U. Scapagnini

Nootropic Drugs Positively Modulate α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid-Sensitive Glutamate Receptors in Neuronal Cultures

Abstract: Micromolar concentrations of piracetam, aniracetam, and oxiracetam enhanced α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐stimulated 45Ca2+ influx in primary cultures of cerebellar granule cells. Nootropic drugs increased the efficacy but not the potency of AMPA and their action persisted in the presence of the voltage‐sensitive calcium channel blocker nifedipine. Potentiation by oxiracetam was specific for AMPA receptor‐mediated signal transduction, as the drug changed neither the stimulation of 45Ca2+ influx by kainate or N‐methyl‐d‐aspartate nor the activation of inositol phospholipid hydrolysis elicited by quisqualate or (±)‐1‐aminocyclopentane‐trans‐1,3‐dicarboxylic acid. Piracetam, aniracetam, and oxiracetam increased the maximal density of the specific binding sites for [3H]AMPA in synaptic membranes from rat cerebral cortex. Taken collectively, these results support the view that nootropic drugs act as positive modulators of AMPA‐sensitive glutamate receptors in neurons.

Ubiquinone protects cultured neurons against spontaneous and excitotoxin-induced degeneration.

Ubiquinone is an endogenous quinone with pharmacological actions mainly related to its antioxidant properties. Here we report that ubiquinone protects cultured cerebellar granule cells against glutamate-induced neurotoxicity. In control cultures at 9 days of maturation in vitro (DIV), a 30-min exposure to 100 μM glutamate induced neuronal degeneration, as reflected by the great percentage (>90%) of cells labeled with propidium iodide 24 h after the exposure. Glutamate-induced neuronal death was dramatically reduced in cultures treated daily with ubiquinone since the second DIV. In these cultures, glutamate failed to induce a “delayed” increase in the influx of 45Ca2+, an established parameter of excitotoxicity. Similarly, repeated addition of ubiquinone attenuated in a concentration-dependent manner the age-dependent degeneration of granule cells that is due to the toxic action of the endogenous glutamate progressively released into the medium. These results suggest that ubiquinone may be a useful drug in the therapy of acute and chronic neurodegenerative diseases related to hyperactivity of excitatory amino acid neurotransmission.

Prolactin induces grooming in the rat: Possible involvement of nigrostriatal dopaminergic system

The possibility that Prolactin-induced grooming involves the nigrostriatal dopaminergic system was studied. Intracerebroventricular injection of rat Prolactin (PRL) in an amount of 10 micrograms induced grooming in male rats, and neostriatal injection of haloperidol (1 microgram/1 microliter) markedly suppressed this effect. Local administration of 6-OHDA in the substantia nigra also abolished the influence of intracerebroventricularly administered PRL. Bilateral injections of PRL (10 micrograms/l microliters) in the neostriatum failed to induce grooming, whereas bilateral injections of peptide into the substantia nigra (1 microgram/0.5 micrograms) elicited the behavioral response. It is probable that PRL induces grooming in the rat by interacting with the nigrostriatal dopaminergic transmission through an action on the cell bodies rather than in presynaptic terminals or at the postsynaptic level of this system.

Behavioral effects of phosphatidylserine in aged rats

The behavioral effects of 5 days of administration of phosphatidylserine (PS) was studied in aged rats. The intraperitoneal (5, 10, and 20 mg/kg) or intracerebroventricular (5, 10, and 20 micrograms/2 microliters) injection of PS liposomes caused a facilitated acquisition of active avoidance behavior as studied in shuttle-box and pole jumping test situations. The retention of active and passive avoidance responses was also improved. No substantial difference between PS-treated and control animals was apparent either in the responsiveness to electrical footshock or in the motor activity tested in an open field. Grooming behavior appeared to be enhanced in rats treated with the highest dose of the substance. Since PS affects both central catecholaminergic and cholinergic transmission, which is known to be impaired in old animals, the possibility that the behavioral effects of PS involve brain dopamine and/or acetylcholine systems is discussed.

Unilateral ovariectomy-induced luteinizing hormone-releasing hormone content changes in the two halves of the mediobasal hypothalamus

The luteinizing hormone-releasing hormone (LHRH) content of the two halves of the mediobasal hypothalamus (MBH) has been studied two weeks after unilateral or bilateral ovariectomy (OVX) in the rat. In control animals, the LHRH content of the right-side MBH was higher than that of the left side. Right-side OVX induced a significant increase in LHRH content on the right-side MBH while left-side OVX was followed by elevated LHRH content on the left-side MBH. In contrast, bilateral OVX induced a significant decrease on the right-side MBH. The observation that unilateral OVX induced increased LHRH content in the ipsilateral half of the MBH to OVX, supports the view that a neural pathway might connect the ovary and the MBH.

Spatial learning potentiates the stimulation of phosphoinositide hydrolysis by excitatory amino acids in rat hippocampal slices

Abstract: Stimulation of phosphoinositide (PI) hydrolysis by excitatory amino acids (glutamate and ibotenate) or nor‐epinephrine was potentiated in hippocampal slices from rats trained in an eight‐arm radial maze, used as a test of spatial learning. No difference in basal or carbamylcho‐line‐stimulated PI hydrolysis was found between control and trained animals. An increased PI response to excitatory amino acids and norepinephrine was not found in hippocampal slices prepared from animals trained in a shock conditioning avoidance test. These results suggest a possible involvement of specific glutamate receptors coupled with PI hydrolysis in the synaptic mechanisms underlying formation and/or storage of spatial memory.

Prevention of compensatory ovarian hypertrophy by local treatment of the ovary with 6-OHDA.

The possible role of a neural mechanism involved in the development of compensatory ovarian hypertrophy has been studied. A new technique, the use of a special plastic capsule, has been developed to allow chronic local treatment of the ovary. Local treatment of one of the ovaries with 6-hydroxydopamine (6-OHDA) resulted in a weight increase in the other ovary. In the unilaterally ovariectomized rat the local application of 6-OHDA on the ovary blocked the development of compensatory ovarian hypertrophy. Local treatment of the ovary with dopamine (DA) did not interfere with the compensatory ovarian growth of the other ovary. Data suggest that intact adrenergic afferent and efferent neural elements of the ovary are required for the development of compensatory ovarian hypertrophy.

Dopamine neurotransmission in the nucleus accumbens may be involved in oxytocin-enhanced grooming behavior of the rat

Intracerebroventricular (ICV) infusion of a low dose of oxytocin enhanced novelty-induced grooming in male rats. The present experiments were undertaken to investigate whether dopamine neurotransmission in the nucleus accumbens is involved in this effect. Bilateral lesions of the nucleus accumbens by microinjections of 6-hydroxydopamine (6-OHDA) totally prevented the enhancement of grooming behavior after subsequent ICV infusion of oxytocin. Furthermore, bilateral injections of the dopamine receptor antagonist, haloperidol, into the nucleus accumbens completely suppressed grooming behavior of rats infused ICV with oxytocin. These results suggest that dopamine neurotransmission in the nucleus accumbens is involved in the behavioral response enhanced by the peptide.

The analgesic activity of calcitonin and the central serotonergic system

The effect of peripherally administered cyproheptadine or reserpine and the administration of 5,7-dihydroxytryptamine (5,7-DHT) in the nucleus raphe dorsalis on the analgesic activity of salmon calcitonin (sCT) injected into the lateral ventricle were investigated in male rats. Cyproheptadine or reserpine, given respectively 30 min or 24 h before the peptide, completely abolished the analgesic activity at all the times studied. However, when reserpine was given before the peptide it increased the effect of sCT at 30 (P less than 0.01), 60 (P less than 0.001), 120 (P less than 0.01) and 180 (P less than 0.01) min. 5,7-DHT injected in the nucleus raphe dorsalis 15 days before the peptide led to complete abolition of the analgesic activity. If neurotoxin was injected 4 days before sCT, the effect of the peptide was significant (P less than 0.05) only at 60 min. The results obtained confirm that the analgesic activity of sCT may involve central serotonergic pathway(s), and that the midbrain raphe nuclei 5-HT content is an important focus for this activity.

Short-term endogenous hyperprolactinaemia and sexual behavior of male rats

Abstract Sexual behavior of male rats was studied in a short-term endogenous hyperprolactinaemic condition. Hyperprolactinaemia was induced by grafting two pituitary glands under the kidney capsule. Five days after operation homografted animals, as compared to the sham operated, displayed an enhancement of several parameters of copulatory behavior. In particular, significant reductions in the mount and intromission latencies were observed. The stimulation of sexual behavior of male rats by short-term hyperprolactinaemia might be due to an enhancement of dopaminergic transmission in specific brain areas by prolactin (PRL).