Carmela Valerio

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.

Effects of cytidine-diphosphocholine on acetylcholine-mediated behaviors in the rat.

The phosphatidylcholine precursor, cytidine-diphosphocholine (CDP-choline), was injected intraperitoneally (IP) at the dose of 10 or 20 mg/kg/day for 20 days to 24-month-old male rats of the Sprague-Dawley strain that showed cognitive and motor deficits. The drug was also injected in animals with behavioral alterations induced pharmacologically with a single injection of the cholinergic receptor antagonist, scopolamine, with prenatal exposure to methylazoxymethanol (MAM rats), or with bilateral injections of kainic acid into the nucleus basalis magnocellularis (NBM). Learning and memory capacity of the animals, studied with tests of active and passive avoidance behavior, was improved after treatment with CDP-choline in all experimental groups. An improvement in motor performance and coordination in the rotorod and open field tests was also observed in aged rats. These results indicate that this drug affects central mechanisms involved in cognitive behaviors, probably through a cholinergic action.

Behavioral effects of amylin injected intracerebroventricularly in the rat

Amylin is a peptide of pancreatic origin that has been reported to possess high-affinity binding sites in the brain and to affect central dopaminergic and serotonergic neurotransmission. Administered ICV the peptide induced a dose-dependent decrease of locomotor activity without affecting grooming and sniffing. At a dose of 5 micrograms/ rat, it antagonized the hypermotility and stereotypies induced by s.c. injection of amphetamine (2 mg/kg) or of the dopamine receptor agonist, apomorphine (250 mg/kg). Amylin did not change significantly the effect of haloperidol (0.5 mg/kg, s.c.) on locomotor activity, grooming, and sniffing. Moreover, the peptide did not modify the locomotor behavior of animals injected with the 5-HT2 antagonist, ritanserin (2 mg/kg, s.c.). These results suggest that amylin may exert motor effects, probably by interfering with central dopaminergic neurotransmission.

Effects of calcitonin gene-related peptide on extrapyramidal motor system

The effects of central administration of calcitonin gene-related peptide (CGRP, 1 or 100 ng/rat) on behavioral and biochemical parameters related to the extrapyramidal motor system were investigated in male rats. The peptide-induced catalepsy occurred only at the dose of 100 ng/rat and hypomotility at both doses used. Calcitonin gene-related peptide increased haloperidol-induced catalepsy and decreased apomorphine-induced hypermotility at the doses of 1 and 100 ng/rat. Although these behaviors are related to dopamine, no significant change of striatal DA or DOPAC concentration were observed after central administration of the peptide. Other neurotransmitters may be directly or indirectly involved in these behavioral effects of CGRP.

Effects of RGH 2202 on cognitive and motor behavior of the rat

The behavioral activity of the thyrotropin-releasing hormone (TRH) analogue, L-6-ketopiperidine-2-carbonyl-leucyl-L-prolinamide (RGH 2202), has been studied in animal models of central neurotransmission disruption. In 24-month-old rats, repeated administration of the peptide (5 or 10 mg/kg/day, injected IP for 20 days) was followed by a facilitated acquisition of active avoidance behavior in the shuttle-box test and retention of passive avoidance reaction in a step-through passive avoidance task. Also, ambulation in an open field was increased and motor performance and co-ordination in the rotorod test was facilitated by the treatment. Scopolamine-induced amnesia was reverted by RGH 2202 in adult rats tested both in active and passive avoidance tasks. Cognitive deficits induced in rats by prenatal manipulation with methylazoxymethanol (MAM) were reduced in adulthood by repeated administration with RGH 2202. These results indicate that the TRH-analogue, RGH 2202 may improve cognitive and motor disturbances in aging or induced by central neurotransmission disruption. It is possible that the peptide is functioning, at least in part, by intervening with the central cholinergic neurotransmission.

Effects of vinburnine on experimental models of learning and memory impairments

Retrograde amnesia can be induced experimentally in mice by injecting them with scopolamine (3 mg/kg, IP) or by inducing seizures with pentylenetetrazol (50 mg/kg, IP), and in rats by subjecting them to hypobaric hypoxia (at a barometric pressure of 300 mmHg for 3 min). We have studied the effects of vinburnine (VNB) in these amnesic states compared to vincamine (VNC) and nicergoline (NCG), in order to assess its activity on drug-induced learning and memory impairments. Vinburnine reduced the disrupting effect of both scopolamine and pentylenetetrazol-induced seizures on the retention of a step-through passive avoidance behavior in mice and on the acquisition of shuttle-box active avoidance behavior in rats. This effect was dose-related up to 20 mg/kg, the peak effect dose after IP administration, and more pronounced than that of VNC and NCG in some tests. These results indicate that VNB influences learning and memory processes disrupted by a pharmacological manipulation. In particular, as scopolamine acts as anticholinergic drug, it is possible that VNB mechanism of action includes also a stimulation of acetylcholine neurotransmission.

Behavioral and neurochemical alterations induced by reversible conductive hearing loss in aged male rats

Eighteen months old male rats of the Sprague-Dawley strain were subjected to a reversible conductive hearing loss (HL) or a sham operation. A series of behavioral tests performed 3 months after surgery, revealed a sustained deficit in learning and memory capacity and a marked depressive attitude of rats with HL. At this time, a group of these animals were allowed to recover from HL for 1 month and were again tested behaviorally compared to those with persistent auditory deficit. A better performance at the active and passive avoidance tests and normal responsiveness to the despair test was found in animals with recovered hearing capacity as compared to those with persistent HL. A biochemical analysis revealed a decrease of dopamine and homovanillic acid content and of choline-acetyltransferase and acetylcholinesterase activity in the striatum and hippocampus of animals with persistent HL as compared to those with recovered auditory deficit. These data suggest that persistent auditory deafferentation affects cognitive mechanism in old rats in a reversible manner.

Memory deficits of aged male rats can be improved by pyrimidine nucleosides and n-acetyl-glutamine

The pyrimidine nucleosides uridine (URI) and cytidine (CYT), alone or associated with n-acetyl-glutamine (NAG), were injected acutely or subchronically to aged (26 months old) male rats of the Sprague-Dawley strain. Learning and memory abilities of the animals were studied with tests of avoidance behavior. The acquisition of active avoidance behavior was studied with the shuttle-box test. A step-through type of passive avoidance task was used to examine the retention of passive avoidance responses. The acquisition of the active avoidance behavior and the retention of the passive avoidance response were reduced in aged animals as compared with those of young animals. Neither the acute treatment of old rats with URI and CYT alone nor that associated with NAG exerted any effect on the behavioral tests. In contrast, the subchronic treatment with URI and CYT was followed by a facilitation of acquisition of active avoidance behavior in the shuttle box and of retention of passive avoidance responses in the dark box. A more potent effect on the acquisition of the shuttle-box behavior and on the retention of passive avoidance reaction was found in animals treated subchronically with the pyrimidine nucleosides associated with NAG. These effects may be related to the role of pyrimidines in the synthesis of ribonucleic acid, which is indispensable for learning and memory processes.

Acetylcarnitine reduces the immobility of rats in a despair test (constrained swim).

Male rats forced to swim in a cylinder adopted an immobile posture. Immobility was reduced by acetylcarnitine (5, 10, and 20 mg/kg) and by antidepressant drugs, such as desipramine and iproniazid, injected 24, 5, and, again, 1 h prior to behavioral testing. Acetylcarnitine also potentiated the anti-immobility effect of antidepressant drugs in the despair test. Chronic (10 days) treatment with acetylcarnitine mimicked the effect found after acute administration. It is possible that the action of the acetylcarnitine on the despair test is indicative of an antidepressant activity of this drug that is dependent on a change in the sensitivity of monoamine receptors in the brain.

Effects of calcitonin on morphine tolerance and withdrawal syndrome in morphine physically dependent rats

We investigated the effect of acute or chronic peripheral administration of [Asu1.7]eel-calcitonin on the development of tolerance to the analgesic effect of morphine and on the naloxone-precipitated withdrawal syndrome in morphine-dependent rats. Neither the analgesic effect of acute morphine nor the development of tolerance to the antinociceptive effect of this drug was modified by calcitonin. However, the chronic but not the acute administration of calcitonin attenuated some signs and symptoms of morphine withdrawal.