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The role of GABAB receptors in various behavioral processes has been largely defined using the prototypical GABAB receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioral paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety, the role of GABAB receptors in these disorders is largely unclear. We recently identified GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) as a selective allosteric positive modulator at GABAB receptors. The aim of the present study was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition, and anxiety. The following tests were included: locomotor activity in rats and mice, rotarod and traction tests (including determinations of core temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital- and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature, or narcosis. Most interestingly, GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABAB receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side effect profile to both baclofen and benzodiazepines.

The climbing behaviour after low doses (0.05, 0.1 and 0.2 mg/kg) or a high dose (1.5 mg/kg) of apomorphine was studied in saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. Following a 3-week recovery from two injections of saline or MPTP (50 mg/kg inter-injection period: 72 h), mice were randomly selected for determinations of contents of neurotransmitters and metabolites (dopamine, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA)) or the apomorphine-induced climbing paradigm. For the climbing experiment, the animals were habituated for 60 min to metal climbing cylinders after which they received a subcutaneous injection of apomorphine or its solvent. Subsequently, the animals were placed back in the cylinders and their climbing scores were recorded every 5 min for 60 min. The biochemical data indicated that striatal levels of dopamine, DOPAC and HVA were significantly reduced following MPTP-treatment whereas striatal 5-HT and 5-HIAA levels were unaffected. In the climbing paradigm saline and MPTP-treated C57BL/6 mice responded diametrically opposite to low doses of apomorphine: 0.1 and 0.2 mg/kg apomorphine reduced the climbing score in saline-treated mice as compared to saline injections whereas 0.2 mg/kg apomorphine increased the climbing score in MPTP-treated mice. A relatively high dose of apomorphine (1.5 mg/kg) increased the climbing score in both saline- and MPTP-treated mice. However, the climbing score was significantly higher in MPTP-treated mice than in saline-treated mice. These data suggest that MPTP-treated mice lack pre-synaptic dopamine receptors and have an increased post-synaptic sensitivity for apomorphine which is in agreement with the fact that MPTP selectively affects the dopaminergic nigro-striatal pathway which then results in an up-regulation of post-synaptic receptors.

Paired groups of rats (derived from divergent, selective breeding or living in divergent environmental conditions) were compared with regard to locomotor activities. Intrapair differences were found to vary non-systematically, depending upon whether the rats were initially exposed to a test-environment with or without a slight environmental modification (reactive activities), or were allowed to habituate extensively to the environment (spontaneous activity). Since the behavioral patterns were found to represent distinct entities, this pointed to the necessity of differentiating clearly between spontaneous and reactive activities and indicated, once again, that both genetic and environmental influences are important in these behaviors and must be taken into account. Accepting and controlling for these variables makes it possible to use the factor of individual differences in laboratory animal behavior to advantage.

The effects of yohimbine and chlordiazepoxide on locomotor activity in an open field were found to depend on the rat's previous habituation to the test environment: chlordiazepoxide induced a locomotor activation in nonhabituated, but not in habituated rats; yohimbine activated in habituated rats only. In a further study, carried out in the rat's homecage (habituated conditions), the effect of both drugs on competition for sucrose pellets was assessed: yohimbine, but not chlordiazepoxide, helped so-called poor-performing rats to temporarily overcome their typical abstention from competition. The presence or absence of drug effects, obviously depending on the rat's previous familiarization with the test environment, are discussed with view to Gray's concept of the behavioral inhibition system.

Differences in locomotor activity in the open field were found between individually and group-housed rats (isol greater than soc). Daily handling, initiated at postnatal day 1, was without effect in group-housed rats but prevented the isolation-induced hyperactivity. For tail-flick latency, strikingly similar differences (isol greater than soc; prevention by handling) have been observed. The isolation-induced aberrations in both locomotor reactivity in a novel environment and in pain sensitivity could be reversed by subsequent resocialization. This indicates that the altered sensitivities to external stimuli are caused by the environmental manipulation.

Individually and group-housed rats of both sexes were compared in respect to spontaneous rotational movements when exposed to a novel environment. Thereby, individually housed animals showed a higher number of rotational movements than group-housed controls. During an L12:D12 cycle, such movements occurred most frequently at the beginning of the dark phase, when locomotor activity was highest. It is assumed that these rotations are part of the hyperreactivity toward a novel environment induced by long-term individual housing.

An interstrain comparison was conducted between male spontaneously hypertensive rats and Wistar-Kyoto rats, in both the open field and the elevated plus-maze. Wistar-Kyoto rats, as compared to the hypertensive animals, showed, beside an attenuated locomotor activity in both test situations, a higher reaction to aversive environments (less entries into the central area of the open field and less visits to the open arms of the elevated plus-maze). Chlordiazepoxide, as potent anxiolytic, increased (1) general activity, (2) the frequency of entries into the open area of the open field, and (3) the number of visits to the open arms of the elevated plus-maze in both rat strains.