A re‐evaluation of the role of α2‐adrenoceptors in the anxiogenic effects of yohimbine, using the selective antagonist delequamine in the rat
Authors: Redfern William S. , Williams Andrew 
Published: July 2012

The acute behavioural effects of the α2‐adrenoceptor antagonists, yohimbine, idazoxan and delequamine (RS‐15385‐197) were compared in two tests of exploratory behaviour in the rat, operated in tandem. These were the elevated X‐maze test (5 min) and a modified holeboard test (12 min), which comprised a holeboard arena with a small roof in one corner as a ‘refuge’. Rats were first placed into this corner, thus enabling measurements of initial emergence latency and the number of forays. The experiments were always done with a concomitant vehicle control group, with 10–12 rats per group, and with the treatment blinded.

In order to validate the tests, the effects of representatives of four classes of psychoactive agents were examined, viz. picrotoxin (anxiogenic), chlordiazepoxide (anxiolytic), (+)‐amphetamine (stimulant) and diphenhydramine (sedative). The modified holeboard tended to be more sensitive than the measurement of total arm entries in the elevated X‐maze at detecting drug effects on exploratory behaviour, but unlike the X‐maze it could not clearly identify each class of agent. Thus, picrotoxin (5 mg kg−1, i.p.) reduced total arm entries and open arm exploration in the X‐maze (P < 0.02) and suppressed most measures of activity in the holeboard (P < 0.05); chlordiazepoxide (7.5 mg kg−1, i.p) increased total arm entries and open arm exploration (P <.02) in the X‐maze, without clear‐cut effects in the holeboard; (+)‐amphetamine (1 mg kg−1, i.p.) had no significant effects in the X‐maze, but increased most holeboard activities (P < 0.05), and diphenhydramine (30 mg kg−1, i.p.) reduced total arm entries in the X‐maze (P < 0.002) and hole exploration in the holeboard (P < 0.05).

The actions of yohimbine most closely resembled those of picrotoxin. In the elevated X‐maze, yohimbine (3 mg kg−1, i.p.) decreased the total number of arm entries (P < 0.02); a larger dose (10 mg kg−1, i.p.) also reduced time spent on the open arms (P < 0.02). In contrast, delequamine (3 mg kg−1, i.p.) and idazoxan (3 mg kg−1, i.p.) had no effect.

In the partially‐shaded holeboard, yohimbine (3 mg kg−1, i.p.) suppressed hole exploration (P < 0.05); a higher dose (10 mg kg−1, i.p.) increased emergence latency (P < 0.002) and virtually abolished all activity. Delequamine (3 mg kg−1, i.p.) and idazoxan (3 mg kg−1, i.p.) did not influence emergence latency or holeboard activities.

The extent of the blockade of central α‐adrenoceptors achieved during the tests was assessed by the ability of the doses used to reverse mydriasis induced by clonidine (300 μg kg−1, s.c.) in anaesthetized rats. At a dose of 3 mg kg−1, i.p., delequamine and idazoxan produced a rapid, sustained reversal of the clonidine response (by 87 ± 2 and 86 ± 2% respectively, 30 min after injection) whereas yohimbine produced a partial reversal of only 43 ± 13%. The higher dose of yohimbine used in the exploratory tests (10 mg kg−1, i.p.) was required in order to achieve 77 ± 4% reversal of clonidine‐induced mydriasis.

We therefore conclude that blockade of central α2‐adrenoceptors per se does not have an anxiogenic effect, at least in the rat. Thus, yohimbine is not an ideal tool for studying α2‐adrenoceptor function in animals and some of the anxiogenic effects of yohimbine previously ascribed to α2‐adrenoceptor antagonism may be secondary to other effects of this poorly selective compound.