| Popis: |
Benzodiazepines (BZ) are a class of drugs that are extensively used for their anxiolytic, anticonvulsant and sedative properties. The therapeutic actions of these drugs may be mediated through the central-type BZ receptors that are linked to the GABA receptor complex (BZ/GABA). When administered in large doses, the pineal hormone, melatonin, can interact with BZ receptors. The pharmacological actions of melatonin, similar to those listed above for BZs, appear to be mediated primarily by BZ/GABA receptors, although other BZ receptors may be involved. Recently, pharmacological doses of melatonin were found to decrease apomorphine-induced rotations in 6-hydroxydopamine lesioned rats. The main objective of this thesis was to determine the mechanism(s) underlying the antidopaminergic effect of melatonin as well as BZs using the 6-hydroxydopamine lesion model of dopaminergic supersensitivity. It was hypothesized that the antidopaminergic action of BZs and melatonin was due to the ability of these drugs to either enhance GABAergic activity (since GABA can suppress striatal dopaminergic activity) or block cyclic AMP (cAMP) production since dopamine enhances cAMP formation in the striatum. The major findings may be summarized as follows: 1) Clonazepam, a central-type BZ agonist, the melatonin blocked apomorphine-induced turning in lesioned animals; 2) intrastriatal injection of the GABA antagonist, bicuculline, caused a significant reduction in the antidopaminergic effect of clonazepam and melatonin; 3) the peripheral-type BZ antagonist, PK 11195, attenuated the antidopaminergic effect of these drugs but with much less potency than bicuculline; 4) the combination of bicuculline and PK 11195, injected directly into the striatum, completely blocked the antidopaminergic action of clonazepam or melatonin; 5) PK 11195 also blocked BZ-induced inhibition of cAMP production which is involved in striatal dopaminergic function. Therefore, in addition to a GAVAergic mechanism, inhibition of a cAMP pathway may be a secondary mechanism in the antidopaminergic action of clonazepam and melatonin. In studying the effects of BZs on the cAMP pathway, a significant increase in the inhibitory effect of diazepam on adenylate cyclase (AC) activity was observed in striatal membranes from lesioned animals. Further studies indicated that this sensitization to the inhibitory effect of diazepam on AC activity may involve upregulation of BZ receptors as well as enhanced functional coupling of these receptors to inhibitory G proteins. Taken together these findings indicate that the antidopaminergic effect of clonazepam and melatonin in lesioned animals involved at least two distinct mechanisms: 1) a predominant GABAergic action and 2) possibly the suppression of cAMP production in the striatum. Doctor of Philosophy (PhD) |
