Biomedical subjects

S Cabib

Publications and source records attributed to S Cabib.

At least 19 recordsLinked to original sources

PubMed2006

Habituation to the test cage influences amphetamine-induced locomotion and Fos expression and increases FosB/DeltaFosB-like immunoreactivity in mice.

Pre-exposure to the testing cage (habituation or familiarization) is a common procedure aimed at reducing the interference of novelty-induced arousal and drug-independent individual differences on neural and behavioral measures. However, recent results suggest that this procedure might exert a major influence on the effects of addictive drugs. The present experiments tested the effects of repeated exposure to a test cage (1 h daily for four consecutive days) on amphetamine-induced locomotion and Fos expression as well as on FosB/DeltaFosB-like immunoreactivity in mice of the C57BL/6J and DBA/2J inbred strains that differ for the response to amphetamine, stress and novelty. Daily experiences with the test cage increased FosB/DeltaFosB-like immunoreactivity in the medial-prefrontal cortex of both strains of mice and in the caudate of mice of the C57 strain, as reported for repeated stress in the rat. Moreover, previous habituation to the test cage reduced the locomotor response to a low dose of amphetamine only in DBA mice while it reduced amphetamine-induced Fos expression in medial-prefrontal cortex, dorsal caudate and the accumbens shell of mice of the C57 strain. These results demonstrate indexes of stress-like plasticity in the brains of mice exposed to a procedure of familiarization to the testing environment. Moreover, they suggest that the procedure of daily familiarization influences the pattern of brain Fos expression induced by amphetamine. Finally, they indicate complex interactions between experience with the testing environment, genotype and drug.

Amphetamine↗

PubMed2005

Susceptibility to conditioned place preference induced by addictive drugs in mice of the C57BL/6 and DBA/2 inbred strains.

RATIONALE: In previous studies, we have demonstrated that mice of the inbred strain C57BL/6J (C57) are more susceptible to amphetamine-induced conditioned place preference (CPP) than DBA/2J (DBA) mice. Moreover, we also observed parallel strain differences for the locomotor-stimulant effects of the drug. However, other studies have reported either no difference or opposite strain differences for cocaine- and morphine-induced CPP as well as for the locomotor effects of these drugs, suggesting that amphetamine-related behavioral phenotypes might depend on a specific pharmacological action of the psychostimulant. OBJECTIVES: This study was aimed at testing strain differences for cocaine- and morphine-related behavioral phenotypes in the same experimental protocol and conditions previously used for amphetamine. METHODS: C57 and DBA mice were tested for CPP induced by cocaine (0, 5, 10, and 20 mg/kg) and morphine (0, 5, 7.5, and 10 mg/kg). Locomotor activity data were simultaneously obtained by measuring distance moved during all different CPP phases and unconditioned locomotor activity, behavioral sensitization and conditioned hyperactivity were measured together with CPP. RESULTS: (a) Either cocaine or morphine promoted significant CPP at lower doses in C57 than in DBA mice; (b) only drug-trained C57 mice showed a significant CPP compared with the control group; and (c) only C57 mice showed dose-dependent effects of cocaine on CPP. Moreover, there was no relationship between drug-induced CPP and locomotion. CONCLUSIONS: The results demonstrate that C57 and DBA mice differ in their sensitivity to cocaine- and morphine-induced CPP and suggest that the two strains differ in sensitivity to the positive incentive properties of drugs of abuse.

Analgesics, Opioid↗

PubMed2004

Distinct patterns of Fos expression induced by systemic amphetamine in the striatal complex of C57BL/6JICo and DBA/2JICo inbred strains of mice.

Mice from the inbred strains C57BL/6 and DBA/2 are characterized by striking differences in their behavioral response to addictive drugs. We used Fos expression as a tool to reveal strain differences in the postsynaptic effects of amphetamine (AMPH; 2.5 mg/kg) within the nucleus accumbens (NAc) (core and shell) and the dorsal caudate (dorsomedial and dorsolateral). AMPH stimulated Fos expression in all striatal regions of mice from both strains. However, while C57BL/6 showed a higher Fos response than DBA/2 mice in both NAc shell and core, the opposite was true for the dorsolateral caudate. The effects of AMPH were prevented by D1 blockade in all striatal regions of both strains and mimicked by the D1 agonist, SKF82958 (0.1 mg/kg), in both regions of the caudate and in the NAc shell, but not in the core. Our results suggest that the functional heterogeneity of the striatal complex is under genetic control and that this control may implicate DA transmission and corticostriatal interactions.

Amphetamine↗

PubMed2002

The contribution of comparative studies in inbred strains of mice to the understanding of the hyperactive phenotype.

Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity and impulsivity. Converging evidence, suggests a primary role of disturbances in brain dopamine (DA) transmission and a role of genetic factors in its pathology. Inbred provide a well-defined and stable genotype for analysis. C57BL/6 (C57) and DBA/2 (DBA) mice are amongst the most studied inbred strains in the behavioral pharmacology of DA, and they differ in several parameters of the DA system that relate directly to behavioral differences. These strains also exhibit several qualitatively different behavior patterns that rely on separate DA networks (e.g. mesoaccumbens vs. nigrostriatal) and on different modes of inheritance. C57 mice are good learners in most tasks also involving associative learning but are totally unable to learn active avoidance although being very active. Moreover, C57 mice show greater novelty-induced locomotor activity than DBA, which is modulated strongly by DA neurons in the ventral tegmental area (VTA) region. Pharmacological studies also indicate a facilitated mesoaccumbens DA transmission in C57 mice when compared to DBAs. Increased density of D2 autoreceptors located on VTA neurons, and lower D2 postsynaptic receptors in the NAS were observed in DBA relative to C57. Activation of D2 autoreceptors inhibits impluse flow, synthesis, and release rates of DA neurons. As would be predicted from their higher D2 autoreceptor: DBA compared to C57 mice show reduced DA synthesis and release within the mesoaccumbens DA system when challenged with DA direct agonists. However, DBA mice are by fare more susceptible than C57s to stress-induced enhanced mesoaccumbens DA release and in stressful situation, they show sustained active behavioral responses whilst C57 adopt extremely passive responses (behavioral despair). Finally, chronic or repeated stress promote opposite adaptation of VTA DA autoreceptors in the two strains and render the hypoactive DBAs as active as the C57 mice. These results indicate that a complex interaction between genetic and environmental factors controls, mesoaccumbens DA functioning and hyperactive phenotype.

Animals↗

PubMed2002

Opposite imbalances between mesocortical and mesoaccumbens dopamine responses to stress by the same genotype depending on living conditions.

The balance between mesocortical and mesoaccumbens dopamine (DA) response to stress may represent a major diathesis in psychopathology. These experiments evaluated the influence of variable living conditions on this phenotype and on behavioral coping. Mesocortical and mesoaccumbens DA responses to stress challenge (restraint) were analyzed in individually housed or food restricted mice of an inbred strain to control for genotype-dependent variability. Mice housed in groups with free access to food were used as controls. Little or no differences among the three conditions were found for basal mesoaccumbens and mesocortical DA and metabolite levels. Stress challenge promoted parallel activation of mesocortical and mesoaccumbens DA metabolism and release in group-housed mice. Individually housed mice showed enhanced mesocortical and reduced mesoaccumbens response to stress challenge. Instead, food restricted mice showed no response by the mesocortical DA system and enhanced mesoaccumbens DA response. Finally, the two differential housing conditions promoted opposite alterations of the behavioral profile exhibited by mice exposed to the forced swimming test. These results indicate opposite imbalances between mesocortical and mesoaccumbens DA responses to stress in intact, drug-naive animals, point to a strict relationship between these unbalanced responses and behavioral coping with aversive events and indicate that central and behavioral responses to stress are highly dependent on individual experiences.

Animals↗

PubMed2002

Genetic susceptibility of mesocortical dopamine to stress determines liability to inhibition of mesoaccumbens dopamine and to behavioral 'despair' in a mouse model of depression.

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 clomipramine reduced immobility and eliminated both mesocortical DA activation and mesoaccumbens DA inhibition in response to FST. These results suggest that a genetically determined susceptibility to stress by the mesocortical DA system may favor the development of pathological behavioral responses through inhibition of subcortical DA transmission.

Animals↗

PubMed2001

Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release.

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.

Aging↗

PubMed2001

Pharmacological evidence of muscarinic-cholinergic sensitization following chronic stress.

RATIONALE: Although much evidence supports a major role of brain cholinergic transmission in memory consolidation processes, little is known about cholinergic functioning under environmental pressure. OBJECTIVES: The present experiments were aimed at investigating possible functional adaptation of muscarinic receptors promoted by a chronic stressful procedure in an inbred strain of mice highly susceptible to stress. METHODS: We tested the effects of post-trial administration of a cholinergic agonist and a muscarinic antagonist on the retention of a passive avoidance task in control animals and compared these effects with those observed following food restriction. RESULTS: Food restriction enhanced the facilitatory effects of oxotremorine and reduced the impairing effects of atropine on memory consolidation. CONCLUSION: Our results support the view that chronic sensitization of muscarinic receptors occurs following chronic stress.

Animals↗

PubMed2001

Opposite genotype-dependent mesocorticolimbic dopamine response to stress.

Identification of relevant phenotypes related to neural functioning has yet to receive the needed attention, although behavioral phenotyping, through comparative studies in inbred strains of mice, has produced some major findings (Cabib et al., 2000; Crabbe, 1999; Gerlai, 1996; Lathe, 1996). Central responses to stress play a major psychopathogenic role in the presence of a genetic liability (Fowels, 1992), and mesocortical and mesoacumbens dopamine metabolism and release are the most relevant among these responses (Abercrombie et al., 1989; Cabib and Puglisi-Allegra, 1994; Chrapusta et al., 1997; Di Chiara et al., 1999; Hervé et al., 1979; Imperato et al., 1991). Therefore, in the present study, we assessed strain-dependent differences in mesocortical and mesoaccumbens dopamine responses to a widely utilized stressful procedure (restraint), by comparing mice of the oldest and most studied inbred strains (Cabib et al., 2000): the C57BL/6JIco and DBA/2JIco. We found that stress produced inhibition of mesoaccumbens dopamine release accompanied by a very fast and strong activation of mesocortical dopamine metabolism in C57BL/6JIco mice, and the opposite in mice of the DBA/2JIco strain. These results suggest a genetic control over the balance between mesocortical and mesoaccumbens dopamine responses to stress, and provide a model for pre-clinical studies on molecular genetics of depression.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Abolition and reversal of strain differences in behavioral responses to drugs of abuse after a brief experience.

Inbred strains of mice are largely used to identify the genetic basis of normal and pathological behaviors. This report demonstrates that a moderate period of food shortage, an ecologically common experience, can reverse or abolish strain differences in behavioral responses to the abused psychostimulant amphetamine. The period of food shortage occurred when the animals were mature and was terminated before the administration of amphetamine. Strain differences in behavior appear highly dependent on environmental experiences. Consequently, to identify biological determinants of behavior, an integrated approach considering the interaction between environmental and genetic factors needs to be used.

Amphetamine↗

PubMed2000

Dramatic brain aminergic deficit in a genetic mouse model of phenylketonuria.

Clinical data suggest that brain catecholamines and serotonin are deficient in phenylketonuria (PKU), an inherited metabolic disorder that causes severe mental retardation and neurological disturbances. To test this hypothesis, brain tissue levels of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT) and their metabolites were evaluated in the genetic mouse model of PKU (Pah(enu2)). Results indicated a significant reduction of 5-HT levels and metabolism in prefrontal cortex (pFC), cingulate cortex (Cg), nucleus accumbens (NAc), caudate putamen (CP), hippocampus (HIP) and amygdala (AMY). NE content and metabolism were reduced in pFC, Cg, AMY and HIP. Finally, significantly reduced DA content and metabolism was observed in pFC, NAc, CP and AMY. In pFC, NAc and CP there was also a marked reduction of DA release.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Behavioral and mesocorticolimbic dopamine responses to non aggressive social interactions depend on previous social experiences and on the opponent's sex.

In these experiments we evaluated the relationship between behavioral and brain dopamine (DA) responses to social interactions. Subjects were group housed male mice confronted with a non aggressive male or female conspecific following either repeated defeat (defeated) or repeated non aggressive experiences (social). Defeated mice showed more defensive/submissive reactions then mice of the social group regardless of the opponent sex. However, mice defeated by females showed reduced social exploration without significant differences in non social exploration whilst the opposite was true for mice defeated by male opponents. Non aggressive social interactions enhanced dopamine metabolism in the prefrontal cortex (pFC) of DEFEATED mice regardless of opponent sex. However, only mice defeated by females showed enhanced dopamine metabolism and release in the nucleus accumbens septi (NAS) and olfactory tubercle (OT) following interaction with the non aggressive opponent. Finally, correlation between central and behavioral responses evidenced that 3,4-dihydroxiphenilacetic acid levels in the pFC were positively correlated with defensive behaviors and negatively correlated with non social exploration in mice confronted with male opponents but not in those confronted with females. The latter, showed a significant positive correlation between 3-methoxytyramine (3-MT) levels in the OT and defensive responses and significant negative correlation between social investigation and 3-MT levels in the OT and in the NAS. These results indicate a strict relationship between mesocorticolimbic dopamine transmission and behavior responses to social cues. Moreover, they strongly support the view that mesocorticolimbic DA modulates social behavior by affecting perceptive processing.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Strain-dependent involvement of D1 and D2 dopamine receptors in muscarinic cholinergic influences on memory storage.

These experiments examined the interaction of muscarinic and dopaminergic systems in influencing memory for one-trial inhibitory avoidance training in mice of the C57BL/6 and DBA/2 strains. In both strains, immediate post-training systemic administration of the muscarinic cholinergic agonist oxotremorine enhanced retention and the cholinergic antagonist atropine impaired retention. No effects were seen with injections 2 h post-training. Furthermore, the drugs did not affect retention performance of animals that received no footshock on the training trial. These results confirm previous findings indicating that muscarinic cholinergic drugs affect memory by influencing memory consolidation. In C57 mice, pretreatment with selective D1 or D2 dopamine (DA) receptor agonists (SKF 38393 or LY 171555, respectively) in otherwise non-effective doses (5 and 0.25 mg/kg, respectively) potentiated the effects of oxotremorine (0.04 mg/kg). Furthermore, in C57 mice pretreatment with selective D1 or D2 receptor antagonists (SCH 23390 or (-)-sulpiride) in otherwise non-effective doses (0.025 and 6 mg/kg, respectively) blocked the memory enhancing effects of oxotremorine. The memory impairing effects of atropine (3 mg/kg) were blocked by the D1 and D2 selective agonists and potentiated by the selective D1 or D2 antagonists. In contrast, in DBA mice, the D1 and D2 selective agonists antagonised the memory enhancing effects of oxotremorine (0.02 mg/kg) and potentiated the effects of atropine (2 mg/kg). Furthermore, the D1 and D2 antagonists potentiated the effects of oxotremorine and antagonised those of atropine. These findings indicate that although muscarinic cholinergic influences on memory storage are comparable in mice of these two strains, the cholinergic-dopaminergic interactions are opposite in the two strains. These results have implications for hypotheses of cholinergic and dopaminergic regulation of memory storage.

Animals↗

PubMed1999

Strain-dependent effects of anandamide on memory consolidation in mice are antagonized by naltrexone.

Post-training administration of anandamide (1.5, 3, 6 mg/kg) dose-dependently impaired retention of an inhibitory avoidance response in DBA/2 mice, while improving it in C57BL/6 mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. They were observed when drug was given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. These effects of anandamide parallel those of opioid agonists, as previously reported. Moreover, the opioid antagonist naltrexone improved retention in DBA/2 mice, while impairing it in C57BL/6 mice. Pre-treatment with the opioid antagonist at a non-effective dose (0.1 mg/kg) antagonized the effects of anandamide on memory consolidation in both strains. These results strongly suggest that endogenous cannabinoids affect memory processes through opioid systems. The possible involvement of other neurotransmitter systems, such as dopamine, in strain-dependent effects of anandamide in memory consolidation is discussed.

Animals↗

PubMed1998

Long-term effects of postnatal manipulation on emotionality are prevented by maternal anxiolytic treatment in mice.

This study investigated the role of maternal behavior on the long-term effects of postnatal manipulation (15 min of daily separation from the dam and exposure to clean bedding from Day 1 to Day 14 of postnatal life) on emotionality in the mouse. Mothers were treated with an antianxiety agent (Chlordiazepoxide: 5 mg/kg), daily upon removal of the litter from the nest. Emotionality in adult offspring was tested in the elevated plus maze. Mice manipulated during postnatal development were more explorative and less anxious than unhandled mice, but this effect was not observable in the offspring of Chlordiazepoxide-treated dams. No effect of maternal Chlordiazepoxide was observed in unhandled offspring. The pharmacological treatment of the mother did not affect either pups' ultrasonic calling during separation, or maternal behavior far apart from the daily manipulation sessions. By contrast, Chlordiazepoxide-treated dams were less responsive toward pups upon reunion following daily separation. This alteration of dams' behavior was not related to alterations in the amount of ultrasonic calls emitted by pups during reunion. Finally, when dams were daily injected with Chlordiazepoxide far apart from pups' removal, the pharmacological treatment was devoid of effects. These results support the view that the mother-infant interaction which follows separation plays a major role in determining the effects of postnatal manipulations on adult emotionality.

Age Factors↗

PubMed1998

Parallel strain-dependent effect of amphetamine on locomotor activity and dopamine release in the nucleus accumbens: an in vivo study in mice.

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 conditions or following saline challenges. However, mice of the C57BL/6 strain were characterized by higher levels of accumbal homovanillic acid in basal conditions, in line with the results obtained in rats rendered more sensitive to the locomotor effects of psychostimulants by repeated administration. Finally, in both strains amphetamine decreased accumbal levels of the two metabolites. These results suggest that genotype modulates the locomotor effects of amphetamine through sensitivity of the mesoaccumbens system to amphetamine-stimulated dopamine release. Moreover, they provide a basis to test the hypothesis of mesoaccumbens dopamine involvement in individual susceptibility to the addictive effects of drugs by quantitative trait loci analysis in recombinant inbred strains.

Amphetamine↗

PubMed1998

Stress promotes major changes in dopamine receptor densities within the mesoaccumbens and nigrostriatal systems.

This study investigated the effects of stress on brain dopamine receptor densities in two inbred strains of mice. Analysis of [3H]SCH23390 binding by quantitative autoradiography revealed that repeated restraint stress significantly increases D1-like receptor density in the nucleus accumbens of mice of the DBA/2 strain whist reducing it in the caudate-putamen of C57BL/6 mice. No significant changes in D2-like receptor quantified by [3H](-)-sulpiride binding were observed in caudate, substantia nigra and accumbens of stressed C57BL/6 mice. Instead, in DBA/2 mice, stress significantly increased D2-like receptor density in the nucleus accumbens whilst reducing it in the substantia nigra. Finally, stress significantly increased D2-like receptor density within the ventral tegmental area of C57BL/6 mice whilst significantly reducing it in mice of the DBA/2 strain. These results indicate that stress promotes major changes in mesoaccumbens and nigrostriatal dopamine receptor densities. The direction of these changes depends on receptor subtype, brain area and strain. Moreover, the opposite changes of D2-like receptor densities promoted by stress in the ventral tegmental area of the two inbred strains of mice suggest that mesoaccumbens dopamine autoreceptors density might be controlled by a major genotype x stress interaction.

Animals↗

PubMed1997

Impairments produced by amphetamine and stress on memory storage are reduced following a chronic stressful experience.

Post-training administration of the psycho-stimulant, amphetamine or post-trial exposure to restraint stress impaired retention of an inhibitory avoidance response in DBA/2 (DBA) mice. The effect of amphetamine was dose-dependent (1-3 mg/kg) whilst the effect of stress depended on restraint duration (15, 30, or 60 min). Both effects on retention performance appeared to be due to an effect on memory consolidation. In fact, they were observed when the drug and the stressor were experienced at short, but not long, periods of time after training, which is when the memory trace is susceptible to modulation. Moreover, these effects could not be ascribed to a rewarding or non-specific action of the two treatments on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training, were not affected by the post-training treatments. Administration of either D1 (SCH23390) or D2 [(-)-sulpiride] dopamine (DA) receptor against prior to amphetamine injection or stress exposure antagonized the impairing effects of both treatments. These data indicate that brain dopamine was involved in both cases. Finally, when mice were food restricted for 13 days than allowed free access to food for 24 h before training, either the effects of amphetamine or restraint stress were reduced. Food restricted mice did not differ from control for stepthrough latencies either on the training or the test days, indicating the absence of amnesic or otherwise impairing effects of the experimental procedure per se. Instead, the results indicated hyposensitization to the effects of amphetamine and stress on memory consolidation in food restricted animals.

Amphetamine↗