Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating.

RATIONALE: Nicotine improves the deficiencies of sensory gating function in schizophrenic patients and in dilute brown non-Agouti (DBA/2) mice. This effect of nicotine has been attributed to activation of the alpha7 nicotinic acetylcholine receptor (nAChR) subtype. OBJECTIVE: The aim of this study was to determine whether the activation of another nAChR subtype, the central nervous system (CNS) prominent alpha4beta2 receptor, also contributes to the effects of nicotine on sensory gating in DBA/2 mice. METHODS: Unanesthetized DBA/2 mice were treated either with nicotine, the alpha4beta2 antagonist dihydro-beta-erythroidine, the noncompetitive nAChR antagonist mecamylamine, or a combination of an antagonist and nicotine. Thereafter, gating was assessed by recording hippocampal evoked potentials (EP), which were elicited by pairs of auditory clicks. The EP response to the second click, or test amplitude (TAMP), was divided by the EP response to the first click, or condition amplitude (CAMP), to derive gating T:C ratios. RESULTS: Nicotine significantly (p<0.05) lowered T:C ratios by 42%, while significantly increasing CAMP by 55%. After a pretreatment with dihydro-beta-erythroidine, nicotine still significantly lowered T:C ratios by 28%; however, the nicotine-induced increase of CAMP was blocked. Mecamylamine blocked the effect of nicotine on both T:C ratios and CAMP. CONCLUSIONS: Activation of alpha4beta2 receptors by nicotine increases CAMP. However, under conditions where alpha4beta2 receptors are blocked, nicotine still lowers T:C ratios and may improve sensory gating, possibly through the activation of other nAChR subtypes such as alpha7. These effects of nicotine on auditory EPs may be indicative of a profile that would improve information processing in schizophrenia and other CNS diseases.

GABAergic drugs alter hypothalamic serotonin release and lordosis in estrogen-primed rats.

The effects of muscimol, a GABA(A) agonist, and phaclofen, a GABA(B) antagonist, on serotonin (5HT) release in the mediobasal hypothalamus and lordosis behavior were studied in freely moving rats using in vivo microdialysis. Two days after implantation of bilateral guide cannulae directed towards the ventromedial nucleus of the hypothalamus (VMH), ovariectomized rats were primed with estradiol (E(2)). The rats were implanted with microdialysis probes 24 h later. Following a pretest for lordosis, perfusate 5HT was measured at 20-min intervals until the baseline was stable. The rats were treated with 10, 30 or 100 microM muscimol or 30 and 100 microM phaclofen in artificial CSF delivered via reverse dialysis for 40 min. Control animals were continuously perfused with artificial CSF. Behavior was tested 20, 60 and 180 min after introduction of the drug. Decreased hypothalamic 5HT (40-60% of baseline) and marked facilitation of lordosis were present 20 min after administration of either drug. The effects of 10 and 30 microM muscimol and 30 microM phaclofen on both 5HT and lordosis were reversed after 180 min. Reversal of the behavioral and neurochemical effects were not evident in either the 100 microM muscimol or 100 microM phaclofen groups at the time-points tested. Proceptive responses were observed in phaclofen-treated rats but not in rats treated with muscimol. Levels of hypothalamic 5HT and lordosis quotients in control rats did not significantly differ from initial values. These results suggest that GABAergic effects on lordosis may be mediated through an interaction with 5HT in the mediobasal hypothalamus.