The therapeutic effects of dopamine replacement therapy and its psychiatric side effects are mediated by pineal function

There are reports that melatonin secretion from the pineal gland gradually diminishes with advancing age. It has been suggested that various forms of neuropsychiatric disease, in particular, Parkinson's disease (PD), is consequentially related to this decrease by virtue of increased oxidative stress which enhances the process of dopamine (DA) degeneration. There is, however, considerable disagreement on this theme as very little is generally known about the role of the pineal gland in the aetiology and treatment of PD. To assess the role of the pineal gland in PD and in dopamine replacement therapy (DART), the effect of three anti-Parkinsonian drugs on motor and psychiatric function was assessed in normal, pinealectomized (PX) and DA deficient, PX rats. In the first study, rats underwent PX or sham operation and were then injected (IP) with Amantadine (30 or 50 mg/kg), Bromocriptine (5 or 10 mg/kg) or l-Dopa (30 or 60 mg/kg plus 50 mg/kg of R-044602) 3–8 weeks after surgery. Open field performance and motor reflex tests were assessed during the light and dark phases of the L/D cycle. In a second study, clinically effective doses of Bromocriptine (10 mg/kg) and l-Dopa (30 and 100 mg/kg with 50 mg/kg R-044602) were injected into depleted, PX or sham operated rats. In study I, sham operated and PX rats responded differently to Bromocriptine and l-Dopa, while Amantadine did not differentially effect motor performance in the two groups. In study II, 6-OHDA induced degeneration of the nigro-striatal system abolished the effects of Bromocriptine and dramatically altered the effects of l-Dopa seen in study I, in sham operated versus PX rats. DART significantly altered emotionality, as measured by escape attempts, agitation and rage in sham operated animals, compared to PX rats. DA deficiency abolished the tendency to escape in all groups except those treated with 100 mg/kg of l-Dopa. Conversely, agitation and rage scores were greater after 100 mg/kg of l-Dopa, in rats with intact pineal function, than in PX rats. These results provide compelling evidence that altered pineal function plays a major role in the aetiology of PD, the therapeutic effect of anti-Parkinsonian drugs and in the psychiatric side effects of DART.