Modulation of spatial alternation and anxiety by septal scopolamine systemic diazepam in mice.

To investigate the behavioral consequences of benzodiazepines in subjects whose septo-hippocampal cholinergic (ACh) activity was impaired, C57BL/6 mice received an injection of 2.5 microg/0.2 microl of scopolamine into the medial septal area with an i.p. injection of 0.5 mg/kg of diazepam. The consequences of these treatments administered in combination or alone were evaluated on anxiety measured in an elevated plus-maze and on spontaneous alternation carried out in a T-maze, using two different intertrial intervals (ITI: 5s or 30s). In these conditions, only the combined treatment provoked a decrease of the anxiety level, which was associated with an impairment of spontaneous alternation restricted to the 5s ITI. Because mice were not impaired during the sequential 30s ITI, this seems to rule out the possibility that this alternation deficit resulted from a working memory loss. These results suggest an involvement of a septal ACh-GABA-A/BDZ interaction in the exaggeration of cognitive deficits produced by benzodiazepines in patients characterized by a cholinergic hypofunction.

Modulation by GABA transmission in the substantia nigra compacta and reticulata of locomotor activity in rats exposed to high pressure.

Helium pressure of > 20 bar causes neuroexcitatory changes referred to as the high pressure neurological syndrome. In rodents, symptoms include locomotor and motor activity (LMA), myoclonia and, at greater pressure, convulsions. We studied the effects of the GABA reuptake inhibitor nipecotic acid, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), the GABAA receptor agonist muscimol, and the GABAB receptor agonist baclofen. Whatever the drug used, bilateral administration in the substantia nigra reticulata (SNR) or in the substantia nigra compacta (SNC) showed no significant effects on myoclonia. In contrast, administration in the SNR of nipecotic acid, GVG, and baclofen resulted in a significant decrease of LMA; administration of muscimol in the SNR increased LMA. No significant effect was seen when drugs were injected in the SNC. These results suggest that changes in GABA transmission in the SNR, but not in the SNC, play a crucial role in the control of motor activity and the regulation of movement.

The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice.

The neurosteroid pregnenolone sulfate (PREG-S) has been shown to modulate positively NMDA receptor activity and to have memory enhancing properties in mice. The present study was designed to evaluate the effects of post-training administration of PREG-S, alone or in combination with D-2-amino-5-phosphonovalerate (D-AP5), a competitive NMDA receptor antagonist, in Y-maze avoidance and appetitively motivated lever-press learning tasks and in a traction reflex test in mice. Intracerebroventricular (i.c.v.) administration of PREG-S (0.01-0.1 nmol/mouse) blocked the selective retention deficits induced by 0.02 nmol D-AP5 in the Y-maze avoidance task. PREG-S (0.1 nmol, i.c.v.) also blocked the retention deficits induced by 0.02 nmol D-AP5 in the lever-press task. Post-training administration of PREG-S alone (0.001-0.1 nmol, i.c.v.) had no effect on retention performance in the Y-maze and the lever-press tasks. PREG-S (1-10 nmol, i.c.v.) significantly reduced the impairment of the traction reflex induced by 2 nmol D-AP5. The ability of PREG-S to block retention performance deficits as well as motor impairment induced by D-AP5 is in agreement with its positive modulatory action at NMDA receptors.