Neuropharmacology
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The present study investigated the effect of acute and repeated administrations of amphetamine (AMPH) on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the two main cytoarchitectonic subterritories of the medial prefrontal cortex (mPFC) (anterior cingulate and dorsocaudal prelimbic cortices vs ventral prelimbic and rostral infralimbic cortices). Both the acute locomotor effects of AMPH and the expression of behavioral sensitization following its repeated administration were also simultaneously assessed. The repeated, intermittent administration of AMPH over five consecutive days led to a significant sensitized locomotor response to a subsequent challenge that occurred following a 48-h withdrawal period. ⋯ In naïve animals, AMPH produced a significant decrease in DA levels in both the ventral and dorsal subregions of the mPFC. However, the inverse relationship was observed in animals that had developed sensitization: dialysate DA levels in response to AMPH remained significantly decreased in the dorsal mPFC, whereas DA went back to baseline levels in the ventral mPFC. Given that a critical concentration of DA is required for normal function of the mPFC, our results suggest that AMPH-induced changes in DA levels in different subregions of the mPFC are critical for both the acute effects of the drug and the expression of behavioral sensitization to its repeated administration by producing either less or more selectivity or sharpening of stimuli to cortico-cortical dendrites and subcortical synaptic afferents to the pyramidal cells located in the dorso-ventral axis of the mPFC.
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Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects, or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D) agonist drugs. CP122,288, a conformationally restricted analogue of sumatriptan that is a potent inhibitor of neurogenic plasma protein extravasation (PPE), was ineffective at inhibiting CGRP release at a single low dose; and is also ineffective as an acute anti-migraine compound. ⋯ In comparison CGRP release was inhibited after a dose of 100 microg/kg 4991W93 from 64+/-6 to 36+/-3 pmol/l (n=5). Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT(1B/1D) agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action. Taken with the clinical results, these data emphasise the importance of CGRP release in migraine, and suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.
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The inwardly rectifying potassium channel IRK1, a member of the Kir 2.0 family, is inhibited by m1 muscarinic receptor stimulation. In this study the mechanism of action underlying the muscarinic response was investigated by identification of the subtype of heterotrimeric G-protein involved in transduction of the signal. tsA201 cells were simultaneously transfected with cDNAs encoding IRK1, m1 and the Galpha subunit of either G(q), G(12) or G(13). The whole-cell patch-clamp technique was used to study the effects of G-protein transfection. ⋯ Transfection with Galpha(q) or Galpha(12) cDNAs greatly increased the levels of G-protein expression in both cell populations. G-protein expression did not interfere with m1 muscarinic receptor expression levels. These findings suggest that the m1 muscarinic-receptor-induced inhibition of IRK1 is mediated by the heterotrimeric G-protein, Galpha(q), in tsA cells.