Effects Of FG7142 Research Articles

The effects of FG7142 on overexpectation of Pavlovian fear conditioning.

Six experiments studied the role of GABA-sub(A) receptor activation in expression of overexpectation of Pavlovian fear conditioning. After separate pairings of CSA and CSB with shock in Stage I, rats received pairings of the compound AB with shock in Stage II, producing overexpectation of fear. The expression of overexpectation was attenuated, in a dose-dependent manner, by the benzodiazepine partial inverse agonist FG7142. FG7142 had no effect on responding to a CS paired with a low magnitude US or a CS subjected to associative blocking. These results suggest that the negative prediction error generated during overexpectation training may impose a mask on fear rather than erasing the original fear learning. They support claims that overexpectation shares features with extinction.

Effects of FG7142 and immobilization stress on the gene expression in the neocortex of mice

Several psychiatric disorders are often precipitated or exacerbated by exposure to stressors. FG7142 ( N-methyl-β-carboline-3-carboxamide), a partial inverse agonist of benzodiazepine receptors, mimics the physiological (an increased release in the adrenal steroid hormone) and neurochemical (an enhanced neurotransmission of monoamines) changes induced by stressful stimuli. We examined the effects of FG7142 and immobilization stress on the gene expression of the mouse neocortex in order to obtain a new insight into the molecular stress-responsive system. The effect of FG7142 (20 mg/kg, i.p.) on the gene expression of the brain area was examined using a DNA microarray method. The genes showing a significant change in expression were investigated in further experiments using the quantitative RT-PCR method. There was an increase in the mRNA of seven genes in the neocortex of mice 1 h after treatment with FG7142. In addition, there was an increase in the mRNAs of five of the seven genes (Fos, Cyr61, Btg2, Adamts1, and Gem) in the neocortex of mice exposed to the stress for 1 h. The up-regulation of these five genes by both FG7142 and immobilization stress indicates that these genes may be involved in the stress-responsive system. Dysfunctions of the system may be associated with the pathophysiology of psychiatric disorders.

The effects of FG7142 on two types of forgetting in 18-day-old rats.

The authors studied the role of gamma-aminobutyric acid (GABA) in 2 types of forgetting of fear in the developing rat. One type of forgetting studied was that observed after an intermediate retention interval (the "Kamin effect"); the other type studied was that observed after a longer interval (infantile amnesia). Rats were given pairings of an auditory conditioned stimulus with shock, and learned fear was assessed by freezing. Forgetting at an intermediate retention interval (1 hr) was not alleviated by the GABA-sub(A) receptor partial inverse agonist FG7142 (0, 1, 5, or 10 mg/kg), whereas forgetting at a longer retention interval (48 hr) was alleviated. These results suggest that in the developing rat, forgetting observed at different retention intervals is mediated by different physiological mechanisms.

Modelling Anxiety Disorders Following Chemical Exposures

The effects of kindling and inverse benzodiazepine receptor agonist beta-carbolines on animal models of anxiety are briefly reviewed in relation to affective disorder associated with chemical exposure. Recent experimental results are described. In the present study, cats were given the inverse benzodiazepine receptor agonist, FG-7142, a powerful anxiogenic compound in humans and animals. Neural transmission in pathways involved in defensive behavior in the cat was monitored using evoked potential techniques. Change in these pathways was related to behavioral changes induced by the drug. It was found that a single dose of FG-7142 lastingly increased defensive response to rodents for at least 40 days after drug administration. Behavioral change was specific to defensive response, since approach-attack behavior remained unchanged, replicating previous studies. The benzodiazepine receptor antagonist, Flumazenil, reversed the increase in defensiveness in a drug-dependent manner, replicating previous findings. Increased defensiveness was paralleled by a delayed onset potentiation of neural transmission between the amygdala and the medial hypothalamus of the left hemisphere. Potentiation in the left hemisphere was transient, decaying between 6 and 12 days after the drug. There was a longer lasting potentiation (LTP) of activity evoked in the left and right amygdalo-periacqueductal gray pathways and in the right amygdalo-medial hypothalamic pathway. Potentiation in these pathways appeared at the time of behavioral change. Potentiation of the right amygdalo-periacqueductal gray and right amygdalo-medial hypothalamic pathways persisted until the end of the experiment. In contrast, potentiation of the left amygdalo-periacqueductal gray pathway faded by 40 days after the drug. Flumazenil decreased potentiation ony in the right amygdalo-periacqueductal gray pathway. These data strongly suggest that lasting affective change is mediated by lasting changes in particular efferents of the amygdala of the right hemisphere. Behavioral and physiological effects of FG-7142 were blocked by the N-methyl-D-Aspartate (NMDA) receptor blocker, AP7. The data suggest that failure of neural inhibition induced by FG-7142 engages NMDA receptor processes to produce lasting potentiation of transmission in neural circuits that mediate defensive response with behavioral consequences. Since FG-7142 interferes with GABA mediated neural inhibition and is proconvulsant, its action might mimic the action of other environmental chemicals with similar properties, such as chlorinated hydrocarbon insecticides. The relationship of the present data to the literature on the neural and behavioral effects of insecticide exposure is discussed. The significance of these findings for multiple chemical sensitivity disorder is also briefly discussed.

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

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.

Acute and lasting effects of FG-7142 on defensive and approach-attack behavior in cats—implications for models of anxiety which use response suppression

The effect of the anxiogenic β-carboline, FG-7142, on defense and approach-attack behavior in the cat was investigated. FG-7142 (10 mg/kg) enhanced defensive responses to rats and mice when tested 10 and 20 min after injection. At the same time, FG-7142 suppressed approach and attack responses to prey. Behavioral effects of FG-7142 were blocked by the specific benzodiazepine receptor blocker RO-15-1788 (10 mg/kg). One or two administrations of FG-7142 were sufficient to produce a lasting (up to 105 days) enhancement of defensive response to rats but not to mice. Defensive response to conspecific threat vocalizations was also lastingly increased. Two injections of FG-7142 produced a lasting suppression of approach-attack on rats only, whereas one injection of FG-7142 did not. The lasting suppression of some measures of approach-attack was found to be independent of the fear-enhancing properties of FG-7142. Tests of the effects of RO-15-1788 on the lasting after-effects of FG-7142 revealed at least two mechanisms which mediate the lasting changes in behavior, one which is dependent upon the benzodiazepine receptor and one which is not. The implications of these findings for rodent models of anxiety which use response suppression to assess fearful 'anxiogenic' effects of drugs are discussed.

The anxiogenic β-carboline FG-7142 increases in vivo and in vitro tyrosine hydroxylation in the prefrontal cortex

Systemic administration of the anxiogenic β-carboline FG-7142, a benzodiazepine inverse agonist, results in a regionally selective increase in dopamine (DA) utilization in the anteromedial prefrontal cortex (PFC). We have examined both in vivo and in vitro tyrosine hydroxylation in the PFC and other mesotelencephalic DA system terminal fields in order to determine if FG-7142 effects changes in DA synthesis, and to determine if the β-carboline biochemically activates certain DA neurons through an action occurring at the cell body level (impulse-dependent regulation) or at the terminal field level (presynaptic regulation). FG-7142 increased in vivo tyrosine hydroxylation in the PFC and in the ventral tegmental area, midbrain source of the DA innervation of the PFC; no changes were observed in mesolimbic or nigrostriatal regions. The β-carboline also increased in vitro tyrosine hydroxylation in the PFC, but decreased tyrosine hydroxylation in striatal slices. The effects of FG-7142 were blocked by the benzodiazepine antagonist RO 15-1788. Another β-carboline inverse agonist, methyl-β-carboline-carboxylate, also increased in vitro tyrosine hydroxylation in the PFC. GABA exerted opposite effects to those of the β-carbolines, decreasing in vitro tyrosine hydroxylation increasing DA synthesis in the CP. These data indicate that the benzodiazepine inverse agonists increase both in vivo and in vitro tyrosine hydroxylation in the PFC, and that the β-carboline may act to increase DA synthesis at both the terminal field and the cell body level.