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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 mice tested 24h after training., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: A polymorphism in the serotonin transporter (5-HTT) gene modulates the association between adverse early experiences and risk for major depression in adulthood. Although human imaging studies have begun to elucidate the neural circuits involved in the 5-HTT x environment risk factor, a molecular understanding of this phenomenon is lacking. Such an understanding might help to identify novel targets for the diagnosis and therapy of mood disorders. To address this need, we developed a gene-environment screening paradigm in the mouse., Methods: We established a mouse model in which a heterozygous null mutation in 5-HTT moderates the effects of poor maternal care on adult anxiety and depression-related behavior. Biochemical analysis of brains from these animals was performed to identify molecular substrates of the gene, environment, and gene x environment effects., Results: Mice experiencing low maternal care showed deficient gamma-aminobutyric acid-A receptor binding in the amygdala and 5-HTT heterozygous null mice showed decreased serotonin turnover in hippocampus and striatum. Strikingly, levels of brain-derived neurotrophic factor (BDNF) messenger RNA in hippocampus were elevated exclusively in 5-HTT heterozygous null mice experiencing poor maternal care, suggesting that developmental programming of hippocampal circuits might underlie the 5-HTT x environment risk factor., Conclusions: These findings demonstrate that serotonin plays a similar role in modifying the long-term behavioral effects of rearing environment in diverse mammalian species and identifies BDNF as a molecular substrate of this risk factor.

Following 10 days of daily restraint stress, sensitization developed to the stimulatory effect of amphetamine on locomotion in DBA/2 but not in C57BL/6 mice tested 24 h after the last stressful experience regardless of their being naive or habituated to the test cages. Saline-injected C57BL/6 mice, however, showed an increase of locomotion 24 h after chronic stress treatment. Chronically stressed mice of the two strains did not exhibit any alteration of dopamine and metabolites (3-4-dihydroxphenylacetic acid, homovanillic acid, and 3-methoxytyramine) levels in the frontal cortex, caudatus putamen, or nucleus accumbens septi, thus ruling out that stress-induced alteration of basal dopamine metabolism affected the behavioral response to amphetamine challenging in DBA/2 mice. Ten daily amphetamine injections (5 mg/kg) did not significantly modify the behavioral response to amphetamine in either strain of mice tested 24 h after the end of the chronic treatment and did not increase locomotion in saline-injected C57BL/6 mice. Finally, chronically stressed hybrids B6D2F1 did not show sensitization to the locomotor effects of amphetamine, suggesting a dominant mode of inheritance in the response to chronic stress of the C57BL/6 strain.

The binding of tritiated spiperone (D2 antagonist) and tritiated SCH 23390 (D1 antagonist), in vivo, was investigated in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of mice submitted to ten daily restraint stress sessions. Mice sacrificed 24 hr after the last stressful experience presented a 64% decrease of D2 receptor density (Bmax) but no changes in D1 receptor density in the NAS. In the CP a much smaller (11%) reduction of D2 receptor density was accompanied by a 10% increase of D1 receptors. These results show that the two types of dopamine (DA) receptors adapt in different or even opposite ways to environmental pressure, leading to imbalance between them.

The D2 dopamine receptor agonist LY 171555 (0.5 to 5 mg/kg) induces dose-dependent catalepsy in C57BL/6, DBA/2 and BALB/c inbred strains of mice. This effect shows marked strain-dependent differences, since the response of C57BL/6 is significantly lower than those presented by the other two inbred strains at all doses tested. In previous studies we have shown that the D2 agonist at doses ranging from 0.5 to 5 mg/kg induces hyperdefensive responses toward nonaggressive opponents in mice of the C57BL/6 and BALB/c but not of the DBA/2 strain. Here we report that the outbred CD1 mice present both cataleptic and hyperdefensive responses when challenged with LY 171555. Forty-five percent of individuals presenting high defensive response and 11% high cataleptic scores. No correlation was found between catalepsy and hyperdefensiveness in CD1 mice following administration of 1 mg/kg of the D2 agonist. These results suggest that D2 receptor stimulation results in different behavioral responses, possibly mediated by different dopaminergic systems, depending on the genetic make up.

Apomorphine (3 mg/kg) produced in C57BL/6 (C57) mice a clear-cut increase in locomotor activity and climbing behavior in comparison with saline, while in DBA/2 (DBA) mice it produced a clear-cut decrease in locomotion and a small reduction in climbing behavior. Genetic analysis involving F1 and F2 hybrids and the backcross populations (F1 X C57; F1 X DBA) indicated that apomorphine-induced locomotion and climbing are inherited through different modes of inheritance. With regard to climbing behavior the mean analysis of apomorphine parameters showed that the additive-dominance model fitted adequately, while this single model did not fit the locomotor activity data for which the best fitting model involved epistatic parameter. Moreover, a zero correlation between the two behaviors in the F2 generation resulted, indicating that no relationship exists between these apomorphine-induced behaviors under our experimental conditions. These results suggest that the horizontal locomotion and climbing are distinct behaviors controlled, at least in part, by different genetic factors related to different dopaminergic mechanisms.

The dopamine agonist LY171555 (quinpirole), a specific D2 receptor agonist, induces catalepsy in mice at doses ranging from 0.3 to 10 mg/kg. The effects of an intermediate dose of this compound (1 mg/kg SC) were antagonized by 25 mg/kg of the selective D2 antagonist (-)-sulpiride (IP) injected 20 min before LY171555. SCH 23390, a selective D1 antagonist, administered (0.3 mg/kg IP) 20 min before LY171555 (1 mg/kg) enhanced the cataleptic effects of this compound. Finally, when the D1 dopamine receptor agonist SKF 38393 (20 mg/kg SC) was administered immediately beforehand, the cataleptic effects of 1 mg/kg of LY171555 were markedly reduced. These results suggest that there is a functional interaction between D1 and D2 dopamine receptors in the modulation of catalepsy.

Pretreatment with naltrexone (2.5 and 5 mg/kg) prevented the decrease of 3-methoxytyramine (3-MT)/dopamine (DA) ratio induced by 2 h immobilization stress in the nucleus accumbens (NAS) of the mouse while it did not affect the stress-induced decrease of 3-MT/DA ratio in caudatus putamen (CP). Naltrexone also produced a slight antagonism of homovanillic acid (HVA)/DA ratio increase produced by stress in the frontal cortex (FC). These results point to an involvement of endogenous opioids in the effects of stress on DA metabolism in the mesolimbic system of the mouse.

Apomorphine (0.1, 0.25, 0.5, 1, 3 mg/kg, SC), induces a dose-dependent reduction of locomotor activity in DBA/2(DBA) and BALB/c(BALB) mice, while it enhances locomotor activity in a biphasic way in C57BL/6(C57) mice. On the other hand, apomorphine is ineffective in modifying climbing behavior in DBA mice while it increases climbing behavior in C57 and BALB mice. The results, taken together, suggest that these are two different behaviors, possibly controlled by different dopaminergic mechanisms depending on the genetic makeup.

Shock-induced aggressive behavior (SIAB) is absent or very weak in C57BL/6 (C57) mice at the age of 12 weeks while it reaches high levels at the age of 20 weeks. This age-dependent increase of aggressive responses is absent in DBA/2 (DBA) mice. Aggressive C57 mice (20 week old) are characterized by lower GABA levels in amygdala, striatum and substantia nigra than both non-aggressive C57 (12 week old) and DBA mice (12-20 week old). Concerning turnover rate, C57 mice at the age of 20 weeks show lower turnover rate values in cerebellum and raphe and higher values in septum in comparison with 12 week old mice of the same strain. These results are discussed in terms of the role of GABA function in brain areas which are involved in the control of emotionality and aggressive behavior.