PubMed · 14824674
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G CHEN, D RUSSELL. 1951. A method for evaluating adrenergic blocking activity.. https://pubmed.ncbi.nlm.nih.gov/14824674/
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We studied the effects of nicotine and epibatidine on rotational behaviour in 6-hydroxydopamine-lesioned rats. The nicotinic agonists were given acutely and repeatedly either alone or in combination with a dopamine uptake inhibitor, nomifensine. Neither nicotine nor epibatidine alone produced acutely ipsilateral rotational behaviour in rats. However, when given repeatedly once a day for five days, nicotine (0.5 mg/kg) and epibatidine (0.6 microg/kg but not 3.0 microg/kg) induced ipsilateral rotations indicating sensitization of the nigrostriatal dopaminergic system to activation by repeated treatment with nicotinic agonists. Nomifensine (3 mg/kg) alone induced acutely ipsilateral rotations and the effect was enhanced after repeated administration of nomifensine. When the combination of nomifensine and nicotinic agonists was given acutely, the rotational effect of nomifensine was enhanced by nicotine (0.5 mg/kg) but not by either dose of epibatidine. When given repeatedly, nicotine and epibatidine 0.6 microg/kg tended to prolong whereas epibatidine 3.0 microg/kg tended to inhibit the enhanced rotational response to repeated nomifensine. The sensitization of the nigrostriatal dopaminergic pathway might be involved in the beneficial effects of nicotine in Parkinson's disease by allowing the remaining dopaminergic synapses to compensate for the functional deficiency of nigrostriatal pathway.
Terminally differentiated neurons derived from a human teratocarcinoma cell line (NT2N or hNT neurons) are promising as a cell source for transplantation, as they have been shown to be safe for transplantation in humans. We have shown previously that hNT neurons can express a catecholaminergic phenotype in a rat Parkinson model. In this study, we investigated the long-term survival and ability of hNT neurons to express tyrosine hydroxylase and reconstruct the dopamine-denervated nigrostriatal pathway. Hemiparkinsonian rats received grafts of 400,000 viable hNT neurons into each of the denervated striatum and substantia nigra. Robust hNT grafts were detected up to 24 weeks posttransplantation, although few cells expressed tyrosine hydroxylase. Many hNT fibers were often associated with ipsilateral and contralateral white matter tracts--corpus callosum, rostral migratory stream, optic tract, and external capsule. Fewer fibers were associated with the superior cerebellar peduncle, medial lemniscus, and nigrostriatal pathway. Axons also projected into the frontal cortex and extended parallel to the surface of the brain in the superficial cortical layers. These pathways were seen in all grafted animals, suggesting that specific guidance cues exist in the adult brain governing hNT fiber outgrowth. Injured adult axons and transplanted embryonic neuronal axons rarely extend for such distances in the adult nervous system. We propose that elucidating the factors promoting and guiding hNT axonal outgrowth could provide important clues to enhancing regeneration and target reinnervation in the adult brain, two factors of critical importance for cell restoration strategies aimed at brain repair.
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 100mg/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.