Lasting effects of FG-7142 on anxiety, aggression and limbic physiology in the cat

Abstract

The effect of the anxiogenic β-carboline, FG-7142, on behavior and limbic physiology was investigated. A single systemic injection of FG-7142 (10 mg/kg) changed behavior for at least 43 days. Two days after drug administration, defensive response to rats was increased. In addition, predatory attack was suppressed in some, but not all, animals. Cats that were more predatory (killers, n=2) before drug administration showed suppression of predatory attack after FG-7142. The attack of less predatory cats (non-killers, n=3) was unaffected by FG-7142. Suppression of attack was not correlated with changes in defense. This finding suggests FG-7142 acts on separate substrates of defense and attack suppression to change these behaviors lastingly. FG-7142 produced long-term potentiation (LTP) in two of three limbic pathways investigated. LTP was observed in the amygdalo-ventromedial hypothalamic (AM-VMH) pathway. AM-VMH LTP depended on changes within the amygdala and not in the efferent synapses or in the VMH. LTP lasted 6 days, returning to baseline by 21 days after FG-7142. The only behavioral change correlated with AM-VMH LTP was defensive response at 2 days after FG-7142. Increased defense from 6 to 43 days after the drug was not correlated with AM-VMH LTP. Therefore, AM-VMH LTP may be necessary for the initiation, but not maintenance, of increased defensive response. LTP of the population spike of the perforant path-CA3 (PP-CA3) field potential in the ventral hippocampus was also seen. LTP appeared 6 days after drug administration, after cats had been exposed to rats. Before the appearance of PP-CA3 LTP, there was a transient failure of recurrent inhibition in area CA3. It is likely that exposure to a rat during the period of failed inhibition facilitated the PP-CA3 LTP. In addition, following FG-7142, facilitation in area CA3 increased lastingly, consistent with a lasting increase in the duration of excitatory neurotransmitter release. Changes in hippocampal inhibition and facilitation correlated with changes in attack behavior, but not with changes in defensive response. Systemic flumazenil (10 mg/kg) partially reversed the lasting changes in defense and approach-attack in a drug-dependent manner. Limbic physiology was unchanged by flumazenil. Flumazenil probably did not affect AM-VMH transmission in the present study because AM-VMH LTP had returned to baseline when flumazenil was given. These findings suggest flumazenil only acts on potentiated AM-VMH transmission.