Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase... more Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase in dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios and a reduction of 3-methoxytyramine (3-MT)/DA ratio in the caudatus putamen (CP) and nucleus accumbens septi (NAS). These effects were already evident after 30 min stress in the NAS, while in the CP 120 min were needed in order to show the effects of stress. Immobilization did not produce any effects on dopaminergic metabolism in the frontal cortex (FC) of the C57 strain either after 30 or after 120 min stress while in mice of the DBA strain a time-dependent effect of stress on the HVA/DA ratio was evident. When B6D2F1 hybrids were considered, the effects produced by 120 min immobilization in the CP and the NAS paralleled those observed in parental strains, while in the FC 120 min stress induced the same increase of HVA observed in DBA mice, thus suggesting that the pattern of response in the FC that characterizes the DBA strain may be inherited through a dominant pattern of inheritance.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Increasing evidence points to a major involvement of cortical areas in addictive mechanisms. Nora... more Increasing evidence points to a major involvement of cortical areas in addictive mechanisms. Noradrenergic transmission in the medial prefrontal cortex (mpFC) has been shown to affect the motor effects of amphetamine, although there is no evidence of its involvement in the rewarding effects of this psychostimulant. The present experiments were aimed at investigating the possibility of a selective involvement of prefrontal cortical norepinephrine (NE) in the rewarding-reinforcing effects of amphetamine. To do so, we evaluated the effects of mpFC NE selective depletion in mice of C57BL/6J inbred strain, a background commonly used in molecular approaches that is known to be highly susceptible to the rewarding effects of the psychostimulant. In a first set of experiments, we demonstrated the absence of amphetamine-induced conditioned place preference in mice bearing prefrontal NE depletion. In a second series of experiments, we demonstrated that the same lesion dramatically reduced amph...
We investigated the effects of post-training administration of dopamine D1 receptor antagonist SC... more We investigated the effects of post-training administration of dopamine D1 receptor antagonist SCH 23390 and β-adrenergic receptor antagonist Propranolol on memory retention of an object sampled in a state of positive emotional arousal. Saline-treated mice trained and tested under high emotional/motivational arousal (High) showed discrimination of a novel object both 24 and 96 h post-training. Instead, mice trained and tested under low motivational arousal (Low) were unable to discriminate the novel object 96 h post-training. Both a high (2 mg/kg) and a low (1 mg/kg) dose of Propranolol reduced object discrimination in High mice tested 24 h post-training, whereas neither dose was effective in Low mice. A high dose of SCH 23390 (0.025 mg/kg) reduced discrimination of the novel object in High mice tested both 24 and 96 h post-training, whereas a low dose of the D1 antagonist (0.01 mg/kg) reduced discrimination in High mice tested 96 h post-training and abolished discrimination in Low ...
Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopa... more Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopathology through regulation of subcortical, especially mesoaccumbens, DA functioning. In these experiments we demonstrate that the high vulnerability to stress-induced 'despair' and mesoaccumbens DA inhibition, exhibited by mice of the inbred strain C57BL/6 (C57) in a common animal model of depression, depends on their being highly susceptible to stress-induced mesocortical DA activation. Thus, C57 mice but not mice of the DBA/2 strain showed an extremely high level of immobility on their first experience with the forced swimming test (FST) as well as immediate and strong activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA metabolism and release. In addition, the behavioral and the mesoaccumbens DA responses to FST in C57 mice were reduced and reversed, respectively, by bilateral mesocortical DA depletion. Finally, chronic treatment with the antidepressant ...
Vulnerability to develop drug abuse could be related to differential sensitivity to some central ... more Vulnerability to develop drug abuse could be related to differential sensitivity to some central effects of such drugs. Several results point to mesoaccumbens dopamine release elicited by psychostimulants as the rate-limiting factor of their reinforcing, hence addictive, effects and to locomotor stimulation as an indirect index of such a response. In this paper, we report parallel differences in sensitivity to amphetamine-induced locomotor stimulation and mesoaccumbens dopamine release in two inbred strains of mice characterized by differential susceptibility to develop drug self-administration. Thus, mice of the C57BL/6 strain responded with a simultaneous increase of locomotor activity and mesoaccumbens dopamine release measured by intracerebral microdialysis to amphetamine challenge. On the contrary, mice of the DBA/2 strain did not present either response. No strain differences in mesoaccumbens dopamine outflow or 3,4-dihydroxyphenylacetic acid concentration were found in basal ...
Post-training administration of morphine (0.25, 0.5, or 1 mg/kg) dose-dependently impairs retenti... more Post-training administration of morphine (0.25, 0.5, or 1 mg/kg) dose-dependently impairs retention of an inhibitory avoidance response in mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, i.e., when the memory trace was susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or nonspecific action of the drugs on retention performance, because the latencies during the retention test of those mice that had not received a footshock during the training were not affected by post-training drug administration. Pretreatment with either selective D1 or D2 dopamine (DA) receptor antagonists SCH 23390 and (-)-sulpiride administered at per se noneffective doses (0.025 and 6 mg/kg, respectively) potentiated the effects of morphine, while either selective D1 or D2 receptor agon...
This study was designed to assess the stress effect of manipulation of the olfactory environment ... more This study was designed to assess the stress effect of manipulation of the olfactory environment in developing mice. In a first experiment it was found that mouse pups could be stressed (as measured by an increase in ultrasonic calls) by removing the litter from the dam for 15 min/day for the first 14 days of life and exposing them to a novel odor (clean bedding). This stress procedure also produced a long-term modification in maternal behavior. The stress response (ultrasounds) and the modification of maternal behavior were prevented by providing the litter with home cage bedding during maternal separation. In a second experiment it was demonstrated that early stress influenced apomorphine-induced wall climbing behavior in 15-day-old mice, suggesting stress-induced alterations in the dopaminergic system. Pups exposed to clean bedding during infancy exhibited more wall climbing behavior than pups never separated from the mother. Moreover, preventing the early stress response during ...
Post-training administration of the selective D1 and D2 agonists SKF 38393 and LY 171555 dose-dep... more Post-training administration of the selective D1 and D2 agonists SKF 38393 and LY 171555 dose-dependently facilitated retention of an inhibitory avoidance response in mice, while the selective D1 or D2 antagonists SCH 23390 and (-)sulpiride produced an impairment of retention. These effects are not to be ascribed to a nonspecific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not increased by the post-training drug administration. The effects on retention performance induced by DA agonists and antagonists seem to be due to an effect on memory consolidation, since they have been observed when drugs were given at short, but not at long, periods of time after training. These results showing a similar role of D1 and D2 receptor types on memory storage appear not to be consistent with a body of neuropharmacological, neurophysiological, and behavioral evidence pointing to a d...
Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose depe... more Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impairs retention of an inhibitory avoidance response in DBA/2 mice. In agreement, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those observed in the C57BL/6 strain, as previously reported. Moreover, B6D2F1 hybrids present a response to SKF 38393, LY 171555, SCH 23390, and (-)-sulpiride that parallels that of the C57BL/6 strain, thus suggesting that the neural mechanisms underlying the effects of DA agonists or antagonists on memory processes may be inherited through a dominant mode of inheritance.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2001
Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serot... more Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serotonin (5-HT) in synaptic vesicles by expressing the plasma membrane serotonin transporter (5-HTT) and the vesicular monoamine transporter (VMAT2). 5-HTT knock-out (ko) mice reveal a nearly complete absence of 5-HT in the cerebral cortex by immunohistochemistry, and of barrels, both at P7 and adulthood. Quantitative electron microscopy reveals that 5-HTT ko affects neither the density of synapses nor the length of synaptic contacts in layer IV. VMAT2 ko mice, completely lacking activity-dependent vesicular release of monoamines including 5-HT, also show a complete lack of 5-HT in the cortex but display largely normal barrel fields, despite sometimes markedly reduced postnatal growth. Transient 5-HTT expression is thus required for barrel pattern formation, whereas activity-dependent vesicular 5-HT release is not.
The effects of selective D1 or D2 dopamine receptor agonists and the indirect dopamine agonist co... more The effects of selective D1 or D2 dopamine receptor agonists and the indirect dopamine agonist cocaine on hippocampal acetylcholine release in mice of the C57BL/6 and DBA/2 inbred strains were investigated using intracerebral microdialysis. The D1 SKF 38393 (10, 20, 30 mg/kg, i.p.), the D2 agonist LY 171555 (0.5, 1, 2, mg/kg, i.p.) and cocaine (5, 10, 15 mg/kg, i.p.)
Although hyperphenylalaninemia causes neurological disturbances and mental retardation, the neuro... more Although hyperphenylalaninemia causes neurological disturbances and mental retardation, the neuropathological effects of phenylalanine excess are still poorly understood. Brain serotonin depletion may play a major role in such disturbances and is a possible target for feasible pharmacotherapies. In the present study, we investigated hyperphenylalaninemia-related brain serotonin depletion using a genetic mouse model of phenylketonuria, the Pah(enu2) mutant. Mutant mice showed severe depletion of whole brain serotonin, a mild reduction in the brain level of tryptophan, its amino acid precursor, and major deficits in the brain level of 5-hydroxytryptophan, the second rate-limiting factor in serotonin synthesis. These results suggest that interference with brain 5-hydroxytryptophan synthesis may be the major cause of serotonin deficits in hyperphenylalaninemia.
Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase... more Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase in dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios and a reduction of 3-methoxytyramine (3-MT)/DA ratio in the caudatus putamen (CP) and nucleus accumbens septi (NAS). These effects were already evident after 30 min stress in the NAS, while in the CP 120 min were needed in order to show the effects of stress. Immobilization did not produce any effects on dopaminergic metabolism in the frontal cortex (FC) of the C57 strain either after 30 or after 120 min stress while in mice of the DBA strain a time-dependent effect of stress on the HVA/DA ratio was evident. When B6D2F1 hybrids were considered, the effects produced by 120 min immobilization in the CP and the NAS paralleled those observed in parental strains, while in the FC 120 min stress induced the same increase of HVA observed in DBA mice, thus suggesting that the pattern of response in the FC that characterizes the DBA strain may be inherited through a dominant pattern of inheritance.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Increasing evidence points to a major involvement of cortical areas in addictive mechanisms. Nora... more Increasing evidence points to a major involvement of cortical areas in addictive mechanisms. Noradrenergic transmission in the medial prefrontal cortex (mpFC) has been shown to affect the motor effects of amphetamine, although there is no evidence of its involvement in the rewarding effects of this psychostimulant. The present experiments were aimed at investigating the possibility of a selective involvement of prefrontal cortical norepinephrine (NE) in the rewarding-reinforcing effects of amphetamine. To do so, we evaluated the effects of mpFC NE selective depletion in mice of C57BL/6J inbred strain, a background commonly used in molecular approaches that is known to be highly susceptible to the rewarding effects of the psychostimulant. In a first set of experiments, we demonstrated the absence of amphetamine-induced conditioned place preference in mice bearing prefrontal NE depletion. In a second series of experiments, we demonstrated that the same lesion dramatically reduced amph...
We investigated the effects of post-training administration of dopamine D1 receptor antagonist SC... more We investigated the effects of post-training administration of dopamine D1 receptor antagonist SCH 23390 and β-adrenergic receptor antagonist Propranolol on memory retention of an object sampled in a state of positive emotional arousal. Saline-treated mice trained and tested under high emotional/motivational arousal (High) showed discrimination of a novel object both 24 and 96 h post-training. Instead, mice trained and tested under low motivational arousal (Low) were unable to discriminate the novel object 96 h post-training. Both a high (2 mg/kg) and a low (1 mg/kg) dose of Propranolol reduced object discrimination in High mice tested 24 h post-training, whereas neither dose was effective in Low mice. A high dose of SCH 23390 (0.025 mg/kg) reduced discrimination of the novel object in High mice tested both 24 and 96 h post-training, whereas a low dose of the D1 antagonist (0.01 mg/kg) reduced discrimination in High mice tested 96 h post-training and abolished discrimination in Low ...
Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopa... more Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopathology through regulation of subcortical, especially mesoaccumbens, DA functioning. In these experiments we demonstrate that the high vulnerability to stress-induced 'despair' and mesoaccumbens DA inhibition, exhibited by mice of the inbred strain C57BL/6 (C57) in a common animal model of depression, depends on their being highly susceptible to stress-induced mesocortical DA activation. Thus, C57 mice but not mice of the DBA/2 strain showed an extremely high level of immobility on their first experience with the forced swimming test (FST) as well as immediate and strong activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA metabolism and release. In addition, the behavioral and the mesoaccumbens DA responses to FST in C57 mice were reduced and reversed, respectively, by bilateral mesocortical DA depletion. Finally, chronic treatment with the antidepressant ...
Vulnerability to develop drug abuse could be related to differential sensitivity to some central ... more Vulnerability to develop drug abuse could be related to differential sensitivity to some central effects of such drugs. Several results point to mesoaccumbens dopamine release elicited by psychostimulants as the rate-limiting factor of their reinforcing, hence addictive, effects and to locomotor stimulation as an indirect index of such a response. In this paper, we report parallel differences in sensitivity to amphetamine-induced locomotor stimulation and mesoaccumbens dopamine release in two inbred strains of mice characterized by differential susceptibility to develop drug self-administration. Thus, mice of the C57BL/6 strain responded with a simultaneous increase of locomotor activity and mesoaccumbens dopamine release measured by intracerebral microdialysis to amphetamine challenge. On the contrary, mice of the DBA/2 strain did not present either response. No strain differences in mesoaccumbens dopamine outflow or 3,4-dihydroxyphenylacetic acid concentration were found in basal ...
Post-training administration of morphine (0.25, 0.5, or 1 mg/kg) dose-dependently impairs retenti... more Post-training administration of morphine (0.25, 0.5, or 1 mg/kg) dose-dependently impairs retention of an inhibitory avoidance response in mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, i.e., when the memory trace was susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or nonspecific action of the drugs on retention performance, because the latencies during the retention test of those mice that had not received a footshock during the training were not affected by post-training drug administration. Pretreatment with either selective D1 or D2 dopamine (DA) receptor antagonists SCH 23390 and (-)-sulpiride administered at per se noneffective doses (0.025 and 6 mg/kg, respectively) potentiated the effects of morphine, while either selective D1 or D2 receptor agon...
This study was designed to assess the stress effect of manipulation of the olfactory environment ... more This study was designed to assess the stress effect of manipulation of the olfactory environment in developing mice. In a first experiment it was found that mouse pups could be stressed (as measured by an increase in ultrasonic calls) by removing the litter from the dam for 15 min/day for the first 14 days of life and exposing them to a novel odor (clean bedding). This stress procedure also produced a long-term modification in maternal behavior. The stress response (ultrasounds) and the modification of maternal behavior were prevented by providing the litter with home cage bedding during maternal separation. In a second experiment it was demonstrated that early stress influenced apomorphine-induced wall climbing behavior in 15-day-old mice, suggesting stress-induced alterations in the dopaminergic system. Pups exposed to clean bedding during infancy exhibited more wall climbing behavior than pups never separated from the mother. Moreover, preventing the early stress response during ...
Post-training administration of the selective D1 and D2 agonists SKF 38393 and LY 171555 dose-dep... more Post-training administration of the selective D1 and D2 agonists SKF 38393 and LY 171555 dose-dependently facilitated retention of an inhibitory avoidance response in mice, while the selective D1 or D2 antagonists SCH 23390 and (-)sulpiride produced an impairment of retention. These effects are not to be ascribed to a nonspecific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not increased by the post-training drug administration. The effects on retention performance induced by DA agonists and antagonists seem to be due to an effect on memory consolidation, since they have been observed when drugs were given at short, but not at long, periods of time after training. These results showing a similar role of D1 and D2 receptor types on memory storage appear not to be consistent with a body of neuropharmacological, neurophysiological, and behavioral evidence pointing to a d...
Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose depe... more Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impairs retention of an inhibitory avoidance response in DBA/2 mice. In agreement, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those observed in the C57BL/6 strain, as previously reported. Moreover, B6D2F1 hybrids present a response to SKF 38393, LY 171555, SCH 23390, and (-)-sulpiride that parallels that of the C57BL/6 strain, thus suggesting that the neural mechanisms underlying the effects of DA agonists or antagonists on memory processes may be inherited through a dominant mode of inheritance.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2001
Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serot... more Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serotonin (5-HT) in synaptic vesicles by expressing the plasma membrane serotonin transporter (5-HTT) and the vesicular monoamine transporter (VMAT2). 5-HTT knock-out (ko) mice reveal a nearly complete absence of 5-HT in the cerebral cortex by immunohistochemistry, and of barrels, both at P7 and adulthood. Quantitative electron microscopy reveals that 5-HTT ko affects neither the density of synapses nor the length of synaptic contacts in layer IV. VMAT2 ko mice, completely lacking activity-dependent vesicular release of monoamines including 5-HT, also show a complete lack of 5-HT in the cortex but display largely normal barrel fields, despite sometimes markedly reduced postnatal growth. Transient 5-HTT expression is thus required for barrel pattern formation, whereas activity-dependent vesicular 5-HT release is not.
The effects of selective D1 or D2 dopamine receptor agonists and the indirect dopamine agonist co... more The effects of selective D1 or D2 dopamine receptor agonists and the indirect dopamine agonist cocaine on hippocampal acetylcholine release in mice of the C57BL/6 and DBA/2 inbred strains were investigated using intracerebral microdialysis. The D1 SKF 38393 (10, 20, 30 mg/kg, i.p.), the D2 agonist LY 171555 (0.5, 1, 2, mg/kg, i.p.) and cocaine (5, 10, 15 mg/kg, i.p.)
Although hyperphenylalaninemia causes neurological disturbances and mental retardation, the neuro... more Although hyperphenylalaninemia causes neurological disturbances and mental retardation, the neuropathological effects of phenylalanine excess are still poorly understood. Brain serotonin depletion may play a major role in such disturbances and is a possible target for feasible pharmacotherapies. In the present study, we investigated hyperphenylalaninemia-related brain serotonin depletion using a genetic mouse model of phenylketonuria, the Pah(enu2) mutant. Mutant mice showed severe depletion of whole brain serotonin, a mild reduction in the brain level of tryptophan, its amino acid precursor, and major deficits in the brain level of 5-hydroxytryptophan, the second rate-limiting factor in serotonin synthesis. These results suggest that interference with brain 5-hydroxytryptophan synthesis may be the major cause of serotonin deficits in hyperphenylalaninemia.
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