A placebo-controlled, double blind study on the effect of a dopamine antagonist (Haloperidol??) on appetitive sexual conditioning in healthy female volunteers

Having too little sexual desire is the most common sexual problem among women
(Mercer et al., 2003; Simons & Carey, 2001). A low level of desire is usually
accompanied by a low level of sexual arousal, and frequently associated with
sexual dissatisfaction (Basson, 2007). Little is known about the causes of
hypoactive sexual desire disorder. According to an incentive motivation view,
sexual motivation is the result of the activation of a sensitive sexual
response system by appropriate stimuli (Agmo, 1999). Sexual behaviour,
particularly orgasm, is regarded as a rewarding event, which can reinforce
learning (Agmo, 1999). The positive affect produced by sexual stimulation can
become associated to environmental stimuli, and these stimuli can thereby
become conditioned sexual incentives. Repeated exposure to the same stimuli
while experiencing sexual reward will enhance the strength of conditioning, and
the intensity of the experienced reward will probably determine the incentive
properties of the conditioned stimuli (Agmo et al 2004). In the aetiology of
sexual desire disorders conditioning may play a pivotal role; low desire may be
caused by a lack of association between sexually rewarding experiences and
stimuli, resulting in a limited number of potential sexual incentives, and it
may be caused by negative sexual experiences that changed the initial positive
valence of sexual incentives into a negative one.
Dopamine is hypothesized to play a role in salience coding during associative
reward learning. Dopamine signalling seems to be required to learn to associate
rewards with cues that predict rewards (Schultz 1998, Schultz 2001). Changes in
burst firing of dopamine neurons (Schultz 1998), and transient increases in
striatal dopamine concentration (Phillips et al 2003), have been shown to
correlate with behavioural adaptations during reward-learning in primates and
rodents. Furthermore, the dopamine hypothesis of motivation posits that
dopamine is necessary for converting a neutral stimulus into an attractive
desirable stimulus that is capable of eliciting an approach response (Berridge
& Robinson 1998; Ikemoto & Panksepp, 1999). According to this incentive
salience hypothesis the mesolimbic dopamine system attributes incentive
salience to representations of stimuli that were associated with appetitive
reward (Berridge & Robinson, 1998).
Several research findings in rats indicate a role of dopamine in sexual reward
processes: dopamine levels increase in response to a sexual appetitive partner,
dopamine agonists promote sexual activity, and dopamine antagonists diminish
appetitive sexual responses (Toates, 2006). From animal research there is also
evidence for a role of dopamine in sexual reward learning. In female prairie
voles, a monogamous species, oxytocin in combination with activation of the
dopaminergic reward system is critical in establishing the link between a
particular partner and appetitive sexual behaviour (Young and Wang, 2004).
Furthermore, Lopez and Ettenberg (Lopez & Ettenberg 2000, Lopez & Ettenberg
2002) observed that a cue associated with sexual reward becomes a conditioned
incentive capable of eliciting approach behavior, but that dopamine receptor
antagonism (with haloperidol at moderate doses) selectively attenuates this
cue-induced motivation.
In humans, recent literature suggests that a polymorphism in the dopamine D4
receptor gene may contribute to individual variation in human sexual desire and
arousal, indicating that variation in dopaminergic activity may influence the
incentive value of stimuli and the tendency to approach such stimuli (Ben Zion
et al., 2006). In human males, we recently observed an enhancing effect of
levodopa, a dopamine agonist, on psychomotor activity in response to sexual
stimuli (Both et al., 2005). In addition, in studies on responses to drug cues
it has been observed that the dopamine antagonist haloperidol attenuated cue
elicited physiological responses (Mahler & de Wit, 2005) and the urge to use
the drug (Berger et al., 1996). Dopamine*s role in learning in humans is
supported by recent findings showing that learning outcome can be improved
pharmacologically by administration of the dopamine precursor levodopa.
Examples are faster and better vocabulary learning (Knecht et al 2004), and
increased motor training success (Floel et al., 2005). To our knowledge, to
date, research in humans on dopaminergic effects on the learning of sexual
reward has not been done.

The purpose of this study is to investigate the role of dopamine in learning
about sexual reward in healthy females. We suppose that repeated associations
between a neutral stimulus and sexual stimulation results, through classical
conditioning, in a learned appetitive sexual response to this stimulus. It is
hypothesized that acute blockade of DA receptors with a dopamine antagonist
(haloperidol©) will attenuate this appetitive conditioning effect due to
blocking of dopamine activity.

The protocol concerns a randomised, double-blind, placebo-controlled study on
the effect of a single dose of haloperidol on learning about sexual reward in
healthy sexually functional female volunteers. To investigate the hypothesized
critical role of dopamine in learning of sexual reward, classical conditioning
of genital and subjective sexual arousal will be studied in a haloperidol
condition (N=64) and in a placebo condition (N= 64) using a between subjects
design. A differential conditioning paradigm will be applied, in which women,
in both conditions, are presented with two neutral stimuli, CS+ and CS-, of
which only the CS+ is followed by an appetitive sexual unconditional stimulus
(US). Genital vibrotactile stimulation will be applied as appetitive sexual US.
During a pre-conditioning, conditioning, and post-conditioning phase women will
view the two neutral pictures repeatedly, while genital sexual arousal is
assessed as vaginal pulse amplitude using vaginal photoplethysmography
(dependent variable). Self-reported ratings of emotional valence and subjective
sexual arousal (dependent variables) are collected during the pre-conditioning
and post-conditioning phase. It is expected that in the placebo condition,
pairing of the CS+ to the vibrotactile stimulation during the conditioning
phase will result in higher genital and subjective arousal and a more positive
valence of the CS+ compared to the CS- during the post-conditioning phase, and
that these associative learning effects will be attenuated under the dopamine
antagonist (haloperidol) condition.
To test the robustness of the experimental paradigm, first a pilot study on
sexual conditioning in healthy sexually functional women that we conducted
previously will be replicated. If in this replication study conditioning of
sexual response is observed, the study will be extended to the placebo and
haloperidol condition.

The vaginal photoplethysmograph used in this study is considered a safe device.
No harmful events have been reported. Furthermore, the device used to measure
genital arousal will be sterilized before each use, according to plasma
sterilization procedure. From previous studies (Both, Laan & Everared, 2007;
Laan & van Lunsen, 2007) it is known that the genital vibrotactile stimulation
will not cause harm or discomfort.

Based on the information provided by the clinical trial pharmacist (LUMC)
serious adverse effects of a single dose of 5 mg haloperidol are not to be
expected. Possible side effects of a single dose of haloperidol 5 mg are
muscle-stiffness or trembling, drowsiness, dizziness, irritability, nausea, and
increased heart-rate. Studies with a comparable single dose of haloperidol (4
mg) conducted by others (e.g. Mahler & de Wit, 2005; Berger, et al., 1996)
report no adverse side effects of the medication.