Either the dorsal hippocampus or the dorsolateral striatum is selectively involved in consolidation of forced swim-induced immobility depending on genetic background.

Healthy subjects differ in the memory system they engage to learn dual-solution tasks. Both genotype and stress experience could contribute to this phenotypic variability. The present experiments tested whether the hippocampus and the dorsal striatum, the core nodes of two different memory systems, are differently involved in 24 h retention of a stress-associated memory in two genetically unrelated inbred strains of mice. Mice from both the C57BL/6J and the DBA/2J inbred strains showed progressive increase of immobility during 10 min exposure to forced swim (FS) and retrieved the acquired levels of immobility when tested 24h later. The pattern of c-fos immunostaining promoted by FS revealed activation of a large number of brain areas in both strains, including CA1 and CA3 fields of the hippocampus. However, only DBA/2J mice showed activation of the dorsolateral striatum (DLS). In addition, FS induced a positive correlation between c-fos expression in the amygdala and CA1 and CA3 in C57BL/6J mice whereas it induced a positive correlation between c-fos expression in the amygdala and DLS in DBA/2J mice. Finally, temporary post-training inactivation of the dorsal hippocampus, by local infusion of lidocaine, prevented 24h retention of immobility in C57BL/6J mice only, whereas inactivation of the DLS prevented retention in DBA/2J mice only. These findings support the view that genetic factors can determine whether the dorsal hippocampus or the DLS are selectively engaged to consolidate stress-related memory.

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.

DeltaFosB accumulation in ventro-medial caudate underlies the induction but not the expression of behavioral sensitization by both repeated amphetamine and stress.

Both repeated psychostimulants and stress have the ability to promote behavioral sensitization, i.e. enhanced behavioral response to drug challenge. To test whether the behavioral phenotype is also accompanied by similar neuroplastic adaptations, the present study evaluated changes in Fos and FosB/DeltaFosB transcription factors induced in the brain of C57BL/6J mice behaviorally sensitized by repeated amphetamine or repeated restraint stress. Groups of mice received repeated injections of D-amphetamine or saline in group-specific environments. Different groups of mice experienced 2 h of restraint daily for 10 consecutive days. Amphetamine- pre-treated mice, drug-challenged in the environment in which they received drug treatments (Paired), as well as repeatedly stressed mice expressed robust sensitization to the locomotor effects of amphetamine. Both stress- and amphetamine-pre-treated groups showed changes in amphetamine-induced Fos expression; however, none of these changes was shared by the two sensitizing treatments. Instead, accumulation of FosB/DeltaFosB immunoreactivity in the ventro-medial caudate was common to both pre-treatments. These results support the hypothesis that a common neuroadaptive process involving DeltaFosB accumulation in the ventro-medial caudate underlies the induction but not the expression of behavioral sensitization by different conditions.

Cortical and subcortical distribution of ionotropic purinergic receptor subunit type 1 (P2X(1)R) immunoreactive neurons in the rat forebrain.

Ionotropic purinergic receptors (P2XR) are ATP-gated cationic channels composed of seven known subunits (P2X(1-7)R) and involved in different functions in neural tissue. Although their presence has been demonstrated in the brain, few studies have investigated their expression pattern. In particular, ionotropic purinergic receptor subunit type 1 (P2X(1)R) has been observed in the cerebellum and in brainstem nuclei. The present study investigates the P2X(1)R expression pattern in the rat forebrain using immunohistochemistry. The specificity of the immunolabeling has been verified by Western blotting and in situ hybridization methods. P2X(1)R immunoreactivity was specifically localized in neurons, dendrites and axons throughout the forebrain. Characteristic differences in the distribution of P2X(1)R were observed in different cortical areas. In prefrontal, cingulate and perirhinal cortices, very intense labeling was present in neuronal bodies. In frontal, parietal, temporal and occipital cortices, immunostaining was lighter and mainly found in dendrites and axons. The hippocampal formation was intensely labeled. Labeling was present almost exclusively in dendrites and axons and never in neuronal bodies. The diencephalon was devoid of P2X(1)R positive neurons or fibers except for the medial habenular nucleus, which showed very intense P2X(1)R immunostaining. Furthermore, two subcortical regions, namely, the nucleus centralis of the amygdala and the bed nucleus of the stria terminalis, showed intense P2X(1)R neuronal labeling. Present data indicate that P2X(1)R are prevalent in forebrain areas involved in the integration of cognitive, limbic and autonomic functions.

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.

Psychopharmacology of dopamine: the contribution of comparative studies in inbred strains of mice.

Comparative studies of behavioral responses to centrally acting drugs in inbred strains of mice which show differences in brain neurotransmitter activity represent a major strategy in the investigation of the neurochemical bases underlying behavioural expression. Moreover, these studies represent a preliminary stage in behavioral genetic research since they allow quantitative scales to be established and suggest correlations to be tested in recombinant inbred strains. The present review evaluates results obtained in mice of the C57BL/6 (C57) and DBA/2 (DBA) inbred strains which have been used for studies of the behavioral pharmacology of dopamine (DA) and investigated for the functional and anatomical characteristics of their brain DA systems. Differences between C57 and DBA strain involve susceptibility and sensitivity as well as qualitative differences in the type or direction of the behavioral effects of DA agonists. Moreover, data on strain-dependent differences for DA metabolism, release and receptor densities and distribution provide important indications about the relationship between behavioral and central effects of DA agonists and, more generally, about the involvement of brain DA in behavior. Comparative studies in C57 and DBA mice have also revealed differences in susceptibility to context-dependent, context-independent and stress-induced behavioral sensitization to psychostimulants. Consequently, they support the view that the term "behavioral sensitization" may define different phenomena in which different, independent genotype-related factors play a major role. Finally, studies on the behavioral and central effects of stressful experiences in C57 and DBA mice together with psychopharmacogenetic analyses, indicate that different symptomatological profiles may derive from genotype-dependent adaptation of brain DA receptors to environmental pressure.

Altered consolidation of extinction-like inhibitory learning in genotype-specific dysfunctional coping fostered by chronic stress in mice.

Genetic and stress-related factors interact to foster mental disorders, possibly through dysfunctional learning. In a previous study we reported that a temporary experience of reduced food availability increases forced swim (FS)-induced helplessness tested 14days after a first experience in mice of the standard inbred C57BL/6(B6) strain but reduces it in mice of the genetically unrelated DBA/2J (D2) strain. Because persistence of FS-induced helplessness influences adaptive coping with stress challenge and involve learning processes the present study tested whether the behavioral effects of restricted feeding involved altered consolidation of FS-related learning. First, we demonstrated that restricted feeding does not influence behavior expressed on the first FS experience, supporting a specific effect on persistence rather then development of helplessness. Second, we found that FS-induced c-fos expression in the infralimbic cortex (IL) was selectively enhanced in food-restricted (FR) B6 mice and reduced in FR D2 mice, supporting opposite alterations of consolidation processes involving this brain area. Third, we demonstrated that immediate post-FS inactivation of IL prevents 24h retention of acquired helplessness by continuously free-fed mice of both strains, indicating the requirement of a functioning IL for consolidation of FS-related learning in either mouse strain. Finally, in line with the known role of IL in consolidation of extinction memories, we found that restricted feeding selectively facilitated 24h retention of an acquired extinction in B6 mice whereas impairing it in D2 mice. These findings support the conclusion that an experience of reduced food availability strain-specifically affects persistence of newly acquired passive coping strategies by altering consolidation of extinction-like inhibitory learning.

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.

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.

Evidence for the involvement of extinction-associated inhibitory learning in the forced swimming test.

The forced swimming test (FST) remains one of the most used tools for screening antidepressants in rodent models. Nonetheless, the nature of immobility, its main behavioral measure, is still a matter of debate. The present study took advantage of our recent finding that mice of the inbred DBA/2J strain require a functioning left dorsolateral striatum (DLS) to consolidate long-term memory of FST to test whether immobility is the outcome of stress-related learning. Infusion of the GABA-A agonist muscimol in the left DLS immediately after a single experience of FST prevented and infusion in the left or the right amygdala impaired recall of the acquired levels of immobility in a probe test performed 24h later. Post-training left DLS infusion of muscimol, at a dose capable of preventing retention of FST-induced immobility, did not influence 24h retention of inhibitory avoidance training or of the escape response acquired in a water T-maze. However, this same treatment prevented 24h retention of the extinction training of the consolidated escape response. These results indicate that a left DLS-centered memory system selectively mediates memory consolidation of FST and of escape extinction and support the hypothesis that immobility is the result of extinction-like inhibitory learning involving all available escape responses due to the inescapable/unavoidable nature of FST experience.

Role of genotype in the adaptation of the brain dopamine system to stress.

Behavioral and biochemical analysis of the effects of stress on brain dopamine (DA) functioning in two inbred strains of mice reveals opposite patterns of adaptation to chronic stress. Chronically stressed mice of the C57BL/6 (C57) strain are characterized by hypersensitive mesolimbic DA autoreceptors and by a dramatic increase of D1/D2 DA receptor ratio (possibly postsynaptic) in the nucleus accumbens septi (NAS) as revealed by in vivo binding of 3H-spiperone and 3H-SCH23390. Chronically stressed DBA/2 (DBA) mice present, on the contrary, hyposensitive DA autoreceptors and no changes in the D1/D2 DA receptors ratio in this brain area. The analysis of the behavioral responses of chronically stressed mice of the C57 strain to the mixed D1/D2 receptor agonist apomorphine, to the selective D2 agonist LY171555 and to the selective D1 agonist SKF 38393 suggest a close relationship between the behavioral alterations produced by chronic stress and the alterations of sensitivity of D2 pre- and postsynaptic receptors in the mesolimbic system. Furthermore, chronically stressed C57 mice present a marked decrease of spontaneous-climbing behavior which is not observed in the mice of the DBA strain and is dependent on the alteration of the biphasic evolution of this behavior during exposure to the test situation which, for these mice, represents a novel environment. Acute exposure to aversive environmental conditions induces a biphasic alteration of DA transmission (initial increase of DA release followed by a decrease under control levels) in the NAS.(ABSTRACT TRUNCATED AT 250 WORDS)

Different effects of repeated stressful experiences on mesocortical and mesolimbic dopamine metabolism.

The effects of repeated stressful experiences (10 min restraint, daily) on the levels of dopamine and metabolites in the nucleus accumbens septi and frontal cortex were evaluated. In naive mice, restraint stress increased 3-4-dihydroxyphenylacetic acid, homovanillic acid, and 3-methoxytyramine levels in the nucleus accumbens and 3-4-dihydroxyphenylacetic acid levels in the frontal cortex. The effects of stress on 3-methoxytyramine and homovanillic acid levels in the nucleus accumbens septi disappeared within five days of daily restraint experiences and the increase in 3-4-dihydroxyphenylacetic acid levels was no longer evident by the 10th day. By contrast, the response of mesocortical dopamine system to restraint (increased 3-4-dihydroxyphenylacetic acid levels) was unaffected by either five or 10 days of exposure to the stressor. Moreover, 10 min of restraint were still able to increase 3-4-dihydroxyphenylacetic acid levels in the frontal cortex of mice repeatedly exposed (nine days) to 120 min restraint. These results indicate that the mesolimbic and the mesocortical dopamine systems adapt differently to repeated exposure to a stressor.

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.

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.

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.

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.

Paw preference and brain dopamine asymmetries.

The hemispheric content of dopamine and its metabolites in the frontal cortex, caudatus putamen and nucleus accumbens septi was evaluated in relation to behavioral lateralization assessed by paw preference. Three groups of C3H/He mice were selected on the basis of their performance in the paw preference test (left-handed, ambidextrous and right-handed) and levels of dopamine and its metabolites were measured in the two hemispheres of each group. Mice showed significant differences in hemispheric content of dopamine and 3-4 dihydroxyphenylacetic acid in the nucleus accumbens septi depending on the behavioral lateralization as expressed by paw preference. The hemispheric dominance (right hemisphere/right hemisphere + left hemisphere content of dopamine and metabolites x 100) was also calculated for each mouse. Significant differences in hemispheric dominance for dopamine, 3-4 dihydroxyphenylacetic acid and 3-methoxytyramine in the nucleus accumbens were found between right-handed and left-handed mice. This dominance was ipsilateral to the preferred paw: % right hemisphere/total content of dopamine and its metabolites were lowest in left-handed, highest in right-handed and intermediate in ambidextrous mice. Finally, individual % right hemisphere/total content for dopamine, 3-4 dihydroxyphenylacetic acid and 3-methoxytyramine in the nucleus accumbens positively correlated with individual paw preference scores. The analysis of the other brain areas did not reveal any significant effect. These results suggest a strong relationship between mesoaccumbens dopamine asymmetries and both the direction and the intensity of behavioral lateralization as expressed by paw preference in mice.

Strain-dependent effects of dopamine agonists on acetylcholine release in the hippocampus: an in vivo study in mice.

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.) all increased, dose-dependently, acetylcholine release in the hippocampus of C57BL/6 mice. Both the D1 agonist and cocaine did not produce any significant effect in DBA/2 mice. In the latter strain, however, LY 171555 produced a decrease in acetylcholine release that was evident after 60 min from injection of the doses of 0.5 and 1 mg/kg, but not at the dose of 2 mg/kg. The effects observed in C57BL/6 mice as well as those produced by low doses of LY 171555 in the DBA/2 strain were consistent with previous results obtained in rats. The present results indicate major strain-dependent differences in the effects of dopamine agonists on hippocampal acetylcholine release in mice. Moreover, they suggest a complex genotype-related neural organization of dopamine-acetylcholine interactions in the mesolimbic system. Finally, the strain differences in the effects of the dopamine agonists on hippocampal acetylcholine release parallel previously reported strain differences in the effects of these substances on memory consolidation.

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.

Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.

The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day x 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.