Anxiolytic effect of carbamazepine in the elevated plus-maze: possible role of adenosine

Abstract

In order to extend previously reported observations with other animal models of anxiety, the effect of carbamazepine (CBZ) was presently measured in rats placed on the elevated plus-maze. Intraperitoneal injection of CBZ (5-40 mg/kg) increased the percentage of open arm entries as well as the percentage of time spent on the open arms of the maze, without affecting the total number of arm entries. This effect is characteristic of anxiolytic drugs. The inhibitor of adenosine neuronal uptake papaverine (5-40 mg/kg) caused a similar anxiolytic effect, whereas the adenosine receptor antagonist aminophylline (1-4 mg/kg) selectively decreased the percentage of open arm entries, indicative of an anxiogenic effect. Furthermore, the combination of an anxiogenic dose (4 mg/kg) of aminophylline with an anxiolytic dose (40 mg/kg) of CBZ resulted in cancellation of each other effects. Since reported neurochemical evidence shows that CBZ interacts with adenosine receptors, the present results provide preliminary support for a participation of this neurotransmitter in the anxiolytic action of CBZ.

Pharmacological Characterization of FR194921, a New Potent, Selective, and Orally Active Antagonist for Central Adenosine A1 Receptors

“…It has been reported that benzodiazepine, the most widely used anxiolytic agent, blocks adenosine uptake (35,36) and decrease adenosine A 1 receptor binding capacity in vivo at doses of clinical relevance (37). In addition, a direct involvement of adenosine in regulating affective state has been suggested by the finding that papaverine, an inhibitor of adenosine uptake, causes anxiolytic effects (38). In the present studies, to detect the anxiolytic effect of FR194921, the social interaction test and elevated plus-maze test were used as relevant animal models of anxiety.…”

Adenosine Signaling in Anxiety

“…A study showing that BZDs prevent NBTI binding revealed ENT1 as a specific target of these drugs (Hammond et al, 1981). This is consistent with the reduced anxiety-like behavior in ENT1 knockout mice and the anxiolytic action of adenosine uptake inhibitor papaverine (Zangrossi et al, 1992). Given their structural similarities with adenosine, it is not surprising that BZDs have also been shown to interact with adenosine receptors in some cases.…”

“…Of the several equilibrative and concentrative transporters expressed in the brain, ENT1 appears to be central to the regulation of anxious states. Some of the first evidence in support of this idea came from a study demonstrating that pharmacological inhibition of adenosine uptake by papaverine was anxiolytic in the elevated plus maze test (Zangrossi et al, 1992). This study also suggested that inhibition of adenosine uptake may be a mechanism of the anxiolytic drug carbamazepine, as its actions were inhibited by adenosine receptor antagonist aminophylline (Zangrossi et al, 1992).…”

“…Some of the first evidence in support of this idea came from a study demonstrating that pharmacological inhibition of adenosine uptake by papaverine was anxiolytic in the elevated plus maze test (Zangrossi et al, 1992). This study also suggested that inhibition of adenosine uptake may be a mechanism of the anxiolytic drug carbamazepine, as its actions were inhibited by adenosine receptor antagonist aminophylline (Zangrossi et al, 1992). It is noteworthy that multiple studies have also pointed to inhibition of ENT1 as a mechanism for benzodiazepine-induced anxiolytic activity (discussed later).…”

“…Carbamazepine, an anxiolytic and anticonvulsant drug, reduces neuronal excitability in several ways, including stabilization of the inactivated state of sodium channels and GABA A receptor activation. Evidence for the involvement of adenosine in carbamazepine-mediated anxiolytic activity comes from a study showing that nonselective adenosine receptor antagonist aminophylline blocked the increase in open-arm time in the elevated plus maze in mice (Zangrossi et al, 1992). It is conceivable that adenosine acts as a permissive factor for GABA A activation, similar to the manner in which adenosine appears to partially mediate BZD action.…”