Of Mice and Women: Animal Models of Desire, Dread, and Despair

Scene from Mon Oncle d'Amérique by Alain Resnais

Dr. James G. Pfaus, a Professor of Psychology at Concordia University in Montreal, recently wrote a post in defense of Naomi Wolf's neuroscience acumen. This is understandable, as he was one of her main sources of scientific information about the "brain-vagina connection" in Vagina: A New Biography. Wolf, as you know, has been under fire for her simplistic and gendered treatment of cortisol and dopamine, as if these chemicals have highly specific effects on adult feminist women (and their vaginas), but no one else.¹

Pfaus's general reply to that line of criticism is that we should let Wolf have poetic license with her storytelling:

Is Wolf right in regarding dopamine as the "ultimate feminist neurochemical"? It is certainly unlikely that sea slugs and nematode worms are feminists. But can't we allow an accomplished writer and social critic a little poetic leeway to make a point?

In Who's Afraid of the Vagina-Brain Connection? Pfaus also described some of his work on the sexual behavior of female lab rats:

Wolf's search took her, among other places, to my laboratory. We had been doing research on the role of clitoral and vaginocervical stimulation in the sex and reproductive lives of female rats, work that has been published in high-quality peer-reviewed scientific journals. This work revealed that such stimulation, when applied in the right way, induces a state of sexual reward that conditions place and partner preferences (the latter of which was unexpected in an allegedly promiscuous and polygamous species). Taken together with previous work from my laboratory showing the profound role of dopamine and opioid neurotransmitters in both male and female sexual behavior, and in the context of a more general scientific literature in animals and humans showing that blockade of those transmitters induces varying degrees of an "anhedonic" state akin to depression in which reward does not occur and animals do not focus their attention toward it anymore, it became clear to Wolf that these neurochemicals were important parts of the sexual desire and pleasure systems of the brain.  

Pfaus is a prolific scientist whose work ranges from basic animal models and translational research to establishing definitions for human sexual disorders. Now that more of Vagina is online at Amazon, I see that Wolf relied heavily on his research (he's mentioned 26 times), and that she cited many original sources from the scientific literature (albeit not always correctly).²

Which brings us to animal models for what we typically regard as profoundly human states: longing, angst, futility.  Or Desire, Dread, and Despair. The words don't easily lend themselves to rodent analogues, because they remind us of an unrequited crush or an existential crisis. Certainly, rats don't write love letters or read Kierkegaard or appreciate Expressionist art. Dark Night of the Soul (the original poem) was written by a Roman Catholic mystic to describe the painful journey of a bride (soul) in search of her groom (God). Today it indicates a spiritual crisis, a state of profound aloneness, a crushing existential despair.

The animal models of these states are more mundane and less abstract, yet important for potentially explaining the neural mechanisms underlying human suffering: addiction, anxiety, and depression. But are they really adequate stand-ins for the human condition? Of course not. My purpose here isn't to critique animal research, but rather to consider actual behaviors and how they map onto the terminology used to describe them.

Desire

For our present purposes, desire is defined in terms of sexual behavior. Specifically, sexual desire includes the anticipation of and motivation for participation in sexual activity. In rats, "Desire is inferred by certain measures, such as solicitations, rates of pacing (in which female rats control the initiation and rate of copulatory contact with male rats), and the strength of operant behavior aimed at acquiring sex partners" (Pfaus, 2006).

Modified from FIG. 1 (Pfaus, 2006). Incentive sequences for human and rat sexual behavior (modified from Pfaus et al., 1999). The behavioral stream moves from left to right, through appetitive, precopulatory, and consummatory phases of behavior. This conforms to the movement of animals from distal to proximal to interactive with respect to the sexual incentive.

In Fig. 1 we can see that female rat Excitement (grooming, investigation, motor activation) maps onto female human Sexual Desire (fantasy, excitement). Sexual fantasy is decidedly absent from the repertoire of rats, so conditioning and preference paradigms serve that purpose. Meanwhile, female rats show subsequent stages of defensiveness and lordosis, while female humans get to have orgasms. Fig. 2 in the Pfaus paper shows four panels of appetitive and consummatory measures of copulation in a pair of rats. Solicitation, investigation, running away, pursuit, lordosis, and mounting took all of 4 seconds. This goes on for several bouts until the male ejaculates. Wolf's "Goddess Array" is nowhere to be found.

Indeed, one of the places where Wolf went most astray in Vagina was in her wild extrapolations from the neurobiology of Pfaus's rats to the "Goddess Array" and what women need sexually: candles, flowers, music, or some other romantic gesture ("A whole set of words, actions, and gestures that women cannot do without"). Even if this were universally true, it obviously involves the kind of cognitive capacity well beyond rats.

Nonetheless, a major goal of the animal model is to serve as a preclinical testing ground for perceived sexual dysfunction in humans, including the categories of Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorders, which are distinct (and yet overlapping, according to some). In his accurately (but inelegantly) titled review Of rats and women: preclinical insights into the nature of female sexual desire, Pfaus (2006) stated:

Many clinicians and motivational theorists alike view desire as distinct from arousal in both animals and humans. This is apparent in the DSM’s categorization of arousal disorders distinct from desire disorders, a distinction that generally reflects blood flow to the genitals and erectile tissues versus a ‘psychological’ sexual interest in which individuals ‘want’ or ‘crave’ sex (Robinson & Berridge, 1993).

The neurochemical distinctions between ‘wanting’ [incentive salience] and ‘liking’ (in sum, dopamine vs. opioids) have been extensively studied by Kent Berridge and colleagues as applied to addiction. However, simplistic notions that low dopamine = low libido and depression in women (Wolf, p. 57) are not clearly supported by the literature.³

It's also important to note that HSDD is a controversial clinical diagnosis, one given to women who have a low (or nonexistent) libido and are distressed about it. However, desire is highly subjective, and what might be distressing to one woman is of no concern to another. Examining the causes of diminished sexual desire is critical, and these can include non-sexual health problems, menopause,⁴ a house full of kids, relationship issues, and having a crappy lover. Dr. Petra Boynton has written extensively about the problematic aspects of the HSDD diagnosis and the screening tools used to assess it, as well as the medicalization of sexuality for pharmaceutical marketing purposes.⁵

In general, you know that something is nosologically amiss when a review article claims that "Over 50% of women are believed to be affected by female sexual dysfunction" (Woodis et al., 2012). Which brings us to a state of dread...

Naomi Watts and Laura Elena Harring in Mulholland Drive

Dread

Desire can turn to dread very quickly in human relationships. This is also true in the rat mesolimbic dopamine system. Recent studies (e.g., Faure et al., 2008) have suggested that "desire" and "dread" reside in close proximity in the nucleus accumbens (NAc). Appetitive and aversive motivations can be elicited by manipulations of glutamate or GABA systems located only millimeters apart in the NAc.(Richard & Berridge, 2011):

NAc and dopamine-related circuits are best known for roles in appetitive motivation, but are also implicated in some forms of aversive motivation related to fear, stress, disgust, and pain. Within medial shell of NAc, neuroanatomical coding plays an important role in determining appetitive versus fearful valence of intense motivations generated by glutamate disruptions.

Scene from Rabbits by David Lynch

The measured behaviors in these experiments are actually called "desire" and "dread" (Richard & Berridge, 2011; 2012). Desire is the time spent eating food chow pellets, and dread (fear) is the time spent kicking up crushed corn cob bedding at threatening stimuli, a behavior known as defensive treading. The figure below shows an anterior-posterior gradient for desire and dread in the NAc medial shell. The glutamate AMPA receptor anatgonist DNQX was microinjected alone or in combination with D1/D2 dopamine antagonists into subregions of the NAc. Glutamate disruption in the anterior region induced eating, but glutamate disruption in the posterior region induced defensive treading. Both effects were reversed by dopamine antagonists, suggesting that the behaviors were mediated by dopamine.

Modified from Fig. 3 (Faure et al., 2008). Magnitude of increases in food intake (A) and defensive treading (B) behaviors elicited by DNQX, mixture, or vehicle microinjections in the anterior and posterior halves of the medial shell of the nucleus accumbens. *p < 0.05; **p < 0.01; ^#p < 0.05, anterior versus posterior. Error bars indicate SEM.


In real life, it seems that such anatomically discrete manipulations of NAc would not be the norm. This might suggest that a mixed feeling of desire and dread is more typical: you want to eat that donut bacon cheeseburger but fear the extra pounds (or a heart attack). Or you desire the sultry stranger who showed up in your shower but dread the consequences of unravelling the mystery (or at least you do in a David Lynch movie).

Laura Elena Harring in Mulholland Drive

Fortunately, the NAc is sensitive to emotional context, so the "desire-dread" map can show plastic changes according to the current environment (Reynolds & Berridge, 2008). Under standard conditions (neither very safe nor very stressful), there's a yellow zone of ambiguity in the middle.

Figure 3 (Reynolds & Berridge, 2008). Summary map of glutamatergic valence generation in the medial shell. Purely appetitive sites are shown in green (where DNQX elicited only eating or drinking behaviors). Purely fearful sites are shown in red (where DNQX elicited only defensive-treading behavior). Ambivalent or mixed valence sites are shown in yellow (where DNQX microinjection elicited both appetitive-eating behavior and defensive-treading behavior from the same rat). The home environment expanded the purely appetitive zone compared with the standard environment, whereas the stressful environment (Iggy Pop music at 80-86 dB) expanded the fearful and ambivalent zones.

Ambivalent states are more computationally intensive for the Bayesian brain, and preferences for novel, surprising, and even inexplicable experiences (such as Mulholland Drive) present a challenge for Bayesian theorists and their "free energy principle" (see Free-energy minimization and the dark-room problem), which seeks to reduce uncertainty. Motivations aren't always clear-cut, even in rat NAc. Fortunately, the NAc doesn't exist in isolation, and top-down influences from medial prefrontal cortex can bias or suppress intense motivations (Richard & Berridge, 2012).

For other realms of dread, there's a very large literature on fear conditioning, as most of you know.

Despair

I'll end this essay on a brief note of despair. Rodent models of depression might be the largest of the three D's, in terms of neuroscience research (Cryan et al., 2002). In The Abject Self:Self-States of Relentless Despair, psychotherapist Dr. Kathleen Adams discusses the anguished experience of abject states in her patients:

In her opus on the powers of horror, Kristeva (1982) delineates a realm of preverbal experience permeated by affects of meaninglessness, dread, and horror. Her constructs of abject states and self-abjection are complex amalgams of identity, attachment disorganization, affect, and enactment.  ... Whereas the masochist suffers to gain nurture, the abject self suffers in the certain knowledge that he/she is beyond help.
...  In the grip of abject feelings, one feels unworthy, unlovable, and in utter despair about the situation ever changing.

That terrifying sense of existential dread and aloneness is not exactly captured by animal models of behavioral despair. There's a gaping chasm between Kristeva's abject states and depressive-like behaviors in mice exposed to chronic stress. The animals may give up in the forced swim test, but they're not filled with self-loathing in the face of their inadequacy.

I tried to write in greater detail about this topic in 2009 but gave up. In despair of ever finishing. The post was titled Is There a Valid Animal Model of Depression? but the literature was too large to sufficiently summarize in a single post. In fact, you might need an entire blog that touches on these issues, so head right over to Functional Neurogenesis to read the posts tagged anxiety/depression. Oh, and you can take a look at my early attempt from six years ago: Sad Cingulate on 60 Minutes and in Rats.

I don't care if you're sad
I don't care if you're heart is breaking
You soothe me and you turn me on
Speed and sleep

-Throwing Muses, Speed and Sleep

 

Footnotes

¹ My pull quote from an initial read of the available excerpts was:

Dopamine is not a feminist neurotransmitter, unless snails and insects have been secretly reading Betty Friedan and listening to Bikini Kill.

² However, the sources she used were misstated at times... as in this gift that just keeps giving (Vagina, p. 290):

Specific scents have been found to boost vaginal blood engorgement: cucumbers and Good & Plenty candies both are at the top of the vaginal-engorgement-activating scents, according to one study (and both are phallic in shape).

"Honey, I'm tired of the cucumber. Can we use the Good & Plenty tonight?" But seriously, she cited Zhou and Chen (2008) for this, which is incorrect. Who fact checked this book??

³ For example, in a group of individuals with Parkinson's disease (all of whom were under dopaminergic treatment), Celikel et al. (2008) found that: "Female patients had reduced sexual drive and they were less satisfied with orgasm, while male patients had easier orgasms than did the controls." Wolf cited a study that reportedly found "a link between well-functioning dopamine (and norepinephrine) systems and strong female sexual response" (p. 58), but the authors themselves did not observe that: "Our prediction that women with HSDD and FSAD would show substantially lower DA and NE responses to sexual stimuli was not supported" (Meston & McCall, 2005). Finally, the dopamine and norepinephrine reuptake inhibitor bupropion has been shown to improve sexual functioning in some studies of depressed humans, but it had no effect on sexual motivation and copulatory behavior in female rats (López et al., 2007). Also see a detailed post by David Dobbs, in response to Dr. Pfaus.

⁴ Naomi Wolf is about to turn 50, and I predict she's already working on a sequel to Vagina: A New Biography -- one that involves menopause. 

⁵ I've previously written about neuroimaging studies of Hypoactive Sexual Desire Disorder: Media HSDD: "Hyperactive Sexual Disorder Detection"  and Underwear Models and Low Libido.

⁶ Original by David Lynch, one of his photos from the collaborative work Dark Night of the Soul. Rodents extra.


References

Adams K (2011). The abject self: self-states of relentless despair. International journal of group psychotherapy, 61 (3), 332-64 PMID: 21728704

Celikel E, Ozel-Kizil ET, Akbostanci MC, Cevik A. (2008). Assessment of sexualdysfunction in patients with Parkinson's disease: a case-control study. Eur J Neurol.15:1168-72.

Cryan JF, Markou A, & Lucki I (2002). Assessing antidepressant activity in rodents: recent developments and future needs. Trends in pharmacological sciences, 23 (5), 238-45 PMID: 12008002

Faure A, Reynolds SM, Richard JM, & Berridge KC (2008). Mesolimbic dopamine in desire and dread: enabling motivation to be generated by localized glutamate disruptions in nucleus accumbens.  Journal of neuroscience, 28 (28), 7184-92 PMID: 18614688

López HH, Wurzel G, Ragen B. (2007). The effect of acute bupropion on sexual motivation and behavior in the female rat. Pharmacol Biochem Behav. 87:369-79.

Meston CM, McCall KM. (2005). Dopamine and norepinephrine responses to film-induced sexual arousal in sexually functional and sexually dysfunctional women. J Sex Marital Ther. 31:303-17.

Pfaus JG (2006). Of rats and women: preclinical insights into the nature of female sexual desire Sexual and Relationship Therapy, 21 (4), 463-476: 10.1080/14681990600967011

Reynolds SM, Berridge KC. (2008). Emotional environments retune the valence ofappetitive versus fearful functions in nucleus accumbens. Nat Neurosci. 11:423-5.

Richard JM, Berridge KC (2011). Nucleus accumbens dopamine/glutamate interaction switches modes to generate desire versus dread: D(1) alone for appetitive eating but D(1) and D(2) together for fear. Journal of Neuroscience, 31 (36), 12866-79 PMID: 21900565

Richard JM, Berridge KC (2012). Prefrontal Cortex Modulates Desire and Dread Generated by Nucleus Accumbens Glutamate Disruption. Biological psychiatry PMID: 22981656

Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. (2011). Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476:458-61.

Wolf N (2012). Vagina: A New Biography. Ecco Press.

Woodis CB, McLendon AN, Muzyk AJ. (2012). Testosterone supplementation for hypoactive sexual desire disorder in women. Pharmacotherapy 32:38-53.

Zhou W, Chen D. (2008). Encoding human sexual chemosensory cues in the orbitofrontaland fusiform cortices. J Neurosci. 28:14416-21.

Untitled (Little Girl #1), Dark Night of the Soul ⁶