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treatment.

We found that those APDs that do not cause weight gain, including haloperidol, did not activate orexin neurons.15 Those that do cause weight gain, such as clozapine, induced Fos in orexin neurons in both the medial and lateral orexin neurons of the LH/PFA (see Fig. 3). However, there was a direct correlation between the weight gain liability of a particular APD and the degree to which orexin neurons were activated in the lateral LH/PFA, while in the medial LH/PFA orexin cells the one-to-one correlation of weight gain liability and Fos induction was not observed.

Most of the APDs that activated orexin neurons are among the newer generation atypical APDs, including clozapine, olanzapine, and risperidone. However, the ability of APDs to activate orexin neurons is not restricted to atypical APDs: the typical APD chlorpromazine induces Fos in orexin neurons,15 consistent with the moderate weight gain caused by this drug.19 Conversely, the atypical APD ziprasidone, which does not appear to cause weight gain in patients,19 did not activate orexin neurons.

4.2. How Do Both Anorexic And Orexigenic Drugs Both Active Orexin Cells?

We have seen that both amphetamine, a drug that inhibits feeding and causes weight loss with repeated administration, and certain APDs, which cause weight gain, are able to activate orexin cells. How can one resolve this paradox?

One clue was the differential distribution across the LH/PFA of orexin cells that were activated by amphetamine and clozapine. Amphetamine challenge, like apomorphine, induced Fos primarily in orexin cells medial to the fornix. Clozapine induced cells more broadly across the LH/PFA, although a significantly greater effect was observed in areas lateral to the fornix. This suggested that there are two different populations of orexin cells, and by extension raises the possibility that among the ways distinct groups of orexin cells might be differentiated is on the basis of projection target.

One concern about this hypothesis the paradox of the very small number of orexin cells that project so widely across the central nervous system. Because so many areas are innervated by orexin neurons, one possibility is that orexin neurons collateralize to innervate multiple targets. This would have evolutionary advantage over an axonal projection restricted to one or even two sites: the loss of even a very small number of target-specific orexin cells, such as by injury or as an age-related process, might result in dysfunction of the projection target.

The prefrontal cortex is strongly activated by both amphetamine and clozapine.25-28 We therefore determined if orexin neurons that innervate the PFC also branch to innervate the dorsal raphe, in which the density of the orexin innervation is comparable to that in the PFC. We found that less than 5% of the orexic cells that were retrogradely labeled from the PFC were also retrogradely labeled from the dorsal raphe, suggesting the at least some orexin neurons project to specific targets.

We were particularly interested in the PFC because orexin neurons were activated by clozapine. Several studies have indicated that the weight gain in patients treated with clozapine is related to the therapeutic outcome.29-31 The cognitive dysfunction in schizophrenia is thought to be related to a decrease in dopaminergic tone in the PFC,32-34 and one action that differentiates clozapine from typical APDs, which are not very effective in targeting cognitive deficits, is the ability of the atypical drug to increase extracellular DA levels in the PFC.35, 36

HPD CLZ

Figure 3. The distribution of orexin cells activated by apomorphine (APO), haloperidol (HPD), and clozapine (CLZ), as reflected by neurons expressing both Fos and orexin (filled circles). Single-labeled orexin cells that did not express Fos are depicted as open circles. Note that the DA agonist apomorphine strongly induced Fos in area just medial and dorsal to the fornix, whereas clozapine activated a more scattered population of orexin cells, of which the majority are in the lateral LH/PFA.

We therefore examined the effects of amphetamine and clozapine on orexin cells that project to the PFC. Clozapine increased Fos expression in the PFC-projecting orexin cells, while amphetamine challenge did not affect these hypothalamo-cortical orexin cells.15 Moreover, the cells that innervated the PFC were concentrated lateral to the fornix, distinct from the DA agonist-driven cells.

These observations are consistent with clozapine and amphetamine regulating two distinct orexin systems: one comprised of orexin cells in the LH that project to the PFC and is activated by clozapine, and the other medially-situated group of orexin cells that project to an as yet unknown target that is activated by amphetamine. It is possible that amphetamine activates orexin cells involved in arousal, including those of medial septum-diagonal band complex, while clozapine targets orexin cells that are involved in feeding but also have a role in regulating the PFC.

5. DOPAMINE, OREXIN, AND SCHIZOPHRENIA

Several case reports have suggested that daytime hypnogogic hallucinations in narcolepsy may lead to an incorrect diagnosis of schizophrenia.37-39 A small number of patients diagnosed with schizophrenia were subsequently shown to have narcolepsy and respond favorably to modafinil treatment.39 On the basis of a structured interview of narcoleptic subjects, Vourdas40 found that about 10% of the subjects had hallucinations, but suggested that the hallucinations were attributable to amphetamine treatment because they cleared when patients were switched to modafinil.

Among the current treatments for narcolepsy are psychostimulants, sodium oxybate, and modafinil;41-44 the latter is gaining increasing favor.43-45 Although the precise mode of action remains elusive, modafinil has been suggested to act through a primary action of orexin neurons, setting into play several downstream effectors, including histamine neurons of the tuberomammillary nucleus.46, 47

Most attention has focused on the wake-promoting effects of modafinil, particularly in narcolepsy. However, several studies have indicated the presence of cognitive dysfunction in narcolepsy, particularly in the realm of attention.48-52 Moreover, recent case reports have suggested that modafinil may be useful in the treatment of clozapine-induced sedation.53-55 Interestingly, Teitelman55 noted that modafinil might also improve attention and reduce cognitive dysfunction. Although some investigators have suggested that in normal adult subjects modafinil does not affect cognition, but does affect mood,56 another more extensive study concluded that modafinil enhances cognitive function, including spatial memory, delayed match-to-sample, and stop-signal reaction time, in normal adult subjects.57 Moreover, an open trial has suggested that modafinil is an effective treatment for schizophrenia,58 and a recent double-blind, placebo-controlled, cross-over study of modafinil concluded that modafinil improves cognitive function in schizophrenia.59

How might modafinil, a drug used extensively to treat narcolepsy, be beneficial in treating the cognitive deficits in schizophrenia? The dopaminergic innervation of the PFC is thought to be a major target of atypical APDs such as clozapine. Clozapine differs from typical APDs by targeting more effectively the cognitive deficits of schizophrenia.60-63 The ability of clozapine to effectively treat some cognitive changes in schizophrenia has bee suggested to occur, at least in part, by increasing DA tone in the PFC.24, 64-67

A single report has suggested that systemic administration of modafinil increases extracellular DA and NE levels in the PFC of the rat.68 More recently, we69 and Berridge and colleagues70 have found in pilot studies that orexin infusion into the PFC results in an increase in both extracellular dopamine and norepinephrine levels. This raises the possibility that orexin may be important in augmenting cortical catecholamine levels, and thereby improving cognitive function.

If orexin augments cortical DA levels and thereby restores to some degree dopaminergic tone in the PFC, do clozapine or other APDs act in part through promoting orexin release? As discussed previously, we found that clozapine and certain other atypical APDs activate orexin cells in the lateral part of the orexin cell cluster,15 with many of these cells projecting to the PFC. In contrast, orexin cells innervating the PFC were not activated by amphetamine. We hypothesize that there are two separable systems involved in dopamine-orexin interactions. One involves PFC-projecting orexin cells and has a functional role in modulating dopaminergic tone and thereby enhancing cognition.

The other involves those orexin cells activated by DA agonists that function in arousal; although the target of such cells is not yet known, the medial septum-diagonal band cholinergic cells are a likely suspect.

Our data indicates that clozapine, olanzapine, and certain other APDs activate a distinct subpopulation of orexin neurons. However, a recent short communication reported that cerebrospinal fluid (CSF) levels of orexin-A are significantly lower in schizophrenic patients treated with haloperidol than unmedicated subjects, but that orexin levels do not differ between haloperidol-treated patients and another group of patients treated with either clozapine or olanzapine.71 The authors suggested that the clozapine-induced activation of orexin neurons seen in the rat is not manifested in human schizophrenic subjects. However, the regional source(s) of orexin in the CSF is not known. We showed that clozapine specifically activated orexin cells projecting to the PFC.15 It is not known if CSF orexin levels are primarily derived from the orexin innervation of the spinal cord, or if they correlate with orexin levels in the PFC or any other site. In other systems it has proven very difficult to define the source of CSF transmitters and their metabolites. For example, there is no correlation between CSF dopaminergic metabolites and striatal DA concentrations in probenecid-treated monkeys,72 despite the fact striatal DA forms the largest single pool of the amine. Given the lack of information concerning the source of orexin in the CSF, and the fact that there are distinct orexin systems that project to different targets, the conclusion that atypical APDs do not activate orexin neurons in humans71 is suspect.

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