Enhancing extinction of conditioned sexual response by a partial NMDA receptors agonist.

Many sexual disorders are thought to involve a learned component. For example,
in hypersexuality or sex addiction, sex-associated cues are thought to elicit
sexual arousal and craving for sex. Clinical interventions to reduce the impact
of cues in eliciting these maladaptive conditioned responses are likely to be
beneficial. Extinction is a method of lessening conditioned responses and
involves repeated exposures to a cue in the absence of the event it once
predicted. Glutamate is the brain's main excitatory neurotransmitter, and also
the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate
receptors are responsible for the glutamate-mediated postsynaptic excitation of
neural cells, and are important for neural communication, memory formation,
learning, and regulation. Research on the role of glutamate in extinction has
led to the development of pharmacotherapeutics to enhance the efficacy of
extinction-based protocols in clinical populations with anxiety disorders.
Despite it hypothesized relevance, studies on pharmacological interventions in
sexual learning and extinction in humans are lacking in the literature. This
knowledge may help in the treatment of sexual motivation disorders such as too
little or excessive sexual desire.

In the present study, the effect of D-Cycloserine (DCS; a partial glutamatergic
N-methyl-D-aspartate (NMDA) receptor agonist) on enhanced conditioning and
extinction memory consolidation of conditioned sexual responses will be
investigated. The study will be conducted in healthy sexually functional women.
To investigate the effects of DCS on extinction memory, genital and subjective
sexual arousal will be studied in women (N=2X34) in a differential conditioning
experiment.

The aim of the study is: to investigate the effect of DCS on the physiological
and subjective correlates reflecting conditioned sexual response and subsequent
extinction thereof.

Hypothesis: We hypothesize that administration of DCS after an extinction
procedure will enhance extinction of conditioned sexual responses. Compared to
the placebo-condition, for the DCS- condition a decrease in sexual conditioned
responses elicited by reward-conditioned cues will be seen in the extinction
context, on a test phase 24hrs later. The DCS condition will show weaker
conditioned genital and subjective responding in the extinction context,
compared to the placebo condition.

Design: Double-blind randomized placebo controlled between-subjects design.
Participants will be randomly assigned to the groups receiving either DCS or
placebo after extinction on day 1.

Day 1: Discrimination Learning and Drug Administration
The experimental design involves conditioning with one stimulus (the CS+) being
followed by the sexual appetitive US during the acquisition phase, whereas
another stimulus (the CS-) never is followed by the US. Which CS is paired with
the sexual appetitive stimulus is counterbalanced among subjects. Participants
view repeated presentations of a male abdomen (CS+ and CS-) projected on a
white screen, with the colour of the depicted picture (Blue or Yellow) the only
difference (CS+ and CS-). Which stimulus serves as CS+ and CS- is
counterbalanced across participants. The CSs are presented for 9 s, followed by
inter-trial intervals that vary between 20 and 30 s. The unconditioned stimulus
(US) is the vibrotactile stimulation for 2 s. Subjects are first habituated to
the CSs and contexts by presenting each CS 4 times (in random order) in each
context prior to the actual experiment. During this preconditioning phase the
CS+ is not followed by the US.
Subjects then learn to discriminate the 2 CSs on the basis of how they
predict genital vibrostimulation to follow each CS. In acquisition phase A1,
the CS+ and the CS- are each presented 10 times in a randomized order in the
centre of the monitor. Presentation of a perfectly predicted reward does not
generate a prediction error and fails to support new learning (Rescorla &
Wagner, 1972;Schultz, Dayan & Montague (1997), therefore we chose a CS+
reinforcement ratio of 80% (8 out of 10 CS+ presentations are followed by
genital vibrostimulation). By introducing this reward prediction uncertainty we
will make conditioning somewhat more extinction resistant and therefore
increase the likelihood of recall of sexual reward memory on day 2. The CS- is
never followed by vibrostimulation.
In the following extinction phase B1, which is different from the
preceding acquisition phase in terms of lighting colour of the experimental
room (see stimulus materials), conditioned sexual responses are extinguished by
presenting the CS+ and CS-each 10 times in a randomized order in the same
fashion but the CS+ is no longer followed by vibrostimulation. At the beginning
of each block, the context is present without any CS for 10 s. This phase is
followed by another acquisition phase (A2) and extinction phase (B2) in its
corresponding context. This design allows subjects to learn to discriminate
between 2 different contexts on the basis of whether the CS+ is (conditioning
context) or is not (extinction context) associated with the US. Immediately
after the experiment participants receive DCS or placebo.

Day 2: Test Phase 24 h Later
Subjects again complete an experimental procedure. Each context is presented 18
times in an alternating order (ABABAB etc). In half of the participants, the
experiment will start with the conditioning context (ABABAB etc.) and in half
of the participants, it will start with the extinction context (BABABA etc). In
these blocks of A and B each, 1 CS+ and 1 CS- are presented in random order for
a duration of 9 s each, followed by inter-trial intervals that vary between 20
and 30 s. In the A blocks, subjects receive genital vibrostimulation 3 s after
the start of the block. Associating context A with vibrostimulation during
recall theoretically promotes reinstatement, thus facilitating recall of the
CS-associated sexual arousal memory in this context.

There will be no benefits nor great risks for the participants. The single dose
of DCS may result in mild side effects like drowsiness, headache, and
dysarthria. If these effects appear, these will usually disappear within
several hours.