Intern. J . Neuroscience, 1992. Vol. 62, p. 269-272 Reprints available directly from the publisher Photocopying permitted by license only

0 1992 Gordon and Breach Science Publishers S.A. Printed in the United States of America

Letter to Editor PARAVENTRICULAR NUCLEUS-PINEAL INTERACTION: RELEVANCE

TO TARDIVE DYSKINESIA

Received September 13, I990

To The Editor: Tardive dyskinesia (TD), a neurologic side effect of chronic neuroleptic treatment, occurs in 20%-30% of psychiatric patients (Kane et al., 1988). Despite intensive research, the pathophysiology of TD remains elusive. Although the dopamine re- ceptor supersensitivity hypothesis of TD has been the most widely accepted (Kla- wans, 1973), evidence since suggests that TD is associated with derangements of other neurotransmitter systems, including GABA, norepinephrine, and serotonin (5 - HT) (Fibiger and Lloyd 1984; Jeste and Wyatt, 1981; Sandyk et al., 1986).

More recently, we have hypothesized that the pineal gland is involved in the path- ophysiology of TD (Sandyk and Fisher, 1989). This position was prompted by the observation of an increased incidence and severity of abnormal perioral dyskinesias in haloperidol-treated pinealectomized rates as compared to controls (Sandyk and Fisher, 1989), and by the findings that persistent TD and its severity are associated with the presence of pineal calcification (PC) on CT scan (Sandyk et al., 1990). More specifically, we have suggested that the pineal gland exerts a protective effect that mitigates against the development of TD and that reduced melatonin secretion may be a key factor in the chain of events that ultimately lead to its emergence (Sandyk, 1990). We now extend our hypothesis and propose that derangement in the mutual functional interactions between the paraventricular nucleus (PVN) of the hypothalamus and the pineal gland may be of consequence for the development of TD .

It has long been assumed that the activity of the pineal gland is regulated pre- dominantly by the environmental light, which is received in the retina and conveyed via the retino-hypothalamic projections to the suprachiasmatic nucleus (SCN), the spinal cord, and the superior cervical ganglion to control melatonin secretion (Klein, 1978). There is growing evidence, however, that the pineal gland also received in- nervation directly from the brain. To our knowledge, the most studied cerebral struc- ture that sends direct projections to the pineal gland is the PVN.

Several lines of evidence, summarized in Table 1, point to the presence of ana- tomic and functional interactions between the PVN and the pineal gland: (a) PVN efferents project to the pineal gland (Korf and Wagner, 1980; Nurenberger and Korf, 198 1); (b) electrophysiological studies reveal that the electrical activity of single pineal cells is influenced by PVN stimulation in the guinea pig (Reuss and Semm, 1982; Reuss et al., 1984); (c) electrical stimulation of the PVN inhibits melatonin synthesis in rats (Klein et al., 1983; Reuss et al., 1985); (d) the PVN plays an im- portant role in the photoperiodic-neuroendocrine circuit and is responsible for relay- ing information from the SCN to the pineal gland (Pickard and Turek, 1983); (e)

Correspondence to: Prof. Reuven Sandyk, P.O. Box 203, Bedford Hills, NY 10507, U.S.A.

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TABLE 1 Evidence for Paraventricular Nucleus (PVN)-Pineal Interactions

(1) Fibers from the PVN project to the pineal gland (2) PVN stimulation influences electrical activity of pineal cells (3) PVN stimulation inhibits melatonin synthesis (4) PVN relays information from the suprachiasmatic nucleus to the pineal gland (5) PVN projections mediate pineal and gonadal responses to photoperiod (6) PVN lesions disrupt the melatonin rhythm generating system (7) Pineal extracts induce hypertrophy of PVN cells (8) Pinealectomy induces atrophy of PVN cells (9) PVN is involved in the control of the thyroid gland by the pineal gland

PVN projections mediate pineal melatonin and gonadal responses to photoperiod in the hamster (Smale et al., 1989); (f) PVN lesions mimic the effects of pinealectomy in their ability to prevent short-day-induced testicular regression in the golden ham- ster (Lehamn et al., 1984); (g) lesions of the PVN disrupt the SCN-pineal circuit in the melatonin rhythm generating system in rats (Klein et al., 1983); (h) administra- tion of pineal extracts to rats produces hypertrophy of the PVN cells; (i) pinealectomy leads to atrophy of PVN cells (Miline, 1963; De Vries and Kappers, 1971); and ( j ) the PVN is a link by which the habenulo-pineal system exerts its inhibitory influence on the pituitary-thyroid axis (Miline, 1963). Thus, given these functional interactions between the PVN and pineal gland and the evidence for involvement of the pineal gland in the pathophysiology of TD, it is conceivable that disruption of these inter- actions may be relevant to TD.

Prior studies have shown that fibers of the PVN relay inhibitory information, i.e., stimuli equivalent to light for the mammalian pineal gland (Nishino et al., 1976; Klein et al., 1983), and stimulation of the PVN in rats has been reported to inhibit melatonin synthesis (Klein et al., 1983; Reuss et al., 1985). It is, therefore, possible that increased activity of the PVN, as reflected by a rise in vasopressin release, can lead to exacerbation of TD by suppressing melatonin synthesis. In fact, several in- vestigators (Lawson et al., 1985; Kirch et al., 1985) have reported an unusually high incidence of persistent TD in chronic schizophrenic patients in conjunction with the syndromes of polydipsia and hyponatremia, which are caused by excessive vaso- pressin secretion (Illowsky and Kirch, 1988). Moreover, Shen and Sata (1983) noted that two of six patients with self-induced water intoxication and hyponatremia ex- hibited transient exacerbation of TD during the period of self-induced water intox- ication. Lawson et al. (1985) and Kirch et al. (1985) noted that only polyuric patients with hyponatremia exhibited TD. Since the syndrome of polyuria and hyponatremia may be caused by inappropriate secretion of vasopressin (SIADH) (Illowsky and Kirch, 1988), which appears to be related to dysfunction of the PVN (Hobson and English, 1963; Illowsky and Kirch, 1988), it is possible that excessive vasopressin secretion may lead to inhibition of melatonin synthesis and secretion and, thereby, to exacerbation of TD. Reduction of melatonin secretion would lead to a compen- satory decrease in the activity of the PVN (Miline, 1963), which would tend to worsen the polyuria and polydipsia.

It is noteworthy that haloperidol and other neuroleptics, which are known to pro- duce TD, may cause inappropriate secretion of vasopressin (Illowsky and Kirch, 1988). Accordingly, one mechanism by which neuroleptics induce TD may con- ceivably involve stimulaton of vasopressin release, which indirectly could lead to reduction of melatonin secretion. Since melatonin inhibits dopamine release and stimulates GABA synthesis (cf. Sandyk, 1990), diminished melatonin secretion would

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LETTER TO EDITOR 27 1

result in increased dopamine activity and decreased GABA functions, both of which have been implicated in the pathophysiology of TD (Klawans, 1973; Fibiger and Lloyd, 1984).

Several studies have demonstrated that nicotine is a potent stimulator of vaso- pressin release (Sklar and Schrier, 1983) and have implicated smoking as a major factor in triggering self-induced water intoxication and hyponatremia (Jose and Even- son, 1980; Blum, 1984). In this context, it is of note that cigarette smoking has also been reported to increase the risk of TD (Yassa et al., 1987). Although this effect may be related to nicotine-induced augmentation of dopamine activity, it is also possible that nicotine worsens TD by releasing vasopressin.

The proposal that increased vasopressin release may be involved in the patho- physiology of TD is not only of theoretical interest, but has several clinical impli- cations for its prophylaxis and treatment: (a) in neuroleptic-treated chronic schizo- phrenic patients, polydipsia and episodic self-induced water intoxication as well as hyponatremia association with polydipsia should be considered risk factors for TD; (b) cigarette smoking should be prohibited in patients who exhibited self-induced water intoxication, as it may heighten the risk for TD; (c) increased plasma vaso- pressin levels and decreased sodium levels could be markers of susceptibility to TD; and (d) demeclocycline, an antibiotic related to tetracycline that reduces the renal response to vasopressin, which has been shown to benefit patients with polydipsia with hyponatremia (cf. Illowsky and Kirch, 1988), could prove useful in the man- agement of persistent TD. We are currently in the process of investigating these issues in our research center.

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REUVEN SANDYK and STANLEY R. KAY Department of Psychiatry, Albert Einstein College of Medicine, Montefore Medical Center, Bronx, NY 10461, U.S.A.

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