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1. Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene.

Author

Wang AL, Fazari B, Chao OY, Nikolaus S, Trossbach SV, Korth C, Sialana FJ, Lubec G, Huston JP, Mattern C, and de Souza Silva MA

Subjects
Administration, Intranasal, Animals, Disease Models, Animal, Dopamine administration & dosage, Male, Nerve Tissue Proteins genetics, Rats, Rats, Sprague-Dawley, Rats, Transgenic, Attention drug effects, Behavior, Animal drug effects, Cognitive Dysfunction drug therapy, Cognitive Dysfunction genetics, Cognitive Dysfunction metabolism, Dopamine deficiency, Dopamine pharmacology, Memory, Long-Term drug effects, Memory, Short-Term drug effects, Nerve Tissue Proteins metabolism
Abstract

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention., Results: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala., Conclusions: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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2. Intranasal application of dopamine reduces activity and improves attention in Naples High Excitability rats that feature the mesocortical variant of ADHD.

Author

Ruocco LA, de Souza Silva MA, Topic B, Mattern C, Huston JP, and Sadile AG

Subjects
Administration, Intranasal, Animals, Attention Deficit Disorder with Hyperactivity diagnosis, Disease Models, Animal, Male, Maze Learning drug effects, Random Allocation, Rats, Rats, Inbred Strains, Attention drug effects, Attention Deficit Disorder with Hyperactivity drug therapy, Dopamine administration & dosage, Dopamine pharmacology, Hyperkinesis drug therapy, Motor Activity drug effects
Abstract

Based on findings of a profound action of intranasally applied dopamine (DA) on dopamine release in the striatum, we examined the possibility that intranasal application of DA would influence indices of attention and activity in juvenile male rats of the Naples High Excitability line. This rat model features the main aspects of Attention Deficit/Hyperactivity Disorder (ADHD). Juvenile NHE rats received an intranasal application of either DA (0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg) or vehicle into both nostrils daily for 15 days. On day 14, 1 h after treatment, they were tested in the Làt maze, and one day later, in the eight arm radial maze. Activity in the Làt maze: The highest dose of DA (0.3 mg/kg) decreased horizontal (HA) and vertical (VA) activity during the first 10 min of the test. No effect was found for rearing duration (RD), which indexes non-selective attention (NSA). Activity in the radial maze: No treatment effects were found for HA and VA components, and for RD. Attention indices: The intermediate dose of DA (0.15 mg/kg) significantly improved the number of arms visited before the first repetitive arm entry in the radial maze, an index of selective spatial attention (SSA). In conclusion, intranasal application of DA reduced hyperactivity at the highest dose used, whereas the intermediate dose improved attention in an animal model of ADHD. These results suggest the potential of employing intranasal DA for therapeutic purposes.

Published
2009
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4. Intranasal Application of Dopamine Reduces Activity and Improves Attention in Naples High Excitability Rats that Feature the Mesocortical Variant of ADHD

Author

RUOCCO L. A., MARIA A., DE SOUZA SILVA M., BIANCATOPIC A., MATTERN C., HUSTON J. P., SADILE, Adolfo, Ruocco, L. A., Maria, A., DE SOUZA SILVA, M., Biancatopic, A., Mattern, C., Huston, J. P., and Sadile, Adolfo

Subjects
Male, medicine.medical_specialty, Intranasal route, Radial maze, Dopamine, Rat model, Striatum, Hyperkinesis, Motor Activity, Random Allocation, Animal model, Internal medicine, NHE rat, medicine, Animals, ADHD, Pharmacology (medical), Attention, Maze Learning, Biological Psychiatry, Administration, Intranasal, Pharmacology, Rats, Inbred Strains, Làt maze, Rats, Psychiatry and Mental health, Disease Models, Animal, Endocrinology, Neurology, Attention Deficit Disorder with Hyperactivity, Anesthesia, Attention deficit, Nasal administration, Olton maze, Neurology (clinical), Psychology, After treatment, medicine.drug
Abstract

Based on findings of a profound action of intranasally applied dopamine (DA) on dopamine release in the striatum, we examined the possibility that intranasal application of DA would influence indices of attention and activity in juvenile male rats of the Naples High Excitability line. This rat model features the main aspects of Attention Deficit/Hyperactivity Disorder (ADHD). Juvenile NHE rats received an intranasal application of either DA (0.075 mg/kg, 0.15 mg/kg and 0.3 mg/kg) or vehicle into both nostrils daily for 15 days. On day 14, 1 h after treatment, they were tested in the Lat maze, and one day later, in the eight arm radial maze. Activity in the Lat maze: The highest dose of DA (0.3 mg/kg) decreased horizontal (HA) and vertical (VA) activity during the first 10 min of the test. No effect was found for rearing duration (RD), which indexes non-selective attention (NSA). Activity in the radial maze: No treatment effects were found for HA and VA components, and for RD. Attention indices: The intermediate dose of DA (0.15 mg/kg) significantly improved the number of arms visited before the first repetitive arm entry in the radial maze, an index of selective spatial attention (SSA). In conclusion, intranasal application of DA reduced hyperactivity at the highest dose used, whereas the intermediate dose improved attention in an animal model of ADHD. These results suggest the potential of employing intranasal DA for therapeutic purposes.

Published
2009

5. Prepuberal intranasal dopamine treatment in an animal model of ADHD ameliorates deficient spatial attention, working memory, amino acid transmitters and synaptic markers in prefrontal cortex, ventral and dorsal striatum

Author

Joseph P. Huston, L.A. Ruocco, Claudio Arra, Placido Illiano, A. Scorziello, A.G. Sadile, Angela Tino, C Treno, Maria Nieddu, Susanne Nikolaus, M.A. de Souza Silva, Cristina Pagano, Claudia Mattern, U.A. Gironi Carnevale, Gianpiero Boatto, L. A., Ruocco, C., Treno, U. A., Gironi Carnevale, C., Arra, C., Mattern, J. P., Huston, M. A., de Souza Silva, S., Nikolau, Scorziello, Antonella, M., Nieddu, G., Boatto, P., Illiano, C., Pagano, A., Tino, A. G., Sadile, Ruocco, L. A., Treno, C., Gironi Carnevale, U. A., Arra, C., Mattern, C., Huston, J. P., de Souza Silva, M. A., Nikolaus, S., Scorziello, A., Nieddu, M., Boatto, G., Illiano, P., Pagano, C., Tino, A., and Sadile, Adolfo

Subjects
Male, medicine.medical_specialty, Intranasal dopamine, Dopamine, Dopamine Agents, Clinical Biochemistry, Substantia nigra, Striatum, L-Aspartate, Biochemistry, Rats, Sprague-Dawley, Internal medicine, medicine, Animals, Humans, ADHD, Attention, Sexual Maturation, Prefrontal cortex, Administration, Intranasal, Dopamine transporter, Dose-Response Relationship, Drug, Tyrosine hydroxylase, biology, Chemistry, Organic Chemistry, Working memory, L-Glutamate, NMDA receptor, Rats, Ventral tegmental area, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, nervous system, Attention Deficit Disorder with Hyperactivity, Anesthesia, Ventral Striatum, biology.protein, medicine.drug
Abstract

Intranasal application of dopamine (IN-DA) has been shown to increase motor activity and to release DA in the ventral (VS) and dorsal striatum (DS) of rats. The aim of the present study was to assess the effects of IN-DA treatment on parameters of DA and excitatory amino acid (EEA) function in prepuberal rats of the Naples High Excitability line (NHE), an animal model for attention-deficit hyperactivity disorder and normal random-bred (NRB) controls. Methods: NHE and NRB rats were daily administered INDA (0.075, 0.15, 0.30 mg/kg) or vehicle for 15 days from postnatal day 28 to 42 and subsequently tested in the Làt maze and in the eight arm radial Olton maze. Soluble Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation and membrane-trapped L-Glutamate (L-Glu) and L-Aspartate (L-Asp) levels as well as NMDAR1 subunit protein levels were determined post mortem in IN-DA- and vehicletreated NHE and NRB rats in prefrontal cortex (PFc), DS and VS. Moreover DA transporter (DAT) protein and tyrosine hydroxylase (TH) levels were assessed in PFc, DS, VS and mesencephalon (MES) and in ventral tegmental area and substantia nigra, respectively. Results: In NHE rats, IN-DA (0.30mg/kg) decreased horizontal activity and increased non-selective attention relative to vehicle, whereas the lower dose (0.13 mg/kg) increased selective spatial attention. In NHE rats, basal levels of soluble EEAs were reduced in PFc and DS relative to NRB controls, while membrane-bound EEAs were elevated. Moreover, basal NMDAR1 subunit protein levels were increased in PFc, DS and VS relative to NRB controls. Also DAT protein levels were elevated in PFc, VS and MES relative to NRB controls. IN-DA led to a number of changes of EAA, NMDRR1 subunit protein, TH and DAT protein levels in PFc, DS, VS, MES and VTA, in both NHE and NRB rats with significant differences between strains. Conclusions: Our findings indicate that the NHE rat model of ADHD may be characterized by (1) prefrontal and striatal DAT hyperfunction, indicative of DA hyperactivty, and (2) prefrontal and striatal NMDA receptor hyperfunction indicative of net EAA hyperactivty. IN-DA had ameliorative effects on activity level, attention, and working memory, which are likely to be associated with DA action at inhibitory D2 autoreceptors, leading to a reduction of striatal DA hyperactivity and, possibly, DA action striatal EAA levels, leading to a reduction of striatal EAA hyperfunction (with persistence of prefrontal EAA hyperfunction). Previous studies on IN-DA treatment in rodents have indicated antidepressant, anxiolytic and anti-parkinsonian effects in relation to enhanced central dopaminergic activity. Our present results strengthen the prospects of potential therapeutic applications of intranasal application of dopamine by indicating also an enhancement of selective attention and working memory in a deficit model.

Published
2014
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