants venlafaxine, nefazodone, bupropion, and trazodone do not increase slow wave sleep.