Relative to our hypotheses, yohimbine administration increased rapid-response impulsivity and accelerated reaction times (Table 3), consistent with results of our pilot study (Swann et al. 2005a). Increase in plasma MHPG, but not plasma HVA, predicted increase in impulsive IMT responses. Yohimbine had no effect on discriminability or correct detections. This is consistent with animal results where NE depletion by 6-hydroxydopamine reduced speed and impulsivity, but not discriminability (Cole and Robbins 1989). As anticipated (Charney et al. 1982; Gurguis and Uhde 1990), yohimbine increased plasma NE metabolites, blood pressure, and pulse. Yohimbine had no significant subjective effects. We will discuss these results in terms of relationships between NE and mechanisms of impulsivity, effects of yohimbine on catecholaminergic activity, relationships between effects of yohimbine on autonomic function and behavior, and specificity of yohimbine effects.

Rapid-response impulsivity and NE

Impulsivity, related to control of the initiation of action, is complex. Three interacting aspects potentially related to NE are behavioral mechanisms, neural mechanisms, and time course. Each will be discussed below.

Behavioral mechanisms

Rapid-response impulsivity, measured by procedures like stop-signal tasks or continuous performance tests, represents inability to conform the response to a stimulus to its context or to assess the stimulus adequately before responding; reward-based impulsivity, sometimes called impulsive choice, is related to inability to delay response for a larger reward (Evenden 2000; Swann et al. 2002). These mechanisms of impulsivity differ in their apparent responses to neurotransmitters, with NE potentially related to analogues of rapid-response, but not reward-based, impulsivity (Evenden 2000; Sun et al. 2010). Because of time constraints, we did not measure choice impulsivity and thus cannot compare yohimbine effects across these two types of impulsivity.

Neural mechanisms

Impulsivity can be related to dysregulation of limbic arousal, imbalance between facilitatory and inhibitory behavioral systems, or impairment of attention (Fineberg et al. 2010). These mechanisms vary in neurotransmitter sensitivity (Evenden 2000). NE, for example, can have opposite effects on impulsivity or attention depending on context, by enhancing attention or orientation (Berridge and Waterhouse 2003; Riba et al. 2005) or by disrupting inhibitory prefrontal cortex function (Arnsten and Li 2005; Fitzgerald 2011).

Time course

Potential for impulsivity may be a trait-like characteristic, but its expression at a given time can depend on internal or external conditions (Barratt 1985), potentially including increased NE due to stress or increased arousal (Soltis et al. 1997). NE-mediated state-dependent increase in impulsive behavior could be reflected in phenomena such as transient hypomania following yohimbine administration in subjects with bipolar disorder (Price et al. 1984).

NE and yohimbine effects

Our results suggest that excessive NE can increase potential for impulsive behavior in a state-dependent manner, consistent with the model proposed by Arnsten and Li (2005). Rapid-response impulsivity is increased in mania (Swann et al. 2003), and manic symptoms correlate with NE metabolite levels (Swann et al. 1987). The results in Table 3 and Fig. 3 show that pharmacologically stimulated NE release increased rapid-response impulsivity, confirming an earlier pilot study (Swann et al. 2005a) and more recent studies in rats (Sun et al. 2010; Torregrossa et al. 2012) (see Table 1). This increase correlated with change in plasma MHPG but not plasma HVA. Laboratory behavioral models of impulsivity may therefore provide a useful strategy for translation between animal and human models of impulsive behavior (Winstanley 2011).

Yohimbine-induced maximal changes in plasma MHPG and impulsive errors were significantly related, but neither correlated with baseline plasma MHPG. This is consistent with models of NE regulation positing two types of NE response, phasic and tonic (Aston-Jones and Cohen 2005; Berridge and Waterhouse 2003). The tonic response may be related to baseline NE, while the phasic effect may represent specific task-focused NE release. The phasic effect could enhance task performance (Aston-Jones and Cohen 2005); excessive tonic release, associated with acute stress or pharmacological alpha-2 receptor blockade, could result in impulsivity and poor task performance (Arnsten and Li 2005; Table 1).

BIS-11 scores did not correlate with catecholamine metabolites or IMT performance, either at baseline or after yohimbine. Previous studies showed that IMT commission errors, but not BIS-11 scores, correlated with severity of ASPD (Swann et al. 2009) and severity of personality disorder symptoms in a mixed population (Swann et al. 2002). Furthermore, history of criminal conviction in bipolar disorder (Swann et al. 2011), or of severe suicidal behavior with (Swann et al. 2005b) or without (Dougherty et al. 2004) bipolar disorder, was associated with increased IMT commission errors and faster reaction times, but not with higher BIS-11 scores. These results are consistent with previous work showing lack of correspondence between laboratory and psychometric markers of impulsivity (Lane et al. 2003; Reynolds et al. 2008).

Yohimbine and catecholamine function

Blockade of alpha-2 NE receptors increases NE release (Aghajanian 1978) and peripheral (Charney et al. 1982; Gurguis and Uhde 1990) and central NE metabolite levels (Peskind et al. 1989), providing a potential probe for effects of increased endogenous NE.

NE released in the brain leaves the CNS as MHPG, which is also produced in the sympathetic nervous system (Maas and Landis 1968). Analogously, DA from either the CNS or periphery is metabolized to HVA. Plasma MHPG, HVA, and VMA are reliable measures in healthy subjects (Baker et al. 1988). Studies using human brain arteriovenous differences (Maas et al. 1979) and peripheral monoamine oxidase inhibition (Swann et al. 1980) show that roughly half of plasma MHPG and about 20–25 % of plasma HVA are from the brain. Plasma VMA is, essentially, exclusively from the peripheral sympathetic nervous system and may be the most sensitive metabolite in response to stressors (Fukuda et al. 1996).

Plasma MHPG is an integrated measure of NE turnover over at least 60 min (Szemeredi et al. 1991). In contrast, effects of yohimbine on blood pressure or performance occur at the time of measurement. Because the effect being measured is of NE rather than MHPG, this complicates studies measuring effects with different time courses. The results suggest that human laboratory studies of oral yohimbine need at least 3 h.

Like yohimbine, selective NE reuptake inhibitors such as atomoxetine can increase synaptic NE (Owen and Whitton 2003). However, their effects on integrated NE function relative to impulsive behavior are quite different from those of yohimbine. For example, Arnsten has reported opposing effects of alpha-1 and alpha-2 NE receptors in prefrontal cortex, where stimulation of alpha-1 receptors disrupts inhibitory prefrontal cortex function, while stimulation of alpha-2 receptors enhances it (Arnsten and Pliszka 2011). NE reuptake blockers increase alpha-2 receptor stimulation, and their effects on impulsive behavior resemble those of alpha-2 agonists (Arnsten and Pliszka 2011; Fernando et al. 2012). Yohimbine, an alpha-2 antagonist, has opposite effects. Furthermore, it blocks the feedback regulation by alpha-2 receptors of NE release, which limits the increase in overall NE function associated with NE reuptake blockade, resulting in reversal of the reduction in NE release by atomoxetine (Owen and Whitton 2003). Therefore, compared to atomoxetine, yohimbine increases net NE release and blocks any direct behavioral effect of alpha-2 receptor stimulation. Although yohimbine and atomoxetine are both considered to be NE-enhancing drugs, they have opposite effects on NE-induced cyclic AMP production and CREB phosphorylation that run parallel to their opposite effects on impulsivity (Sun et al. 2012).

Relationships between autonomic and behavioral effects of yohimbine

Effects of yohimbine could have interacted with stress of testing. Yohimbine was reported to increase autonomic responses to mental arithmetic in controls, but had no interaction with a continuous performance task (Albus et al. 1992). Cognitive task administration was reported not to alter salivary MHPG (Li et al. 2004).

Yohimbine had no significant effects on POMS or ISS symptom measures. In our pilot study, yohimbine increased ISS activation (Swann et al. 2005a). The studies differed in doses of yohimbine, order of administration (counterbalanced in this study, progressive in the earlier study), timing of measures (a single posttreatment measure at 90 min in the earlier study, instead of serial measures), and in the greater number and frequency of procedures during the current study. Repeated structured nonstressful task performance reduces subjective effects of pharmacologically altered NE (Albus et al. 1992; Li et al. 2004), consistent with the lack of subjective effects in the present study. Behavioral responses to yohimbine in healthy subjects have varied, with relatively modest effects in controls, especially in low-anxiety subjects (Mizuki et al. 1996), and more prominent effects in anxiety disorders (Goddard et al. 1995;Gurguis and Uhde 1990) or controls with high baseline anxiety (Mizuki et al. 1996). Therefore, the combination of multiple structured procedures and low baseline anxiety may have contributed to the lack of significant subjective effects.

Timing of yohimbine effects varied. Effects on blood pressure preceded those on IMT performance and plasma MHPG. IMT effects might be expected to take longer than those on blood pressure, as they involved more complex attentional and stimulus discrimination processes in the CNS. Effects on metabolites, requiring reuptake of released NE, oxidative metabolism, and equilibration of metabolites into plasma, were the slowest to appear.

Non-noradrenergic effects of yohimbine

Heterosynaptic alpha-2 receptors can also inhibit release of dopamine, serotonin, and acetylcholine (de Villiers et al. 1995; Kalsner and Abdali 2001). Stimulation of postsynaptic alpha-2 receptors also has endocrine effects, including release of growth hormone (Baumann et al. 2004) and inhibition of CRH release (Vythilingam et al. 2000). Many alpha-2 noradrenergic receptor ligands also act through imidazoline receptors, which alter blood pressure but not attentional state (Tibirica et al. 1991). Yohimbine is relatively selective for alpha-2 relative to imidazoline receptors (Szabo and Urban 1995), but effects such as increased blood pressure, which did not correlate with MHPG change, could have resulted from non-noradrenergic effects of yohimbine.

Yohimbine is also a ligand for other behaviorally relevant receptors. Yohimbine was reported to bind to monoaminergic receptors with greatest affinity for alpha-2 NE receptors, followed by 5HT-1A (agonist), 5HT-1B and 1-D, and D3 receptors, with lowest affinity for D2 receptors (Millan et al. 2000). While affinity was highest for alpha-2 receptors, the 5HT1A effect appears to account for disruption of prepulse inhibition of acoustic startle by yohimbine (Powell et al. 2005). Serotonergic and noradrenergic effects of yohimbine may interact in anxiety (Goddard et al. 1995) and alcohol reinstatement (Dzung et al. 2009). However, 5HT1A receptors have effects on accuracy (conservative bias) and speed of responding (slowed) that are opposite to those of yohimbine reported here (Carli and Samanin 2000).

Limitations

The limitations of this study are the following: (1) While effect sizes for NE metabolites and autonomic effects were substantial, the number of subjects was too small to investigate complex interactions across time; (2) these results cannot distinguish direct behavioral effects of alpha-2 receptor blockade from indirect effects mediated by increased NE release; (3) roles of other possible results of alpha-2 receptor binding, such as growth hormone and heteroceptor effects (except for plasma HVA), and other potential non-alpha-2 effects, were not determined; and (4) while effects of yohimbine on impulsive responding correlated with those on NE metabolites, contributions of serotonergic and other systems cannot be ruled out.