Mice lacking the Parkinson's related GPR37/PAEL receptor show non-motor behavioral phenotypes: age and gender effect.

Non-motor symptoms in Parkinson's disease (PD) have been often described at different stages of the disease but they are poorly understood. We observed specific phenotypes related to these symptoms in mice lacking the PD-associated GPR37/PAEL receptor. GPR37 is an orphan G-protein-coupled receptor highly expressed in the mammalian central nervous system. It is a substrate of parkin and it is involved in the pathogenesis of PD. GPR37 interacts with the dopamine transporter (DAT), modulating nigro-striatal dopaminergic signaling and behavioral responses to amphetamine and cocaine. GPR37 knockout (KO) mice are resistant to MPTP and exhibit several motor behavioral abnormalities related to altered dopaminergic system function. To evaluate non-motor behavioral domains, adult and aged, male and female GPR37 KO mice and their wild-type (WT) littermates were analyzed in a series of cross-sectional studies. Aged GPR37 KO female mice showed mild improvements in olfactory function, while anxiety and depression-like behaviors appeared to be significantly increased. A reduction of the startle response to acoustic stimuli was observed only in adult GPR37 KO mice of both genders. Furthermore, HPLC analysis of major neurotransmitter levels revealed gender differences in the striatum, hippocampus and olfactory bulb of mutant mice. The absence of GPR37 receptor could have a neuroprotective effect in an age and gender-dependent manner, and the study of this receptor could be valuable in the search for novel therapeutic targets.

Nucleus accumbens dopamine receptors in the consolidation of spatial memory.

Nucleus accumbens dopamine is known to play an important role in motor activity and in behaviours governed by drugs and natural reinforcers, as well as in non-associative forms of learning. At the same time, activation of D1 and D2 dopamine receptors has been suggested to promote intracellular events related to neural plasticity. Therefore, in this study we wished to investigate the role of the two classes of dopamine receptors within the nucleus accumbens on the consolidation of spatial information. On day 1, CD1 male mice were placed in an open field containing five different objects and, immediately after three sessions of habituation, the animals were focally injected within the nucleus accumbens with either the D1 antagonist SCH 23390 (12.5, 25 or 50 ng/side), or the D2 antagonist sulpiride (25, 50, 75 or 100 ng/side). Twenty-four hours later the ability of mice to discriminate an object displacement was assessed. Both the D1 and the D2 antagonists impaired the ability of mice to detect the spatial change. If the highest doses of the two antagonists were injected 2 h after the end of the last of the habituation sessions, no effect was observed in the reactivity to spatial change examined 24 h later. These data demonstrate that activation of both D1 and D2 receptors within the accumbens is necessary in the early stages of the consolidation of spatial information. The data are discussed in terms of involvement of nucleus accumbens dopamine in information processing in the absence of explicit reinforcers.

Hippocampal gene expression is modulated by hypergravity.

We used the cDNA microarray technique to monitor simultaneously possible changes induced by hypergravity in the expression level of thousands of hippocampal genes. We tested the mRNA level of about 5000 genes in the hippocampus of mice subjected to 1.09 g (1g) or to 1.85 g (2g) for five repeated 1-h daily rotations in a centrifuge (g = 9.81 m/s2). Data were compared with those obtained for mice kept stationary (C). The ratios 1g/C and 2g/C identified genes affected by rotation and rotation + hypergravity, respectively, whereas 2g/1g ratio identified those affected by hypergravity. We found that about 200 genes were affected by rotation and/or rotation + hypergravity. Almost all the genes affected by rotation + hypergravity were up-regulated, only five being down-regulated. The modulated genes code for proteins involved in a wide range of cellular functions (DNA/RNA metabolism, protein processing, intermediate metabolism, cytoskeleton and motility, cell cycle and apoptosis, signal transduction, neuronal structure/function), suggesting that rotation + hypergravity may affect several aspects of the hippocampal function in order to compensate for environmental changes. Six genes directly or indirectly involved in synaptic transmission and plasticity (proSAAS, neuroblastoma ras oncogene, ESTs moderately similar to thymosin beta-10, syndet, inhibin beta E and Ngfi-A binding protein 2) were found to be significantly modulated by hypergravity and unaffected or only slightly affected by rotation. The modulation by hypergravity of these genes suggests that this stimulus might induce plastic remodelling of the hippocampal circuits, possibly both at structural and functional level.

Repeated administration of phencyclidine, amphetamine and MK-801 selectively impairs spatial learning in mice: a possible model of psychotomimetic drug-induced cognitive deficits.

Cognitive deficits are a key feature of schizophrenia. N-Methyl-D-aspartate (NMDA) receptor antagonists and amphetamine are known to induce psychotic behaviors and cognitive deficits in animals and humans, often affecting visuo-spatial abilities. Phencyclidine (PCP), MK-801 and amphetamine (AMPH) have been used in pharmacological animal models of schizophrenia, but none of these models has focused so far on spatial learning after repeated administration of the drugs. The objective of this study was to test whether repeated administration of PCP, AMPH or MK-801 influenced the performance of mice in a non-associative spatial learning test. CD-1 male mice were given i.p. daily injections of either saline, PCP (5.0, 10.0 mg/kg), AMPH (2.5, 5 mg/kg) or MK-801 (0.3, 0.6 mg/kg), for 5 days. On day 6 all mice were tested in an open field containing five different objects. After three sessions of habituation, each animal's reactivity to object displacement and object substitution was assessed. No significant differences among treatment groups were observed in object exploration or locomotion during the habituation phase. Five days of repeated PCP, AMPH or MK-801 administration selectively and differentially impaired the ability of mice to discriminate a spatial change, while leaving intact the ability to react to a non-spatial change. These data suggest that neurobiological adaptations to drug regimens known to induce psychotic behaviors and alterations in locomotor activity or stereotypies can also alter spatial learning, as assessed in this test, thus indicating that these regimens could also mimic some of the cognitive deficits observed in schizophrenia.

Chronic sucrose intake augments antinociception induced by injections of mu but not kappa opioid receptor agonists into the periaqueductal gray matter in male and female rats.

Chronic intake of a palatable sucrose solution enhances the antinociceptive potency of systemically administered mu, and kappa opioid receptor agonists. To investigate whether the effects of sucrose on the actions of opioid drugs are mediated within the central nervous system (CNS), antinociception was examined following the administration of mu and kappa opioid receptor agonists into the periaqueductal gray area (PAG). Male and female Long-Evans rats consumed either water and ground chow, or water, chow and a 32% (w/v) sucrose solution. After adaptation to the dietary conditions, a guide cannula was stereotaxically implanted into the PAG. Injections of the mu agonist, morphine (0.0, 2.5, 5.0, 10.0 and 20.0 microg), into the PAG led to dose-related increases in antinociceptive responses on a tail flick test in both male and female rats. Rats which had consumed sucrose displayed significantly greater levels of antinociception than rats not given the sugar. Antinociceptive responses to morphine did not differ as a function of sex. Injections of the kappa agonist, spiradoline (0, 100, 300, 600 microg), into the PAG increased tail flick latencies in male and female rats. However, antinociceptive responses did not vary as a function of diet in rats injected with spiradoline. In both diet conditions, spiradoline led to greater levels of antinociception in female rats than in male rats. These results support the hypothesis that intake of palatable foods and fluids act within the CNS to moderate the behavioral actions of opioid drugs.

Chronic sucrose intake enhances nicotine-induced antinociception in female but not male Long-Evans rats.

Previous work has demonstrated that intake of palatable foods can alter the behavioral actions of opioid drugs. To investigate whether intake of palatable fare only affects opioid-induced behaviors or more generally influences drug-induced responses, this study examined the effects of chronic intake of a palatable sucrose solution on nicotine-induced antinociception. Eight male and eight female Long-Evans rats were provided with ground chow and water (control group), while eight males and eight females were provided with chow, water and a 32% sucrose solution (sucrose group). After 3 weeks of exposure to the dietary conditions, all rats were tested for nicotine-induced antinociception using the tail flick test. Nicotine, administered using a cumulative dose regime (0.03, 0.1, 0.3 and 1.0 mg/kg sc), led to dose-dependent increases in tail flick latencies in male and female rats. Females in the sucrose group displayed significantly greater antinociceptive responses to nicotine than those in the control group. Similar results were obtained when females were retested after an additional 2 weeks. Comparison of males and females, revealed that sucrose enhanced nicotine's antinociceptive action in female but not in male rats. While previous research suggested that sweet tasting substances might affect drug action by acting on the endogenous opioid system, the present results indicate that sucrose intake could also alter the cholinergic system and possibly other systems involved in nicotine antinociception.

Male olfactory cues affect mothers' behavior in mice: effects of benzodiazepines.

RATIONALE: Threatening social stimuli were used in this study as aversive conditions to test anxiety in lactating female mice. The odors of potential infanticidal males or the "stress odor" left by restrained mice represented two aversive conditions that have been suggested to modulate the time spent by the mothers to reach their pups after 30 min of separation. OBJECTIVES: The effects of drugs acting at the benzodiazepine receptors were evaluated on the behavior of mothers exposed to different threatening social cues. METHODS: Lactating mice of the NMRI outbred strain with 8-day old pups were treated with (1) chlordiazepoxide (CDP) 2.5, 5.0 and 10 mg/kg i.p.; (2) flumazenil 10 mg/kg i.p. and (3) methyl beta-carboline-3-carboxylate (beta-CCM) 3.0 mg/kg i.p. RESULTS: The odors left by stressed females changed the mothers' exploratory behavior, but not the latency to reach pups. The latency was higher in the presence of cues from potentially infanticidal males. CDP (5.0 mg/kg) reduced the time spent to contact pups, whereas the other CDP doses did not modify the dam's behavior. Flumazenil, given in combination with CDP (5.0 mg/kg) antagonized the latter anxiolytic effect. In addition, in the presence of cues from potentially infanticidal males beta-CCM had anxiogenic activity, increasing latency to reach pups. The same CDP and beta-CCM doses were ineffective in the presence of cues from stressed females and in the absence of olfactory cues from conspecifics. CONCLUSIONS: This study provides behavioral and pharmacological validation of a new model of anxiety specifically designed for lactating females.

Ethanol drinking in socially housed squirrel monkeys.

This study proposes a method to assess voluntary alcohol drinking in socially living squirrel monkeys. Group-housed squirrel monkeys were induced to drink a sucrose solution and subsequently an ethanol/sucrose solution in an experimental chamber attached to the home colony room, allowing the daily intake to be monitored for each individual without disrupting the social context. Sucrose concentration (0.03-0.6 M, corresponding to 1-20%) and ethanol concentration (0-4%) were gradually increased in tap water and in a 0.6 M (ca. 20%) sucrose solution during daily 30-min and 10-min sessions, respectively. Blood ethanol levels ranged from 10-50 mg/dl and remained below intoxication level. These experiments demonstrate that it is feasible to arrange conditions under which individual socially housed squirrel monkeys voluntarily drink a sweetened ethanol solution.

Effect of strange male odour on parental care in lactating female mice

This paper analyses the behaviour of lactating female outbred mice, Mus musculus domesticusin the presence of male conspecific odours. When olfactory cues were left in the environment by a sexually naive adult male, a potentially infanticidal animal, the mother took longer to reach her litter following 30 min of separation. Odours left by the sexual partner, by an unknown male of parental status, or by a young naive male did not modify the mother's behaviour, compared with the control situation (absence of male odour). The number of ultrasonic calls of pups varied according to the characteristics of the male but did not modify the behaviour of the dam. Females took longer to reach pups on day 8 of lactation than on days 4 or 12. We suggest adaptive reasons why females take longer to reach pups when the situation is more risky. We tested the hypothesis that the loss of an 8-day-old litter is more expensive, in term of the mother's future reproductive success, than the loss of younger and older litters. Females conceived a new litter within a few days (the inter-birth interval varied according to the age of the litter previously removed) but, even though no difference in size and weight of litters was recorded, females that had the litter removed on day 8 postpartum (compared with days 4 and 12) suffered from a higher mortality rate in the next litter. We suggest that the time the mother takes to reach her pups in the presence of a potentially infanticidal male could represent a measure of parental investment.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour