International Journal of Impotence Research (2000) 12, Suppl 1, S64±S69 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir CLINICAL RESEARCH Effects of alpha-2 blockade on sexual response: experimental studies with Delequamine (RS15385) J Bancroft1 1The Kinsey Institute, Indiana University, USA The role of alpha-2 receptors and alpha-2 antagonists in central and peripheral mechanisms of sexual response are discussed. It is concluded that the predominant role of the alpha-2 antagonist centrally is to increase arousal which in certain circumstances, is sexual. It is further concluded that the predominant role of the alpha-2 antagonist peripherally is to modulate (block) the norepinephrine (NE)-induced contractility in the smooth muscle of the penis. How the central arousal mechanisms are speci®cally linked to sexual response is not understood. Experimental studies with a selective alpha-2 antagonist, delequamine, are brie¯y reviewed and their complex results discussed. Evidence from sleep studies was consistent with delequamine having both central excitatory and inhibitory effects, dependent on dosage. The possibility that men with psychogenic erectile dysfunction might have increased central alpha-2 tone was considered. The apparent loss of responsiveness to the alpha-2 antagonist in older dysfunctional men was discussed. More questions are raised than answered; further research is needed in this area. International Journal of Impotence Research (2000) 12, Suppl 1, S64±S69 Keywords: alpha-2 blockade; delequamine Role of adrenergic agonists locus coeruleus (l.c.) and the lateral tegmental nucleus (l.t.n.).2 Each nucleus has neurons with ascending and descending projections. Of the two, The pharmacological agent with the longest history the l.c. system is most likely to be relevant to sexual for enhancing sexual response is yohimbine, origin- arousal and response; it is activated by novel 1 ally available as a plant (bark) extract. Yohimbine's sensory input to produce a state of central arousal principal pharmacological action is as an alpha-2 which may be associated with aversive or rewarding adrenoceptor antagonist. Activation of presynaptic situations. The ascending projections of the l.c. alpha-2 receptors increases re-uptake of norepi- terminate, quite widely, in the dorsal thalamus, nephrine (NE) at the synapse, hence reducing NE hypothalamus, basal forebrain, including hippocam- transmission. Antagonism of presynaptic alpha-2 pus, and the frontal cortex. The descending projec- receptors will therefore have the principal effect of tions from the l.c. go to the spinal cord (mainly increasing NE transmission. Antagonism of post- ventral horn) and to sensory nuclei in the brain synaptic alpha-2 receptors will inhibit NE action at stem. The l.c. neurons are populated with alpha-2 the smooth muscle. Both central and peripheral receptors.3 effects of such a drug need to be considered. Davidson's group showed that yohimbine and other alpha-2 antagonists such as idazoxan, could substantially restore sexual behavior in the castrated The role of the norepinephrine system male rat and that the sexually enhancing effect of yohimbine was independent of any direct effect on Central effects erection, leading them to conclude that the drug's principal effect was on central arousal.4 There are good reasons for expecting an alpha-2 antagonist to have central effects. The NE system in Peripheral effects the brain originates in two brain stem nuclei, the Some attention has been paid to the presence and Correspondence: Dr J Bancroft, The Kinsey Institute, possible function of alpha-2 receptors in the erectile 5 Morrison Hall 313, Bloomington, IN 46164. tissue. Saenz de Tejada et al concluded that Received 2 September 1999; accepted 15 November 1999 adrenergic activity is modulated, in part, by pre- Effects of alpha-2 blockade on sexual response J Bancroft S65 synaptic alpha-2 receptors in the corpus caverno- satiation or exhaustion in rats. This state, which sum; in those circumstances an alpha-2 antagonist results from repeated copulation, is characterized by would be expected to increase NE transmission and a prolonged period of sexual unresponsiveness, hence smooth muscle contractility. Andersson6 lasting for several days before recovery.13,14 This suggested that such alpha-2 receptor activity may unresponsive state can be partially corrected with a play an important role in the cavernous artery wall, variety of pharmacological manipulations including but not in the trabecular smooth muscle. However, the opioid antagonist, naloxone (indicating that Traish et al7 identi®ed post-synaptic alpha-2 recep- opioid inhibition is probably involved), 8-OH- tors on the trabecular smooth muscle, though the DPAT, a 5HT1a agonist (indicating that serotonergic function of these receptors remains unclear.8 The inhibition is involved), and yohimbine. However, very limited evidence of the effects of injecting the effects of the ®rst two require an intact NE alpha-2 antagonists into the corpus cavernosum system, indicating complex interactions between indicates very little effect.9 If a drug produces a peptide and catecholamine systems.15±17 predominantly presynaptic antagonistic effect on Thus, in those circumstances where central alpha-2 receptors in the erectile tissues, the con- arousal is elicited by an aversive situation, we sequence would be an increased release of NE and should not be surprised if this NE system produces a resulting increase in contractile tone. The central arousal of `anxiety' type and peripheral possibility of a post-synaptic effect of alpha-2 inhibition of sexual response at the same time. receptor antagonist on inhibition of NE binding on Conversely, when central arousal is in response to the trabecular smooth muscle has to be considered, sexual stimuli we might expect a reduced pre- with two such contrasting effects possibly cancel- synaptic peripheral inhibition of genital response, ling each other out. although there does not appear to be any evidence directly relevant to that point. The integrating component of the system is presumably the l.c., The relationship between the central and with both its upwards and downwards projections. peripheral effects of the NE system It may be relevant that of the two sources of neuronal input to the l.c., one of them is from the nucleus paragigantocellularis (nPGi) which has We thus have a paradox; central effects of NE on direct, serotonergically mediated inhibitory in¯u- sexual response are excitatory and presynaptic ences on the erectile response.18 peripheral effects are probably inhibitory. The ®rst In conclusion, whereas it is clear that the central fundamental point in tackling this paradox is to NE system is of fundamental importance to sexual recognize that the excitatory central effects of the NE arousal and response, we remain largely ignorant of system are not con®ned to sexual arousal. The how it functions in that respect. upward projections of the l.c. are involved in general arousal, and in many circumstances it is entirely appropriate that elicitation of general central arousal should require localized peripheral inhibition of genital response. Thus if the NE system generates `arousal' in response to the threat of Pharmacological studies in humans punishment, an emotional state which in those circumstances Gray10 would call `anxiety', then inhibition of other response patterns, such as sexual A series of clinical studies of the effect of yohimbine response, which might interfere with an appropriate in men with erectile dysfunction have been carried avoidance response would be adaptive. However, out.19±22 Most of these studies have been affected by one of the principal mysteries of the central NE methodological problems of various kinds, but a system is how it is mobilized to serve sexual consistent though weak average bene®cial effect on function in some situations and avoidance behavior erectile function has been reported, presumably due in others.11 Testosterone may be relevant to this to central effects of the drug. In experimental selective process, because of the capacity for alpha-2 studies, yohimbine induces anxiety23 and combined antagonists to restore sexual behavior in castrated with naloxone, it produces both anxiety and penile male rats (see above), though the mechanism of this erection.24 Anxiety has not been a problem as a side hormonal effect is far from clear. Further complexity effect in the treatment studies cited above, and it is suggested in a study by Sala et al,12 showing a remains a question of some interest why anxiety has curvi-linear dose response relationship between an been evoked in such experimental studies, but not alpha-2 antagonist and central excitation, with in treatment studies. It may be a matter of acute middle range doses producing maximal excitatory dosage contrasted with chronic dosage; or it may be effects and high doses inhibitory effects. dependent on the context in which the drug is The relevance of the central NE system to sexual taken. Given its theoretical importance, further arousal is further indicated from studies of sexual research should be directed at this issue. International Journal of Impotence Research Effects of alpha-2 blockade on sexual response J Bancroft S66 Experimental human studies with a speci®c alpha-2 Two types of experimental procedures were antagonist, Delequamine therefore used, both involving intravenous infusion of the drug in two contrasting dosages (`high'