Commentary on: “Neuroscience research fails to support claims that excessive pornography consumption causes brain damage”, by Hilton and Watts

Perhaps the most startling aspect of the response to our editorial is the lack of understanding, perspective, or acknowledgment that there is a growing and credible body of research strongly supporting the existence of natural addiction, which encompasses pornography addiction. It is apparent the authors have rejected this premise of natural addiction that leading addiction neurobiologists continue to support, and therefore it is not surprising that they would view pornography addiction with skepticism.

Particularly noteworthy is their lack of awareness of the growing evidence of ΔFosB and its role as a molecular switch in addictive states, both drug and natural. For an understanding of the current perspective on ΔFosB, Dr. Eric Nestler’s review paper published in the Philosophical Transactions of the Royal Society is most helpful. This paper was published in the issue titled “The Neurobiology of Addiction – new vistas,” in summary of a discussion meeting of prominent addiction neurobiologists.[24] Because of confusion the commenters may have created with their comments, some of the main points of Nestler’s paper, and even more recent work on ΔFosB in relation to sexuality will be reviewed in this response.

ΔFosB is a member of the Fos family transcription factors.[24] Fos family proteins are induced by administration of drugs of abuse. These proteins, in general, are released and degraded quickly, with their point of action focusing on reward areas such as the nucleus accumbens and the dorsal striatum. They are unstable, and are gone within hours.

ΔFosB differs from other members of the Fos family in that it accumulates with drug abuse, across the spectrum of drugs of abuse.[19] Thus ΔFosB continues to exert changes in gene expression even during periods of drug withdrawal. Nestler and others have proposed that ΔFosB is a “sustained ‘molecular switch’ that helps initiate and maintain an addicted state.”[24]

Bitransgenic mice can be induced to selectively produce ΔFosB in the dynorphin-containing medium spiny neurons, which is specifically where drugs of abuse are thought to exert their effect. They show an exaggerated behavioral response to drugs of abuse, as if they had been chronically given the drug, as compared to mice who do not inherently overexpress ΔFosB; this phenomenon is seen both with cocaine[14] and opioids.[33] Studies with mice which are induced to overexpress ΔFosB in a viral-mediated gene transfer model have replicated this response.[33] In other words, drug naïve animals overexpressing ΔFosB behave as if they are already addicted.

So how does this relate to the existence of natural addiction? The purpose of the nucleus accumbens is integral in salience of natural reward behaviors such as food, sex and rewarding interpersonal interactions. Nestler discusses the evidence supporting a role for ΔFosB in the nucleus accumbens in “so-called natural addictions: e.g., pathological overeating, gambling, exercise, sexual addiction.”[24] Significantly, ΔFosB accumulates in the nucleus accumbens in mice that exhibit higher levels of wheel running than normal, a model for exercise addiction.[32] This also occurs after chronic over consumption of sucrose or sex.[30] The viral-mediated mice overexpressing ΔFosB referred to earlier which exhibit behavior consistent with drug addiction also “increases drive and consumption for these natural rewards.”[23] Blocking the action of ΔFosB in these animals with an antagonist (dominant negative Jun protein) prevents overconsumption of these natural rewards. Dr. Nestler summarizes: “These findings suggest that ΔFosB in this brain region sensitizes animals not only for drug rewards but for natural rewards as well, and may contribute to a state of natural addiction.”[24]

Other recent studies strengthen the premise that sexuality is strongly tied to ΔFosB, a marker of addiction. For instance, ΔFosB overexpression in the nucleus accumbens has been shown to enhance sexual reward in female Syrian hamsters.[18] Pitchers et al., published a paper last year demonstrating that sexual experience causes an accumulation of ΔFosB in limbic-associated brain regions, such as the nucleus accumbens core and shell, the medial prefrontal cortex, the ventral tegmental area and the caudate putamen. Significantly, “blocking ΔFosB attenuated experience-induced facilitation of sexual motivation and performance, while overexpression of ΔFosB in the nucleus accumbens caused an enhanced facilitation of sexual behavior, in terms of increased sexual performance with less experience.”[27] (emphasis added) This is most interesting when considered in light of Nestler’s comment in the Royal Society paper, that the level of ΔFosB may become a “biomarker to assess the state of activation of an individual’s reward circuitry, as well as the degree to which an individual is ‘addicted’, both during the development of an addiction and its gradual waning during extended withdrawal or treatment.”[27] These perspectives are clearly supportive of a neurobiological marker for sexual addiction. Pitchers et al., work summarizes “…these data are the first to indicate an obligatory role of ΔFosB in the acquisition of experience-induced facilitation of sexual behavior… We propose that this long-term expression of facilitated behavior represents a form of memory for natural reward; hence, ΔFosB in NAc is a mediator of reward memory.”[16] (emphasis added) Another paper from Pitchers et al., last year established that physiologic sexual experience, interrupted by a period of abstinence with resumption of sexual behavior actually increases numbers of dendrites and dendritic spines in medium spiny neurons. Again they summarize, “The structural alterations induced by sexual experience and subsequent abstinence resemble those seen after repeated exposure to psychostimulants… the data presented here demonstrate that sexual behavior – a natural rewarding stimulus – can induce long-lasting neuroadaptation in the mesolimbic system. Our findings suggest that behavioral plasticity, particularly a sensitized locomotor response, is an immediate and long-term outcome of sexual experience.”[26] (emphasis added)

Another metabolic parameter strongly supporting a neurobiological basis for natural addiction is found in studies examining dopamine receptor depletion. Wang et al., demonstrated dopamine (D2) receptor downgrading with obesity similar to that seen in drug addiction, and the levels correlated with BMI.[31] An animal study recently published by Johnson and Kenny found that rats exposed to “palatable, energy-dense food develop a profound state of reward hyposensitivity and compulsive-like eating. The maladaptive behavioral responses in obese rats probably arise from diet-induced deficits in striatal D2R signaling. Overconsumption of drugs of abuse similarly decreases striatal D2 receptor density, induces a profound state of reward hypofunction, and triggers the emergence of compulsive-like drug taking behaviors. Our findings therefore support previous work in indicating that obesity and drug addiction may arise from similar neuroadaptive responses in brain reward circuits.”[20] (emphasis added)

Pathologic gambling has demonstrated decreased activation in the mesolimbic reward system as compared to controls,[28] and administration of dopamine to patients with Parkinson’s disease has iatrogenically induced both hypersexuality and pathological gambling.[13] Reuter et al., summarizes “…a decrease activation of the ventral striatum, which is a hallmark of drug addiction, and decreased VMPFC activation, which is related to impaired impulse control, favor the view that pathological gambling is a non-substance-related addiction.”[28] (emphasis added)

In our opinion the seminal work on ΔFosB by Nestle and others is pioneering, and changes the landscape in considering aspects of neuromodulation as related to natural addiction. It casts a biologic light on all aspects of this concept. We feel this data is confirmatory with regard to the existence of neuromodulation in natural addiction, especially considering the recent work exploring the relationship between ΔFosB and sexuality. The points we made on the VBM studies regarding hypoplasia of neuronal populations associated with reward centers emanated from this perspective. These correlative papers concluded that atrophy occurred in four different addictive states, two drug and two natural. Certainly the authors of these papers were not addressing causation, although the cocaine[14] and obesity[25] papers both recognize that the areas of atrophy are associated with reward pathways. Inherency, which certainly may be a factor, does not explain the reversibility, with recovery, of selective atrophy associated with the use of methamphetamine.[22]

Our premise is that selective atrophy of cortical areas associated with reward pathways may be viewed in a neuromodulatory light, given current research confirming neuroplasticity in overindulgence in natural rewards, specifically sexuality. The inability of those challenging our conclusions to understand even the most basic of these concepts is illustrated by their comments about specific processes. For instance, their dismissal of the importance of ΔFosB is illustrated by their manifest lack of insight into the research concerning this protein. While mentioning that stress can induce ΔFosB, they fail to understand that the pattern of expression with stress extends broadly across both dynorphin+ and enkephalin+ medium spiny neurons and is not confined to dynorphin+ medium spiny neurons as it is in the overexpression associated with overconsumption of natural rewards and with drug addiction.[24] The following comment is illustrative of their lack of understanding the importance of ΔFosB as a molecular switch in addiction: “That’s great news for the sexually inexperienced rats! Put your name on the list for more ΔFosB and your sexual performance will be on par with more experienced rats.” They correctly point out that atrophy is associated with aging, and may be affected by comorbidities, neurotoxicity, and the like, but fail to appreciate selective atrophy in cortical areas associated with reward centers. The concept of upstream neuronal atresia as illustrated in figure 2 in the Nestler paper, focusing on a common pathway for drug and natural addiction,[23] may be an important mediator in this process. This atresia is associated with decreased dopaminergic input into the NA from the VTA, and with decreased glutaminergic input from the cortex, both being associated with an increase in ΔFosB in the medium spiny neuron. The cortex can atrophy in response to decreased downstream stimuli.[21] That there is a functional frontal deficit in addiction is the hallmark, whether drug induced or naturally induced, and the hypofrontal syndrome displayed is similar to that seen in traumatic brain injury.[16] Another recently reported example of selective cortical atrophy in reward-associated regions in adolescents manifesting Internet “addiction” is of interest in this context.[34]

While a role for inherency is obvious, to deny any role for causation is to envision a world of selectively preatrophied individuals destined to act out in addiction. We find this premise much less plausible than at least a partial role for causation given what we consider confirmatory data with regard to the role of ΔFosB in the induction and then perpetuation of addictive states.

Whether or not future structural studies confirm our premise that at least partial causation is supported in this regard, the question of neuromodulation with regard to natural addiction is independently supported by the ΔFosB studies, and strengthened by the D2R and fMRI studies on obesity and pathological gambling previously cited. Particularly convincing with regard to a causation role of subsequent addictive behavior after induction is the previously cited work on bitransgenic and virally induced mice which behave as if addicted, both in natural and drug addiction, overexpression of ΔFosB being the only variable.[24]

As stated in our editorial, no less that the head of the National Institute for Drug Abuse (NIDA), Dr. Nora Volkow, called, in the journal Science, for changing the name of the NIDA to the National Institute on Diseases of Addiction, to “encompass addictions such as pornography, gambling, and food…She would like to send the message that we should look at the whole field.”[15] Dr. Eric Nestler at Mount Sinai uses the phrase “natural addiction” in describing what he calls “pathological overeating, pathological gambling, and sexual addictions.” Dr. Howard Shaffer at Harvard said, “I had great difficulty with my own colleagues when I suggested that a lot of addiction is the result of experience…” and continued, “Although it is possible to debate whether we should include substance or process addictions within the kingdom of addiction, technically there is little choice.”[29] When scientists such as Drs. Volkow, Nestler and Shaffer use the word “addiction” with regard to processes such as food and sex, they are not using this term lightly. Neurobiologists understand that this word has neuromodulatory implication.

For Reid et al., to suggest to the reader that it is irresponsible to use the word addiction in this context, we believe, is irresponsible. They seem to ignore substantial evidence that natural addictions do indeed exist, and that specifically sexual addiction can induce neuroplasticity. They fail to grasp the significance of neuromodualtion in sexuality when they state, “…current research offers little support for conceptualizing excessive pornography problems as an addictive disorder.” If natural addiction exists, as we and others believe, then it strains credibility to argue that patients struggling with pornography addiction like the one described by Bostwich and Bucci are not prime examples.[12]

Recently a colleague experienced in functional neurosurgery was visiting with another similarly experienced neurosurgeon. This latter surgeon opined that the next field which might be addressed through functional neurosurgery may be addiction. However, unlikely it appears now to some, we envision a day when drug addiction, severe obesity and sexual addictions with legal implications might be treated with limbic targeting, hence the relevance to our present subject.

We found the perspective and tone of these authors disappointing, in that they are desperately dismissive of any neurobiologic evidence supporting natural models of addiction. Particularly remarkable, in our opinion, is their blatant disregard for the context which leading neurobiologists view not only ΔFosB, but any data which supports neuromodulation in natural addiction. In refutation, the only evidence they cite is their own work, which is behavioral in nature, rather than neurobiologically based. Their perspective is permeated with an apologetic bias against any study suggesting pathologic neuromodulation on a macro or micro scale with regard to natural addiction.

As of this writing a report out of Yale published in the Archives of General Psychiatry titled “Neural Correlates of Food Addiction” describes activation in reward pathways using fMRI as being similar in obese individuals and in those with substance addiction. They summarize, “the current findings suggest that food addiction is associated with reward-related neural activation that is frequently implicated in substance dependence. To our knowledge, this is the first study to link indicators of addictive eating behavior with a specific pattern of neural activation.”[17] (emphasis added) Emerging data continues to strengthen and support the concept of neuromodulation with natural addiction.

Footnotes

Available FREE in open access from: http://www.surgicalneurologyint.com/text.asp?2011/2/1/64/81427

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