"Although the details of human hopes are surely beyond the imagination of other creatures," writes Jaak Panksepp in Affective Neuroscience: The Foundations of Human and Animal Emotions (1998), "the evidence now clearly indicates that certain intrinsic aspirations of all mammalian minds, those of mice as well as men, are driven by the same ancient neurochemistries." Regarding what he has labeled the SEEKING system, Panksepp explains that the mesolimbic and mesocortical dopamine pathways, which we previously discussed in Dopamine action, synthesis, and pathways, "tend to energize and coordinate the functions of many higher brain areas that mediate planning and foresight (such as the amygdala, nucleus accumbens, and frontal cortex)." Both of these important pathways originate from the ventral tegmental area within the ancient midbrain, which is part of the brain stem (see Brain stem structures and the reticular formation). a red box is drawn around the midbrain in the image above right, courtesy of John A. Beal of Louisiana State University.
To be very specific regarding neurocircuitry for the SEEKING system, Panksepp refers to the extended lateral hypothalamic corridor, which is part of the previously discussed medial forebrain bundle (MFB), a prominent tract of nerve fibers, both ascending and descending, within which is incorporated the mesolimbic and mesocortical dopamine pathways of the SEEKING system. Although we have discussed the MFB previously, here again is the illustration from the HOPES Brain Tutorial, a project of Stanford University (image links to source). In real tissue, this MFB pathway appears as white matter (see Gray matter, white matter, glial cells). It is this tiny pathway of a multitude of nerve fibers that motivates us via the SEEKING system.
In locating the SEEKING system, Panksepp refers to the nucleus accumbens, which is part of the corpus striata (basal ganglia). The lateral hypothalamic corridor, explains Panksepp, "running from the ventral tegmental area (VTA) to the nucleus accumbens, is the area of the brain where local application of electrical stimulation will promptly evoke the most energized exploratory and search behaviors an animal is capable of exhibiting." The "corridor" to which Panksepp refers is also called the mesolimbic pathway, first discussed in Dopamine action, synthesis, and pathways.
The SEEKING System, obsessions, and compulsions:
If you are interested in obsessions and compulsions, it is important to remember that the SEEKING system as a whole and the nucleus accumbens in particular play important roles in generating these behaviors. We will discuss the mechanics of the nucleus accumbens in greater detail in Part 3 of CorticalBrain.com.
When the mesolimbic pathway from the dopamine-producing VTA to the nucleus accumbens is stimulated, SEEKING behavior ensues. Panksepp writes: "For instance, stimulated rats move about excitedly, sniffing vigorously, pausing at times to investigate various nooks and crannies of their environment. If one presents the animal with a manipulandum, a lever that controls the onset of brain stimulation, it will readily learn to press the lever and will eagerly continue to 'self-stimulate' for extended periods, until physical exhaustion and collapse set in. The outward behavior of the animal commonly appears as if it is trying to get something behind the lever."
In the coronal image below you can see the nucleus accumbens within the corpus striata. The image is from the Temple University School of Medicine's Department of Anatomy and Cell Biology website, created by Marvin Sodicoff and adapted by Rod Bain, Andrew Blum, and David Ni. the labeling is added here. To see an unlabeled version and to practice identifying structures, click on the image.
When rats self-stimulate the mesolimbic dopamine pathway, as Panksepp describes above, their consequent behavior reminds me of obsessive-compulsive disorder in humans. We will discuss this similarity in greater detail below. Panksepp points out that the lateral hypothalamic circuits have been experimentally stimulated in humans. He writes: "People typically have not reported simple sensory pleasures from the LH [lateral hypothalamic] stimulation, but, rather, invigorated feelings that are difficult to describe. They commonly report a feeling that something very interesting and exciting is going on." Panksepp contrasts these kinds of feelings with those of humans stimulated in the medial septal area. Humans stimulated in the septal area, which is contiguous with the hypothalamus, "report pleasurable sexual feelings."
These observations lead me to think that perhaps stimulation of the SEEKING system feels good at first, in moderation. But there is a difference between being massaged and being pummeled. It is this difference, that separates feel-good seeking and problem solving from painful obsessive-compulsive symptoms.
Panksepp describes the SEEKING system as follows:
This emotional system is a coherently operating neuronal network that promotes a certain class of survival abilities. This system makes animals intensely interested in exploring their world and leads them to become excited when they are about to get what they desire. It eventually allows animals to find and eagerly anticipate the things they need for survival, including, of course, food, water, warmth, and their ultimate evolutionary survival need, sex. In other words, when fully aroused, it helps fill the mind with interest and motivates organisms to move their bodies effortlessly in search of the things they need, crave, and desire. In humans, this may be one of the main brain systems that generate and sustain curiosity, even for intellectual pursuits. This system is obviously quite efficient at facilitating learning, especially mastering information about where material resources are situated and the best way to obtain them. It also helps assure that our bodies will work in smoothly patterned and effective ways in such quests.
The SEEKING System and pattern generation:
The SEEKING system has been in place a very long time. It even exists in very primitive creatures such as the Aplysia. A baby Aplysia is pictured to the right (image links to coursework developed by Henry Jakubowski of St. John's University; image originally from Björn Brembs http://www.brembs.net/learning/aplysia/). Panksepp writes: "The Aplysia is generally a sluggish and behaviorally inflexible creature that crawls along the seabed, sucking in nutrients such as seaweed and waste products of other animals. It its journey from rock to rock, it uses an intrinsic behavioral strategy of reaching out and swinging from side to side in search of a new anchor point. In so doing, it exhibits a phototactic preference for darker rather than lighter environments."
In the laboratory, using a bright light, scientists can teach the Aplysia to swim on only one side of the pool—the dark side. The Aplysia thus exhibits patterned behavior. "What is important here," writes Panksepp, "is that Aplysia, as all other animals, have endogenous behavior generators that make them spontaneously active creatures in their environment. Indeed, intrinsic motor pattern generation may have been the earliest solution for exerting coherent behavioral control. One of the earliest animal behaviors to have evolved was rhythmic undulation in the primordial seas."
OCD, depression, addictive drugs, incentive salience, and metabolic memory:
So we know that animals with electrodes implanted in their dopamine circuits will ceaselessly press a lever to self-stimulate this system. As pointed out in the previous subsection, the human equivalent of this kind of behavior sounds to me like obsessive-compulsive disorder. Although there is probably some kind of correlation between the rodents' self-stimulating lever pressing and drug addiction, such a link does not mean that the rodents are taking a ride of the hedonic highway. In Affective Neuroscience, Jaak Panksepp writes: "Perhaps the most puzzling feature of the behavior pattern during these bouts of SS [self stimulation] was the fact that the animals simply did not have the behaviorally settled outward appearance of animals consuming conventional rewards. Self-stimulating animals look excessively excited, even crazed, when they worked for this kind of stimulation."
Rather than a reward circuit, Panksepp proposes that stimulation of the SEEKING system prompts an animal "into an appetitive search strategy," analogous to "an animal caught in a "do-loop" (i.e., a repetition of the same instruction), where each stimulation evokes a reinvigorated search strategy.
As anyone who has suffered from obsessive-compulsive symptoms can tell you, there is no reward in symptoms, no "feel-good" moments. It is contended that the reason rats continue to press the lever is to attempt escape from some threat their system perceived when the system was first overstimulated. Pressing the lever provides continued motivation to escape the threat, to keep going rather than lying down to die. Could some forms of obsessive-compulsive disorder serve as a primal defense against depression in that you feel if you stop trying, you're not likely to ever get up? We discussed this earlier in Part 2 of CorticalBrain.com, in Depression, mania, and anxiety. It will be reiterated here some of what Robert M. Sapolsky says on the subject in Why Zebras Don't Get Ulcers: The Acclaimed Guide to Stress, Stress-Related Diseases, and Coping (2004). "When it comes to psychiatric disorders, it seems that increases in the catecholamines have something to do with still trying to cope and the effort that involves, where overabundance of glucocorticoids seems more of a signal of having given up on attempting to cope." It is important to remember that one of the catecholamines—dopamine—is the primary neurotransmitter operative in the SEEKING system's mesolimbic pathway.
Researchers testing the effectiveness of antipsychotic drugs often perform experiments in which mice are forced to swim. This do-or-die exercise greatly increases the levels of dopamine in the brains of these mice and researchers test the effects of antipsychotics in reducing these dopamine levels. My point in recounting this technique is that when scientists take these extremely stressed out mice out of the water, what do they do? They groom themselves furiously. Regarding mice with electrodes implanted into dopamine circuits, grooming is one behavior that frequently disrupts self stimulation. In Affective Neuroscience, Panksepp writes:
To the chagrin of early investigators, highly excited self-stimulating animals often would run away from the lever and stop responding. Instead of returning promptly, they would go into a prolonged grooming sequence of the type that is common after animals finish their meals or complete their sexual activities. Such animals would not readily resume SS [self-stimulation], especially early in training. However, it was noted that giving the animal a few free priming stimulations would often revoke the appetitive mood. This was often necessary to induce animals to behave at the beginning of the test session as well. No such priming was necessary for hungry and thirsty animals working for conventional rewards.
Panksepp points out that when animals are in an appetitive state, anticipating a reward such as food or sex with a receptive mate, dopamine levels increase. But once an appetitive state turns into a consummatory state, dopamine levels immediately begin to decrease. So increasing levels of dopamine are not associated with consummatory, pleasurable activity. Rather the opposite is true. Pleasure is associated with decreasing dopamine levels. This does not mean that "reward" circuitry does not exist. Panksepp writes: "Temporal and frontal cortices contain an abundance of neurons that fire only in response to stimuli that have acquired meaning by being predictably associated with rewards."
Panksepp suggests that the SEEKING system "responds not simply to positive incentives but also to many other emotional challenges where animals must seek solutions." In "The Involvement of Nucleus Accumbens Dopamine in Appetitive and Aversive Motivation" (1994), J.D. Salamone explains that dopamine release and metabolism within the nucleus accumbens "is activated by a wide variety of stressful conditions." Salamone points out that blocking dopamine transmission or otherwise interfering with nucleus accumbens dopamine transmission "has been shown to disrupt active avoidance behavior." In other words, when dopamine is decreased, animals cease trying to escape aversive stimulation. Instead of trying to cope with stress, they give up. Salamone writes: "A review of the literature indicates that there are substantial similarities between the characteristics of dopaminergic involvement in appetitive and aversive motivation."
Regarding addictive drugs, in Why Zebras Don't Have Ulcers, Sapolsky writes: "these compounds all cause the release of dopamine in the ventral tegmentum-nucleus accumbens pathway [the mesolimbic pathway]." As we previously discussed, such dopamine activity does not necessarily correlate with pleasure. Rather, it correlates with exploratory behavior towards either attaining some resource deemed necessary or escaping a perceived threat. So why are certain drugs addictive? Recently, research regarding addiction has instead focused on a type of learning called incentive salience. Sapolsky writes: "This process of associating drug use with a particular setting is a type of learning, and a lot of current addiction research explores the neurobiology of such learning."
In Part 1 of CorticalBrain.com, in our discussion about the role of the amygdalae in shaping behavior, we read from an Vilayanur S. Ramachandran's and Lindsay M. Oberman's article in the November 2006 issue of Scientific American titled "Broken Mirrors: A theory of Autism." It is going to be repeated here that same excerpt here since the authors do such a great job of succinctly explaining the concept of salience.
When a person looks at the world, he or she is confronted with an overwhelming amount of sensory information—sights, sounds, smells, and so on. After being processed in the brain's sensory areas, the information is relayed to the amygdala, which acts as a portal to the emotion-regulating limbic system. Using input from the individual's stored knowledge, the amygdala determines how the person should respond emotionally—for example, with fear (at the sight of a burglar), lust (on seeing a lover) or indifference (when facing something trivial). Messages cascade from the amygdala to the rest of the limbic system and eventually reach the autonomic nervous system, which prepares the body for action. If the person is confronting a burglar, for example, his heart rate will rise and his body will sweat to dissipate the heat from muscular exertion. The autonomic arousal, in turn, feeds back into the brain, amplifying the emotional response. Over time, the amygdala creates a salience landscape, a map that details the emotional significance of everything in the individual's environment.
The image to the right of drug paraphernalia links to source. If the pipe in the picture was yours, you would remember situations in which you had used it. All animals associate environmental surroundings with the mental state they were in when they occupied those surroundings, and this kind of salience certainly contributes to addiction—a sort of I'm in this place so I need to get that kind of feeling again state of being. For example Panksepp reports that male rats exhibit a preference for locations in which they have copulated. Secondly, in addition to conscious learning, humans and other animals learn in metabolic ways, resulting in what is thought to be a kind of needy feeling rooted in our biology. Panksepp writes:
This intrinsic memory capacity was strikingly demonstrated many years ago by investigators who exposed sodium-replete animals to salt either in certain locations in their environment or within water supplies which they were required to work for while thirsty. When these animals were first confronted by rapidly induced sodium depletion, they immediately sought out the locations at which sodium had previously been encountered, and they worked more vigorously for water sources that had contained the salt (even though there were now on an extinction schedule on which no salt reward was forthcoming). In other words, the memory of salt had been firmly recorded in their brains at a time when salt was not needed. This memory was retrieved at a future time when sodium was desperately needed. This remarkable feat suggests that the brain is evolutionarily prepared to remember sodium sources because that rare and precious commodity may be needed at unforeseen times.
We humans also have a kind of metabolic memory for those situations that generate opioids in our brains. Panksepp explains that "it is now clear that positive social interactions derive part of their pleasure from the release of opioids in the brain." He writes:
For instance, the opioid systems of young animals are quite active in the midst of rough-and-tumble play, and when older animals share friendly time grooming each other, their brain opioid systems are activated…. Finally, sexual gratification is due, at least in part, to opioid release within the brain. From all this, it is tempting to hypothesize that one reason certain people become addicted to external opiates … is because they are able to artificially induce feelings of gratification similar to that normally achieved by the socially induced release of endogenous opioids such as endorphins and enkephalins. In doing this, individuals are able to pharmacologically induce the positive feeling of connectedness that others derive from social interactions. Is it any wonder that these people even become intensely attached (classically conditioned) to the paraphernalia associated with their drug experiences, or that addicts tend to become socially isolated, except when they are approaching withdrawal and seeking more drugs?… Investigators have been able to increase opiate consumption in experimental animals simply by separating them from companionship.
Another surprising fact about metabolic memories is that they extend backwards in time to our prenatal environment. Regarding needy or deficit prenatal experiences that can cause lifelong "programming" of the brain and body, in Why Zebras Don't Get Ulcers, Sapolsky writes:
Stress a pregnant rat and her offspring will have an increased propensity for drug self-administration as adults. Give a rat an experimentally induced birth complication by briefly depriving it of oxygen at birth, and you produce the same. Ditto if stressing a rat in its infancy. The same works in nonhuman primates—separate a monkey from its mother during development, and that animal is more likely to self-administer drugs as an adult. The same has been shown in humans.
DRUG INFORMATION: For more information on specific additive drugs, you may want to check out AddictionLibrary.org.
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