Yohimbine's effects on increasing levels of extracellular norepinephrine are thought to be the mechanism by which the drug produces it's pro-anxiety effects [17
]. Increased extracellular norepinephrine levels with yohimbine would also be consistent with the fact that antidepressant drugs that block norepinephrine reuptake (amitriptyline, imipramine, desipramine) can have similar effects on extinction in rats [31
].The pharmacology of yohimbine is, however, complex, with actions on dopamine D2 receptors and multiple 5-HT receptor subtypes (5-HT1A, 5-HT1B, 5-HT1D) [32
] (). The potential contribution of these actions on the behavioral effects of yohimbine, including fear and extinction, has largely been ignored. Some recent findings do shed some light on this issue, however. Work in (C57BL/6J strain) mice has shown that systemic treatment with atipamezole, a more selective α2-adrenoreceptor antagonist than yohimbine, failed to improve extinction retrieval and actually trended towards impairing extinction [25
]. The same study also examined the effects of both yohimbine and atipamezole on another form of extinction in mice: extinction of a conditioned place preference for cocaine. Results showed that yohimbine impaired, rather than facilitated, extinction of cocaine CPP, while atipamezole had no effect. Moreover, when mice with a targeted null mutation of the αa2-adrenoreceptor were employed to test whether these effects of yohimbine were dependent upon the receptor, extinction was not only present but actually enhanced in the mice.
Table 2 Pharmacological effects of yohimbine at dopamine and 5-HT receptors. Data are radioligand binding affinity (pKi) measurements in human hippocampal, CHO and cells originally reported in Millan et al. 
Collectively, these data make two important points. First, the impairing effects of yohimbine on an appetitive form of extinction contrast with the putative extinction-facilitating effects on fear extinction. Second, for cocaine CPP extinction at least, the effects of yohimbine do not appear to be mediated by the α2-adrenoreceptor, which is the putative primary site of the drug's behavioral effects. A key question for future studies is whether facilitating effects of yohimbine on fear extinction (under the specific experimental conditions and genetic backgrounds in which they occur) are also mediated by a mechanism that is independent of the α2-adrenoreceptor. Indeed, a recent report showed that systemic blockade of noradrenergic beta receptors with propranolol treatment had no effect on fear extinction [41
], further calling into question the extent to which extinction requires noradrenergic stimulation.
If not the α2-adrenoreceptor, the question then becomes, what is the target? One obvious candidate is the 5-HT1A receptor. Yohimbine has high affinity for the 5-HT1A receptor (pKi
] and acts as a 5-HT1A receptor partial agonist [42
]. The selectivity of yohimbine for α2-adrenoreceptors over 5-HT1A receptors is relatively poor, as estimated by receptor-binding [34
]; ~10-fold in humans and even less (~4-fold) in rats. In mouse drug discrimination studies, yohimbine effectively generalizes to drugs such as 8-OH-DPAT that are 5-HT1A receptor agonists with little affinity for α2-adrenoreceptors [43
]. Moreover, a variety of yohimbine effects, including disruption of prepulse inhibition of startle [45
], hypothermia [33
], increased alcohol seeking [46
], and anxiogenic-like effects [47
], have been attributed to actions at 5-HT1A receptors rather than α2-adrenoreceptors. Finally in vivo
microdialysis in rats showed that systemically administered (2.5-20 mg/kg) yohimbine reduced firing of 5-HT dorsal raphe neurons and decreased extracellular levels of 5-HT in cortex (in addition to increasing norepinephrine and dopamine levels) [33
]. Clearly, yohimbine treatments shown to alter extinction likely had potent effects on the 5-HT1A receptor and the 5-HT system more generally. However, the potential involvement of 5-HT actions to yohimbine's effects is far from clear - in part, because the contribution of the 5-HT system to fear extinction is itself uncertain. For example, while certain genetic perturbations of the 5-HT system impair fear extinction in mice [49
], pharmacological treatments (e.g. anti-depressant medications) that boost 5-HT levels alter fear but not extinction in rats and mice [50
]. In terms of the 5-HT1A receptor per se
, we are unaware of any reports on the effects of 5-HT1A receptor drugs on fear extinction. As such, there are not yet solid grounds for suggesting that actions at the 5-HT1A receptor account for the pro-extinction effects of yohimbine.
Perhaps a more likely ‘off-target’ candidate for these effects is the dopamine D2 receptor. As noted, yohimbine has high affinity (pKi
=6.4) for the dopamine D2 receptor and acts as an antagonist at the receptor [33
]. Blockade of D2 autoreceptors may contribute to yohimbine-induced increases in cortical levels of dopamine [52
] and striatal dopamine synthesis [39
] -although α2-adrenoreceptors on dopamine terminals are probably involved too. Systemic pre-extinction administration of the D2-like receptor antagonist sulpiride facilitated fear extinction in mice [54
] while administration of the D2-like agonist quinpirole impaired fear extinction in mice [54
] and rats [55
].Although more studies are needed to substantiate the contribution of the D2 receptor to fear extinction, we can speculate that blockade of these receptors could contribute to the pro-extinction effects of yohimbine. It will be important to test this hypothesis because if actions at D2 receptors do account for these effects, then the focus of further drug development could be more mechanistically focused. On the other hand, if the D2 receptor (or any other specific pharmacological target of yohimbine), is alone sufficient to account for the drug's pro-extinction effects, then this would suggest these effects in fact result from the combined, multi-target (‘dirty’) pharmacological profile of the drug.