FG 7142

Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142.[Pubmed:20015619]

Eur Neuropsychopharmacol. 2010 Feb;20(2):112-22.

Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0-8.0mg/kg), the CB1 antagonist AM4113 (3.0-12.0mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects.

An anxiogenic drug, FG 7142, induced an increase in mRNA of Btg2 and Adamts1 in the hippocampus of adult mice.[Pubmed:22913326]

Behav Brain Funct. 2012 Aug 22;8:43.

BACKGROUND: Anxiety and stress-related disorders are among the most common psychiatric disorders. The hippocampus is a crucial brain area involved in the neural circuits of the pathophysiology of anxiety and stress-related disorders, and GABA is one of most important neurotransmitters related to these disorders. An anxiogenic drug and a pharmacological stressor, FG7142 (N-methyl-ss-carboline-3-carboxamide), produces anxiety in humans and experimental animals, acting at the benzodiazepine sites of the GABAA receptors as a partial inverse agonist. This drug as well as immobilization stress produced an increased mRNA in a number of genes, e.g., Btg2 and Adamsts1, in the cortex of rodents. The present study was carried out to clarify the effect of the anxiogenic drug on the gene expressions in the hippocampus and to obtain a new insight into the GABAergic system involved in the pathophysiology of the disorders. METHOD: We examined the effects of FG7142 on the gene expression of Btg2 and Adamts1 in the hippocampus of mice using a quantitative RT-PCR method as well as an in situ hybridization method. RESULTS: The intraperitoneal administration of FG7142 at a dose of 20 mg/kg, but not 10 mg/kg, induced a statistically significant increase in the hippocampal mRNA of both genes in adult mice (postnatal days 56), being blocked by co-administrations of flumazenil (twice of 10 mg/kg, i.p.), an antagonist at the benzodiazepine binding site, while FG7142 failed to produce any change in the gene expressions in infant mice (postnatal days 8). In addition, the in situ hybridization experiment demonstrated an upregulation of the gene expressions restricted to the dentate gyrus of the hippocampus in adult mice. CONCLUSIONS: The present study suggests a functional coupling between the GABAergic system and the transcriptional regulation of the two genes (Btg2 and Adamsts1) in the hippocampus of adult mice, which may play a role in the brain function related to anxiety and stress such as memory of fear.

The effects of FG 7142 on sensory-specific satiety in rats.[Pubmed:20117147]

Behav Brain Res. 2010 May 1;209(1):131-6.

Three experiments used intake, clusters, and licks per cluster to study the effects of the GABA inverse agonist, FG 7142, on sensory-specific satiety in rats. In Experiment 1, rats were offered one of two palatable solutions and 30min later tested with the same or the other solution. Rats that received the same solution consumed less, exhibited fewer clusters, fewer licks per cluster and a more rapid decline in rate of licking than rats tested with the other solution. In Experiments 2 and 3, rats tested with the same solution under FG 7142 showed fewer clusters and fewer licks per cluster than vehicle rats. Rats tested with the other solution under FG 7142 showed fewer licks per cluster but more clusters than vehicle rats. The results were discussed in terms of the distinction between "liking" and "wanting" and the role of GABA in the former but not the latter.

Chronic cocaine self-administration attenuates the anxiogenic-like and stress potentiating effects of the benzodiazepine inverse agonist, FG 7142.[Pubmed:21635914]

Pharmacol Biochem Behav. 2011 Sep;99(3):408-13.

Stress is a well-known risk factor in relapse to drug abuse. Several forms of stress in animals have been used with varied degrees of success to elicit reinstatement of drug-seeking after chronic drug self-administration. Here, we tested the ability of the benzodiazepine (BZ) inverse agonist, FG 7142, to elicit anxiety-like behavior and potentiate stress responses in rats as measured by standard behavioral and hormonal indices and for its ability to affect reinstatement of cocaine-seeking in rats with a prior history of cocaine self-administration. FG 7142 elicited anxiety-like behavior on the elevated plus maze (EPM) in cocaine-naive rats, and cocaine-naive rats injected with FG 7142 exhibited increased plasma corticosterone levels following EPM exposure. However, in animals with a history of cocaine self-administration, FG 7142 failed to affect elevated plus maze performance and did not affect plasma corticosterone response to the EPM. Furthermore, FG 7142 failed to reinstate cocaine-seeking, nor did it alter conditioned cue-induced reinstatement. These data indicate that the anxiety-related and stress potentiating qualities of BZ inverse agonism are attenuated in cocaine-experienced animals and do not lead to reinstatement of cocaine-seeking.

Evidence for an excitatory action of the benzodiazepine receptor inverse agonist FG 7142 on C-fibre afferents.[Pubmed:2478895]

Naunyn Schmiedebergs Arch Pharmacol. 1989 Sep;340(3):352-4.

(1) The stimulation of adrenocorticotrophic hormone (ACTH) release by FG 7142 was found to be 50% inhibited in capsaicin-desensitized rats indicating that the excitatory effect of this inverse benzodiazepine agonist is partly mediated through capsaicin-sensitive afferents. (2) The in vitro release of substance P from spinal cord slices was stimulated in a tetrodotoxin-resistant manner by FG 7142. No stimulation of the substance R release by FG 7142 was observed when spinal cord slices were taken from capsaicin-pretreated rats which lack afferent C-fibres. (3) Ro 15-1788 antagonized the in vivo as well as the in vitro stimulatory effects of FG 7142 indicating that they were brought about by interaction with benzodiazepine receptors. (4) It is concluded that FG 7142 has a direct excitatory effect on central terminals of capsaicin-sensitive afferents and that neurotransmitters released from primary afferents are involved in inducing ACTH release following administration of FG 7142 in vivo.

The anxiogenic beta-carboline FG-7142 increases in vivo and in vitro tyrosine hydroxylation in the prefrontal cortex.[Pubmed:2765936]

Brain Res. 1989 Aug 28;495(2):355-61.

Systemic administration of the anxiogenic beta-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 beta-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 beta-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 beta-carboline inverse agonist, methyl-beta-carboline-3-carboline-3-carboxylate, also increased in vitro tyrosine hydroxylation in the PFC. GABA exerted opposite effects to those of the beta-carbolines, decreasing in vitro tyrosine hydroxylation in the PFC and 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 beta-carboline may act to increase DA synthesis at both the terminal field and the cell body level.

Behavioral studies with the beta-carboline FG 7142 combined with related drugs in monkeys.[Pubmed:2498110]

Eur J Pharmacol. 1989 Apr 25;163(2-3):219-25.

The beta-carboline FG 7142 was studied alone and in combination with Ro 15-1788, CGS 8216 and lorazepam in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of food presentation. FG 7142 (0.3-5.6 mg/kg i.v.) produced dose-related decreases in the rate of FI responding, effects opposite to those of moderate doses of lorazepam (0.03-0.3 mg/kg i.v.). Pretreatment with low doses of Ro 15-1788 (0.1 and 0.3 mg/kg i.v.) shifted the dose-response curve of FG 7142 progressively to the right indicating pharmacological antagonism at benzodiazepine recognition sites. In comparison, pretreatment with the pyrazoloquinoline CGS 8216 (0.1-1.0 mg/kg i.v.), which alone decreased responding, did not alter the effects of FG 7142 in a systematic manner. Combinations of behaviorally active doses of FG 7142 and lorazepam had primarily additive effects: the opposing actions of one drug tended to cancel the other's effect on responding. These results show that the reduction in behavior by FG 7142 is modified predictably by Ro 15-1788 but not by CGS 8216, and behaviorally active doses of both FG 7142 and lorazepam may be needed for their mutual antagonism.

A single dose of FG 7142 causes long-term increases in mouse cortical beta-adrenoceptors.[Pubmed:3032657]

Eur J Pharmacol. 1987 Feb 24;134(3):313-9.

There is evidence that central monoamines are involved in the actions of benzodiazepines. We have investigated the effects of a single dose of the benzodiazepine partial inverse agonist, FG 7142, on radioligand binding to alpha 2- and beta-adrenoceptors in mouse cerebral cortex. We found that seven days after a single injection of FG 7142 there was a large increase in the density of beta-adrenoceptors. This rise was not detectable either 15-30 min, or 24 h after the injection and no statistically significant changes in alpha 2-adrenoceptor binding were found at any of these times. Administration of the benzodiazepine antagonist Ro 15-1788 at the same time as FG 7142 prevented the rise in beta-adrenoceptor density. We discuss the possibility that the beta-adrenoceptor upregulation is related to the behavioural effects of FG 7142.

FG 7142 (ZK 39106; LSU-65), a non-selectively benzodiazepine inverse agonist, has high affinity for the α1 subunit-containing GABAA receptor (Ki=91 nM). FG 7142 (ZK 39106; LSU-65) also modulates GABA-induced chloride flux at GABAA receptors expressing the α1 subunit (EC50= 137 nM). FG 7142 (ZK 39106; LSU-65) can increase tyrosine hydroxylation and cause upregulation of β-adrenoceptors in mouse cerebral cortex.

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