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The immediate post-trial injection of the centrally active muscarinic agonist oxotremorine (0.025, 0.050 and 0.100 mg/kg, IP) can facilitate the retention of a passive-avoidance response in mice, as indicated by performance on a retention test 24 h later. Injections given 10 min after training also significantly facilitated retention, but given 120 min after training did not affect retention. These findings suggest an action of oxotremorine on memory mechanisms. The enhanced retention was neither the result of a punishing effect of oxotremorine nor of a nonspecific proactive pharmacological action of the drug. The memory facilitation produced by oxotremorine (0.050 mg/kg, IP) was not antagonized by pretreatment with phentolamine (10 mg/kg, 30 min, IP), phenoxybenzamine (10 mg/kg, 120 min, IP) or piperoxane (20 mg/kg, 30 min, IP). The alpha-noradrenergic blocking agents had no effect by themselves. On the other hand, the immediate post-trial injection of oxotremorine (0.050 mg/kg, IP) did not enhance retention when mice were pretreated with haloperidol (0.5 mg/kg, 120 min, IP). Haloperidol injected either before training or before the retention test did not alter performance during the retention test. This suggests that haloperidol impairs neither acquisition of the avoidance response nor its retrieval. Thus, it is probable that haloperidol pretreatment impaired oxotremorine-induced memory facilitation. We suggest a possible participation of brain catecholamines in memory facilitation induced by oxotremorine in mice.

These experiments investigated the effects of central noradrenaline (NA) depletion and its interaction with cholinergic and dopaminergic mechanisms upon retention of a passive-avoidance response in mice. The NA selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP 4) (50 mg/kg IP, 7 days) was injected into mice to produce depletion of NA in frontal cortex, hypothalamus, cerebellum, midbrain and brain stem without any significant change in dopamine (DA) levels in frontal cortex, striatum, hypothalamus and midbrain. Depletion of brain NA produced by DSP 4 was significantly but not completely prevented by the NA uptake inhibitor desmethylimipramine (DMI) (10 mg/kg IP, 30 min before DSP 4 injection). Despite the marked NA depletion, DSP 4 neither impaired the retention of a passive-avoidance response in mice nor prevented the enhancement of retention of this response induced by the central muscarinic agonist oxotremorine (OTM) (0.05 mg/kg IP, immediately after training. This lack of effect of DSP 4 on retention was prevented neither by DMI nor by the serotonin uptake inhibitor fluoxetine (5 mg/kg IP, 30 min before DSP 4 injection). The enhancement of retention induced by OTM in the groups of mice injected with either water or DSP 4 was prevented by atropine (0.5 mg/kg IP, 20 min before training) but not by methylatropine in the same experimental conditions. This suggests that both in controls and DSP 4-pretreated mice, the primary effect of OTM is due to an interaction with muscarinic brain receptors.(ABSTRACT TRUNCATED AT 250 WORDS)