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G Grigoryan

Publications and source records attributed to G Grigoryan.

5 recordsLinked to original sources
PubMed1997

Latent inhibition: the nucleus accumbens connection revisited.

It has been proposed that dopaminergic transmission in the nucleus accumbens plays a key role in regulating latent inhibition (LI), i.e. the retardation of conditioning that occurs if a to-be-conditioned stimulus is first presented a number of times ('preexposure') without other consequence. New evidence in support of this hypothesis is presented or reviewed here, showing that: (1) intra-accumbens injection of haloperidol at the time of conditioning potentiates LI; (2) destruction of dopaminergic terminals in the nucleus accumbens potentiates LI; (3) intra-accumbens haloperidol reverses the blockade of LI caused by systemic nicotine; (4) intra-accumbens haloperidol reverses the blockade of LI caused by systemic amphetamine; (5) after a single systemic injection of amphetamine (insufficient on its own to block LI), a subsequent intra-accumbens injection of amphetamine at the time of conditioning blocks LI; and (6) intra-accumbens (like systemic) amphetamine administered 15 min before conditioning, without prior systemic amphetamine, failed to block LI. The difference between the effects on LI of one and two administrations of amphetamine, respectively, is interpreted in terms of the need for sensitisation of the response to amphetamine, with the result that the response to the second administration includes a component of impulse-dependent dopamine release in the nucleus accumbens that is otherwise lacking. Data from dialysis experiments suggest that such impulse-dependent accumbens dopamine release also occurs at relatively long delays after a single systemic administration of amphetamine. It was accordingly predicted, and found, that, although LI is intact 15 min after an i.p. injection (confirming previous results), it is abolished at 90 min after the injection of amphetamine. This finding is consistent with the effects of amphetamine in human subjects, in whom LI is blocked 90 min after a single oral administration. Overall, these results strengthen the case that the blockade of LI by elevated, and potentiation of LI by decreased, dopaminergic transmission are both due specifically to actions in the nucleus accumbens; and also add to the similarities between LI studied in animal and human subjects, respectively.

Animals↗
PubMed1996

6-OHDA lesions of the nucleus accumbens accentuate memory deficits in animals with lesions to the forebrain cholinergic projection system: effects of nicotine administration on learning and memory in the water maze.

The separate and combined effects of lesions to the forebrain cholinergic projections system (FCPS) and to dopamine (DA) terminals in the nucleus accumbens (n.acc) were assessed in two water maze tasks: (1) standard acquisition using two trials/day with a 10 min intertrial interval (ITI) for 15 days with the platform in the same position and (2) a working memory task requiring matching to a platform position located by chance on Trial 1, with four trials/day separated by a 30-s ITI and a different platform position on each of 4 days. Effects of nicotine (0.1 mg/kg) were also examined in animals with FCPS, n.acc, and combined lesions in order to determine whether facilatory effects of nicotine in FCPS lesioned animals are mediated by dopamine release in the n.acc. The FCPS and combined lesion groups were impaired in both tasks, but the combined lesion group was substantially worse than animals with FCPS lesions alone. The n.acc lesion group did not differ from controls. Nicotine did not affect acquisition in either the FCPS or combined lesion group, but impaired learning in animals with n.acc lesions. In the working memory task nicotine exerted a nonspecific facilatory effect in the FCPS and combined lesion groups, by reducing latency to find the platform both on the first trial and on the subsequent matching to position trials. Choline acetyltransferase (ChAT) activity was reduced in hippocampus and cortex in the FCPS lesion group, whereas DA levels in n.acc were increased. Conversely, in the n.acc lesion group accumbal DA levels were reduced, while cortical and hippocampal ChAT activity was increased, suggesting that reciprocal changes were induced by the separate lesions. However the combined lesion group showed mixed and more widespread effects; ChAT activity was unaltered in cortex and substantially reduced in hippocampus, and DA levels were reduced in both n.acc and caudate. The results indicate that combined FCPS and n.acc lesions impair spatial learning and working memory far more severely than FCPS lesions alone, although this does not reflect simple additive reductions in DA and ChAT activity. Nicotine improved spatial search strategy, and effect detected in the in the working memory task with daily changes in platform position, rather than in the standard acquistion task, but did not appear specifically to improve working memory. Since the facilitatory effect of nicotine was seen in both FCPS and combined lesion groups, the findings suggest that nicotine-induced improvements do not depend on accumbal DA release.

Animals↗
PubMed1996

RJR-2403: a nicotinic agonist with CNS selectivity II. In vivo characterization.

We have evaluated the physiological and behavioral effects of the CNS-selective nicotinic agonist (E)-N-methyl-4-(3-pyridinyl) -3-butene-1-amine (RJR-2403) using a number of different methods, including 1) reversal of pharmacologically induced amnesia in a step-through passive avoidance paradigm, 2) radial arm maze performance in rats with chemically induced brain lesions, 3) changes in HR and blood pressure in rats and 4) changes in body temperature, Y-maze activity, acoustic startle response and respiration in mice. Our results indicate that RJR-2403 is equal to or better than nicotine on measures of CNS function and cognitive enhancement. Specifically, RJR-2403 significantly improved passive avoidance retention after scopolamine-induced amnesia and enhanced both working and reference memory in rats with ibotenic acid lesions of the forebrain cholinergic projection system in an 8-arm radial maze paradigm. By comparison, RJR-2403 was 15 to 30-fold less potent than nicotine in decreasing body temperature, respiration, Y-maze rears and crosses and acoustic startle response. RJR-2403 also demonstrated greatly reduced cardiovascular effects. RJR-2403 was approximately 10-fold less potent than nicotine in increasing HR and 20-fold less potent in increasing blood pressure. These results are consistent with in vitro data indicating this compound's high selectivity for CNS nicotinic ACh receptor subtypes relative to peripheral ganglionic and muscle-type nicotinic ACh receptors. Therefore, RJR-2403 may be a valuable tool for understanding the central and peripheral pharmacology of nicotinic cholinergic systems as well as a potential lead compound for the development of nicotinic therapeutics to treat neurological diseases where cholinergic neurotransmission has been compromised.

Animals↗
PubMedDate not supplied

Conditionally immortalized, multipotential and multifunctional neural stem cell lines as an approach to clinical transplantation.

Experiments are described using rats with two kinds of brain damage and consequent cognitive deficit (in the Morris water maze, three-door runway, and radial maze): 1) ischemic damage to the CA1 hippocampal cell field after four-vessel occlusion (4VO), and 2) damage to the forebrain cholinergic projection system by local injection of excitotoxins to the nuclei of origin or prolonged ethanol administration. Cell suspension grafts derived from primary fetal brain tissue display a stringent requirement for homotypical cell replacement in the 4VO model: cells from the embryonic day (E)18-19 CA1 hippocampal subfield, but not from CA3 or dentate gyrus or from E16 basal forebrain (cholinergic rich) led to recovery of cognitive function. After damage to the cholinergic system, conversely, recovery of function was seen with cell suspension grafts from E16 basal forebrain or cholinergic-rich E14 ventral mesencephalon, but not with implants of hippocampal tissue. These two models therefore provided a test of multifunctionality for a clonal line of conditionally immortalized neural stem cells, MHP36, derived from the E14 "immortomouse" hippocampal anlage. Implanted above the damaged CA1 cell field in 4VO-treated adult rats, these cells (multipotential in vitro) migrated to the damaged area, reconstituted the gross morphology of the CA1 pyramidal layer, took up both neuronal and glial phenotypes, and gave rise to cognitive recovery. Similar recovery of function and restoration of species-typical morphology was observed when MHP36 cells were implanted into marmosets with excitotoxic CAI damage. MHP36 implants led to recovery of cognitive function also in two experiments with rats with excitotoxic damage to the cholinergic system damage, either unilaterally in the nucleus basalis or bilaterally in both the nucleus basalis and the medial septal area. Thus, MHP36 cells are both multipotent (able to take up multiple cellular phenotypes) and multifunctional (able to repair diverse types of brain damage).

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