Effect of estradiol benzoate microinjection into the median raphe nucleus on contextual conditioning.

Estrogen deficiency has been associated with stress, anxiety and depression. Estrogen receptors have been identified in the median raphe nucleus (MRN). This structure is the main source of serotonergic projections to the hippocampus, a forebrain area implicated in the regulation of defensive responses and in the resistance to chronic stress. There is reported evidence indicating that estrogen modulates 5-HT1A receptor function. In the MRN, somatodendritic 5-HT1A receptors control the activity of serotonergic neurones by negative feedback. The present study has evaluated the effect of intra-MRN injection of estradiol benzoate (EB, 600 or 1200 ng/0.2 microl) on the performance of ovariectomized rats submitted to contextual conditioning. Additionally, the same treatment was given after intra-MRN injection of Way 100635 (100 ng/0.2 microl), a 5-HT1A receptor antagonist. Both doses of EB decreased freezing and increased rearing, indicating an anxiolytic effect. Pretreatment with Way 100635 antagonized the anxiolytic effect of estradiol. On the basis of these results, it may be suggested that estrogens modulate anxiety by acting on 5-HT1A receptors localized in the MRN.

Effects of apomorphine and clozapine on conditioned freezing and latent inhibition.

Consistent evidence has shown that learning may be produced in paradigms using electrical stimulation of the inferior colliculus as unconditioned stimulus (US). Much evidence has also been provided for the involvement of dopamine in the setting up of adaptive responses to aversive states generated at this mesencephalic level. The aim of the present study was to determine whether dopaminergic mechanisms are involved in the conditioned freezing behavior and latent inhibition (LI) using either foot shocks (Experiment 1) or inferior colliculus stimulation (Experiment 2) as US and light as conditioned stimulus (CS). To this end, the authors examined the effects of the dopaminergic agonist apomorphine (AP; 0, 0.5, 1.0, and 2.0 mg/kg) and the atypical antipsychotic clozapine (CLZ 0, 1.0, 2.5, and 5.0 mg/kg) on the acquisition of conditioned freezing and LI. Rats were either simply placed in the experimental chamber non-preexposed (NPE) or preexposed (PE) to 50 light presentations. Next, they were submitted to 10 light plus foot shock (or inferior colliculus stimulation) pairings. In the testing session, conditioned freezing under the CS was measured. In both experiments, conditioned freezing was highly significant in the NPE group while previous exposure to nonreinforced light (PE) weakened the strength of the conditioning. Although weaker than that caused by foot shock/light pairings, the occurrence of freezing and LI with the use of inferior colliculus stimulation as US gives additional support to the participation of this structure in the filtering processes of relevant information to higher brain regions. The drug effects depended on whether foot shock or inferior colliculus stimulation was used as US. In Experiment 1, AP produced a dose dependent increase in conditioned freezing without changing LI. On the other hand, CLZ did not change freezing and LI. In Experiment 2 while AP did not change freezing and LI, CLZ clearly increased freezing without changing LI with the use of inferior colliculus as US. The selective effect of AP on conditioned freezing due to light/foot shocks association is consistent with the heightened attentional and cognitive functions of dopaminergic mechanisms of the mesocorticolimbic systems in the setting up of adaptive responses aimed at coping with or signaling the presence of stimuli of aversive nature. The selective effect of CLZ on conditioned freezing is due to light/IC stimulation and may also be due to the known antagonism of 5-HT(2) receptors produced by low doses of this atypical antipsychotic.