Molecular convergence of presynaptic inhibition and presynaptic facilitation on common substrate proteins of individual sensory neurons of Aplysia.
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Biomedical subjects
Publications and source records attributed to A Volterra.
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Chronic administration of different antidepressant drugs reduced the number of [3H]imipramine [( 3H]IMI) binding sites in rat cerebral cortex. In the same experimental conditions, fluvoxamine and dothiepin, as well as desmethylimipramine, induced an increase in the maximal velocity of high affinity serotonin (5HT) uptake in cortical slices, whereas citalopram and viloxazine were ineffective in this regard. Our results indicate that even if 5HT uptake and [3H]IMI binding sites are located on the same nerve terminals, they are differently modulated. Increased Vmax of the 5HT uptake process could be due to a rebound phenomenon after withdrawal from drugs that acutely inhibit 5HT uptake. The effect on [3H]IMI sites might be explained through either the agonist properties of the drugs towards these sites or the involvement of mechanisms still unknown.
The ontogenetic pattern of multiple opioid binding sites in rat brain from birth until weaning has been investigated. [3H]-dihydromorphine ([3H]-DHM)3 [3H]-D-Ala2-D-Leu5-enkephalin ([3H]-DADLE) and [3H]-dynorphin A (1-8) ([3H]-DYN) as markers of mu (mu), delta (delta) and Kappa (kappa) sites were utilized respectively. The analysis of the kinetic parameters of [3H]-DHM binding shows that, at birth, mu sites possess an affinity similar to that of adult animals, and a density of 50%, which reaches 80% of the adult value at day 4. On the contrary, [3H]-DADLE binding in the first post-natal days shows low affinity and low density and delta-sites do not reach values comparable to the adult ones until the second week of life. The kinetic parameters of [3H]-DYN binding are almost undetectable during the preweanling period, due to the very low density of kappa sites at this stage of life. Displacement studies with mu-, delta- and kappa-selective ligands show that the Ki values on [3H]-DHM binding sites were similar in 4 day old and adult animals for all the tested compounds, whereas Ki values on [3H]-DADLE and [3H]-DYN binding sites reflected an immaturity of delta and kappa receptors. In conclusion, our data suggest that multiple opioid receptors follow different ontogenetic patterns. In the first stages of life only mu receptors are almost mature and possibly mediate endogenous opioid actions and exogenous opiate pharmaco-toxicological effects.
beta-Casomorphins (beta-CMs) are peptidic fragments of bovine beta-casein with potent opioid activity. In view of a possible physiological meaning of these milk-derived compounds, we have studied the affinity of some natural beta-CMs and some semisynthetic analogues for mu-, delta- and kappa-brain opioid receptors in newborn and adult rat. Moreover we have investigated whether a chronic treatment with the potent analogue D-Ala2-beta-CM-4-NH2 during the suckling period could affect mu and delta opioid receptor function. Our findings demonstrate that beta-CMs are mu-oriented compounds both in adult and in newborn rat brain. They display the same mu-affinity in newborn as well as in adult animals, however delta and kappa-affinities appear different, probably due to the lower degree of maturation of these two receptors in the first days of life. A prolonged treatment with D-Ala2-beta-CM-4-NH2 during the preweanling period is able to induce a delay in the ontogenetic increase of delta-receptor affinity, whereas it affects neither the affinity nor the density of mu-receptors. This effect could be related to a general action of opioids on cerebral maturative processes; moreover we point out that a beta-CMs analogue, given orally to newborn animals, can induce modifications at central level, suggesting thus the hypothesis that beta-CMs could be a biologically active peptide in the first stages of life.
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The decrease in the Bmax value of 3H-dihydroalprenolol (3H-DHA) binding to cortical membranes of rat brain induced by long-term administration of desipramine (DMI) was prevented by concomitant treatment with parachlorophenylalanine (pCPA). Acute administration of DMI significantly decreased locomotor activity in saline- and (pCPA)-pretreated rats. DMI-induced inhibition of locomotor activity was abolished in (pCPA)-pretreated rats chronically treated with DMI. Conversely, in pCPA-pretreated animals, acute DMI could still significantly decrease the locomotion of chronically DMI-treated rats. The data presented indicate that an intact serotoninergic system is required to enable antidepressant drugs to induce biochemical and behavioral changes following their chronic administration.
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C57 BL/6J (C57) mice display a particular pattern of responses following morphine administration, such as a rapid development of tolerance to the pharmacological action of the opiate and an increase in locomotor activity after a single injection of the drug. We have measured met-enkephalin content and the responsiveness of different opiate receptors after repeated administration of morphine and naloxone. Prolonged morphine administration changes neither met-enkephalin levels, nor the density of the opiate receptors in mice brain. In contrast repeated administration of the opiate antagonist naloxone, produced a marked increase in the number of 3H- DHM and 3H- DADLE binding sites in striatum and brainstem without modifying met-enkephalin concentrations. Behavioral studies have indicated that the morphine-induced increase in locomotor activity is enhanced in naloxone pretreated mice, thus suggesting a possible correlation between the behavioral response to morphine in C57 mice and the higher number of opiate receptors in the striatum.
A long term treatment with the delta-selective opiate antagonist NN-bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH (ICI 154129) produces an increase in the number of delta-opiate binding sites, whereas the same treatment with the non selective opiate antagonist naloxone results in an enhancement of both mu- and delta-binding sites. This biochemical effect in naloxone-pretreated mice is paralleled by a more pronounced increase in locomotor activity induced by a challenge dose of morphine. In contrast, no difference in the effect of morphine was seen in ICI 154129-pretreated mice with respect to control. These data suggest that the locomotor response to morphine in C57 mice is not mediated through delta-opiate receptors.
Biochemical and biophysical studies on Aplysia sensory neurons indicate that inhibitory responses to the molluscan peptide FMRFamide are mediated by lipoxygenase metabolites of arachidonic acid. These compounds are a new class of second messengers in neurons.
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