Several compounds have been administered intravenously (i.v.) during H-reflex studies and during long-term investigation of cataplexy in humans; more sophisticated studies have been performed using animal models, particularly narcoleptic-cataplectic Dobermans (Delashaw et al., 1979; Foutz et al., 1981; Mignot et al., 1988).
The effects of REM sleep-modulating agents and tricyclic antidepressant compounds have been investigated. Compounds with norepinephrine and serotonin reuptake-blocking properties have been shown to suppress cataplexy in man. The most potent were compounds combining norepinephrine and serotonin reuptake-blocking properties with atropinic effect. Drugs such as protriptyline, imipramine, and clomipramine were shown to significantly reduce cataplectic attacks. Atropine i.v. injections reversed cataplectic attacks in humans, and more specific reuptake blockers — such as viloxazine, a specific norepinephrine reuptake blocker, and fluoxetine, a serotonin reuptake blocker—were shown to suppress cataplexy without inducing the atropinic side affects (e.g., impotence) often seen with tricyclic antidepressants with anticholinergic properties. Earlier studies had also shown that levadopa (L-dopa), a precursor of dopamine, might have an effect on cataplexy.
The fact that clomipramine and, to a lesser extent, fluoxetine suppress cataplexy shed light on the neurochemical control of cataplexy. Progressively, it was shown in humans that both drugs have active metabolites: desmethyl-clomipramine and norfluoxetine (Nishino et al., 1993). These active metabolites strongly inhibit norepinephrine reuptake. This finding, associated with the findings that amphetamine and the amphetamine drugs that act presynaptically to release norepinephrine, improve cataplexy, and viloxazine, a norepinephrine blocker without serotonin activity, also controls human cataplexy, suggests the involvement of a norepinephrine synapse.
More specific pharmacological studies have been performed in Doberman pinschers. First, we documented that nicotinic cholinergic stimulation had no effect on muscle atonia (Delashaw et al., 1979). However, muscarinic cholinergic stimulation with arecoline and physostigmine salicylate, an anticholinesterase with a short biological half-life, increases cataplexy in Dobermans, while cholinergic blockade using atropine sulfate or scopolamine hydrobromide, compounds which cross the blood-brain barrier, eliminates the symptom (Delashaw et al., 1979). Methyl atropine and methyl scopolamine, which do not cross the blood-brain barrier, are completely ineffective.
In conjunction with these pharmacological investigations, a comparison of the muscarininc receptors in different parts was carried out (Kiliduff et al., 1986). The comparison revealed that M2 subtype muscarinic receptors are upregulated in the pontine reticular formation of narcoleptic dogs, more particularly in the nucleus reticularis pontis caudalis, the nucleus reticularis giganto cellularis, and the interpenducularis. Further studies demonstrated that the norepinephrine reuptake blocker nisoxetine also had a strong effect on canine cataplexy. These findings suggest the possibility of the involvement of a neurotransmitter other than norepinephrine, as well as the involvement of a second synapse.
To resolve this issue of serotonin activity, a specific investigation of sero-toninergic reuptake inhibition properties was performed (Nishino et al., 1993). Fluoxetine, zimelidine, clomipramine, and amitriptyline were investigated in the animal model; and their activity was compared with that of their active desmethyl metabolites: norfluoxetine, norzimelidine, desmethylclomipramine, and nortriptyline. These active metabolites more potently block adrenergic uptake and more potently suppress cataplexy. These results demonstrated that anti-cataplectic potency is positively correlated with adrenergic reuptake inhibition and negatively correlated with serotoninergic uptake inhibition. These studies provide further support for the concept that the adrenergic system is the main monoaminergic system involved in the regulation of cataplexy and that muscarinic cholinergic and adrenergic synapses are involved in the pathway responsible for the symptom.
To distinguish the roles of the different norepinephrine receptor subtypes, selective studies of alpha- and beta-adrenergic compounds were performed. Central beta-1 and beta-2 adrenergic receptors were found not to play a significant role in the muscle atonia, but alpha-1 adrenergic compounds were very active. Prazosin, an alpha-1 antagonist, significantly worsened canine cataplexy. This same compound, used as an antihypertensive agent in human narcoleptics, also significantly worsens cataplexy. Further investigation demonstrated that there are at least two alpha-1 receptor subtypes, classified as alpha-la or alpha-lb. Drugs with a high affinity for alpha-lb receptors, such as Prazosin and phenoxybenzamine, were found to increase cataplexy, while alpha-lb agonists reduced the attacks (Mignot et al., 1988; Fruhstorfer et al., 1989; Nishino et al., 1993).
The alpha-2 adrenergic system has also been investigated (Fruhstorfer et al., 1989). Alpha-2 agonists were found to increase cataplexy, while alpha-2 antagonists such as yohimbine reduced the symptom. However, treatment of human narcolepsy with yohimbine in a double blind study we performed did not demonstrate positive results. Also, the effect of yohimbine in canine cataplexy seems transitory. Alpha-2 receptors are located pre- and postsynaptically, but results to date suggest the presynaptic alpha-2 receptors are more actively involved in cataplexy. Analysis of brain tissue from narcoleptic and control dogs showed a general increase in catecholamine in the narcoleptic dog brain. Further chemical studies revealed a higher concentration of dopamine D2 receptors in discrete regions, particularly the amygdala, of cataplectic dogs (George et al., 1964).
In interpreting these findings, it must be remembered that receptors may be pre- or postsynaptitic and that several synapses may be involved in muscle atonia; that is, there must be a descending pathway associated with normal REM sleep muscle atonia. Muscarinic cholinergic and catecholaminergic systems— especially cholinergic and adrenergic systems undoubtedly play a role in human and canine cataplexy, although how they interact remains unclear.
Pharmacological coadministration experiments were performed to investigate the interaction of cholinergic and adrenergic systems. Pretreatment with muscarinic cholinergic antagonists such as atropine sulfate or scopolamine hydro-bromide, followed by administration of the alpha-lb antagonists prazosin, block the effect of Prazosin and improve canine cataplexy. This suggests that the cholinergic muscarinic synapse is farther down on the descending pathway, impinging on the spinal cord motor neurons involved in cataplexy.
Some investigations were performed at Stanford involving dialysis and in situ injection. George et al. (1964) showed that injections of carbachol, a cholinergic agonist, into the pontine tegmentum of the cat produce abrupt muscle atonia, with development of the REM and pontogeniculooccipital waves seen during REM sleep. Injection of carbachol into the pontine reticular formation induced status cataplecticus in our cataplectic Dobermans. Acetylcholine release in the same region confirmed the previous pharmacological studies. Still, the pontine reticular formation is not the only muscarinic cholinergic region in the central nervous system, and our pharmacological investigations support the existence of a multisynaptic descending pathway involved in the muscle atonia of cataplexy.
The basal forebrain muscarinic cholinergic system (nucleus basalis, substan-tia-innominata, diagonal band, and medial septum) is linked to the limbic (emotional) system and sends and receives information to and from the entire cerebral cortex, the thalamus, and the limbic system. Injection of carbachol into the basal forebrain of cataplectic dogs induced status cataplecticus with very long-lasting muscle atonia, while atropine sulfate reduced cataplexy. Such injections had no effect on muscle tone of control dogs, but increased (at the same dosage) alertness. Bilateral injection (compared with unilateral injection in cataplectic dogs) of a much higher dose (50 versus 10 nmol in cataplectic dogs) of carbachol finally induced muscle atonia of abrupt onset in control dogs. These findings suggest that a hypersensitivity of the muscarinic cholinergic system exists in different parts of the cataplectic dog brain. The hypersensitivity of this system is, as mentioned, directly linked to the limbic system, which is known to be involved in the control of emotions.
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