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INTRA-CRANIAL SELF-STIMULATION




       The story of the biochemical roots of paradise is illuminating, but it's not very edifying. In the 1950s, James Olds and his colleagues invented a procedure known as intracranial self-stimulation. By implanting a permanent thin wire-electrode in a rat's brain, the captive rodent was given the ability to self-administer a small electric shock. The current used is typically less than 0.0005 amperes. The pulse lasts for less than a second: the rodent wirehead must press the lever again to get another hit. Different placements of the electrode elicit different intensities of response. Rates of up to 10,000 bar-presses an hour may be recorded - but only for pulses delivered to the most rewarding brain-areas. An animal will self-stimulate for a whole day and night without rest, and cross a powerfully electrified grid, to gain access to the lever when its reward-centres are wired up.
       Olds mapped the whole brain. Stimulation of some areas - the periaqueductal grey matter, for instance - proved aversive: an animal will work hard to avoid it. "Aversive" is probably a euphemism: electrical pulses to certain neural pathways may be terrifying or excruciating. euphemisms aside, our victims are being tortured.

       Happily, more regions in the brain are rewarding to stimulate than are unpleasant. Yet electrical stimulation of most areas, including the great bulk of the neocortex, is motivationally neutral.

       One brain region in particular does seem especially enjoyable to stimulate: the medial forebrain bundle. The key neurons in this bundle originate in the ventral tegmental area (VTA) of the basal ganglia. VTA neurons manufacture the catecholamine neurotransmitter dopamine. Dopamine is transported down the length of the neuron, packaged in synaptic vesicles, and released into the synapse. Crucially, VTA neuronal pathways project to the nucleus accumbens. VTA dopaminergic neurons are under continuous inhibition by the gamma-aminobutyric acid (GABA) system.

       In recent years, a convergence of neuropharmacological evidence, clinical research, and electrical stimulation experiments has led many researchers to endorse some version of the "final common pathway" hypothesis of reward.

       There are anomalies and complications which the final-common-pathway hypothesis still has to account for. Any story which omits the role and complex interplay of, say, "the love hormone", oxytocin; the "chocolate amphetamine", phenylethylamine; the multiple receptor sub-types of serotonin, noradrenaline and the opioid families; and most crucially of all, the intra-cellular post-synaptic cascade within individual neurons, is going to be simplistic. Yet there is accumulating evidence that recreational euphoriants, clinically useful mood-brighteners, and perhaps all rewarding experiences critically depend on the mesolimbic dopamine pathway.

        One complication is that pleasure and desire circuitry have intimately connected but distinguishable neural substrates. Some investigators believe that the role of the mesolimbic dopamine system is not primarily to encode pleasure, but "wanting" i.e. incentive-motivation. On this analysis, endorphins and enkephalins - which activate opioid receptors most especially in the ventral pallidum - are most directly implicated in pleasure itself. Mesolimbic dopamine, signalling to the ventral pallidum, mediates desire. Thus "dopamine overdrive", whether natural or drug-induced, promotes a sense of urgency and a motivation to engage with the world, whereas direct activation of mu opioid receptors in the ventral pallidum induces emotionally self-sufficient bliss.

       Certainly, the dopamine neurotransmitter is not itself the brain's magic pleasure chemical. Only the intra-cellular cascades triggered by neurotransmitter binding to the post-synaptic receptor presumably hold the elusive, tantalising key to everlasting happiness; and they are not yet fully understood. But it's notable that dopamine D2 receptor-blocking phenothiazines, for example, and other aversive drugs such as kappa opioid agonists, tend to inhibit activity, or increase the threshold of stimulation, in the mesolimbic dopamine system. Conversely, heroin and cocaine both mimic the effects of direct electrical stimulation of the reward-pathways.

       Comparing the respective behavioural effects of heroin and cocaine is instructive. If rats or monkeys are hooked up to an intravenous source of heroin (or other potent mu opioid agonist such as fentanyl), the animals will happily self-administer the drug indefinitely; but they still find time to sleep and eat. If rats or monkeys have the opportunity to self-administer cocaine without limit, however, they will do virtually nothing else. They continue to push a drug-delivery lever for as long as they are physically capable of doing so. Within weeks, if not days, they will lose a substantial portion of their body weight - up to 40%. Within a month, they will be dead.

       Humans don't have this problem. So what keeps our mesolimbic dopamine and opioidergic systems so indolent? Why does a "hedonic treadmill" stop us escaping from a genetically-predisposed "set-point" of emotional ill-being? Why can't social engineering, politico-economic reform or psychotherapy - as distinct from germ-line genetic re-writes - make us durably happy?

       Evolution provides some plausible answers. A capacity to experience many different flavours of unhappiness - and short-lived joys too - was adaptive in the ancestral environment. Anger, fear, disgust, sadness, anxiety and other core emotions each played a distinctive information-theoretic role, enhancing the reproductive success of our forebears. Thus at least a partial explanation of endemic human misery today lies in ancient selection pressure and the state of the unreconstructed vertebrate genome. Selfish DNA makes its throwaway survival-machines feel discontented a lot of the time. A restless discontent is typically good for promoting its "inclusive fitness", even if it's bad news for us. Nature simply doesn't care; and God has gone missing, presumed dead.

       On the African savannah, naturally happy and un-anxious creatures typically got outbred or eaten or both. Rank theory suggests that the far greater incidence of the internalised correlate of the yielding sub-routine, depression, reflects how low spirits were frequently more adaptive among group-living organisms than manic self-assertion. Group living can be genetically adaptive for the individual members of the tribe, but we've paid a very high psychological price.

       Whatever the origins of malaise, a web of negative feedback mechanisms in the CNS conspires to prevent well-being - and (usually) extreme ill-being - from persisting for very long.

       Life-enriching emotional superhealth will depend on subverting these homeostatic mechanisms. The hedonic set-point around which our lives fluctuate can be genetically switched to a far higher plateau of well-being.

       At the most immediate level, firing in the neurons of the ventral tegmental area is held in check mainly by gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the vertebrate central nervous system. Opioids act to diminish the braking action of GABA on the dopaminergic neurons of the VTA. In consequence, VTA neurons release more dopamine in the nucleus accumbens. The reuptake of dopamine in the nucleus accumbens is performed by the dopamine transporter. The transporter is blocked by cocaine. Dopamine reuptake inhibition induces euphoria, augmented by activation of the sigma1 receptors. [Why? We don't know. Science has no understanding of why sentience - or insentience for that matter - exists at all.] Amphetamines block the dopamine transporter too; but they also act directly on the dopaminergic neurons and promote neurotransmitter release.

       The mesolimbic dopamine pathway passes from the VTA to the nucleus accumbens and ascends to the frontal cortex where it innervates the higher brain. This architecture is explicable in the light of evolution. Raw limbic emotional highs and lows - in the absence of represented objects, events or properties to be (dis)satisfied about - would be genetically useless to the organism. To help self-replicating DNA differentially leave more copies of itself, the textures of subjective niceness and nastiness must infuse our representations of the world, and - by our lights - the world itself. Hedonic tone must be functionally coupled to motor-responses initiated on the basis of the perceived significance of the stimulus to the organism, and of the anticipated consequences - adaptively nice or nasty - of simulations of alternative courses of action that the agent can perform. Natural selection has engineered the "encephalisation of emotion". We often get happy, sad or worried "about" the most obscure notions. One form this encephalisation takes is our revulsion at the prospect of turning ourselves into wirehead rats - or soma-pacified dupes of a ruling elite. Both scenarios strike us as too distasteful to contemplate.

       In any case, wouldn't we get bored of life-long bliss?

       Apparently not. That's what's so revealing about wireheading. Unlike food, drink or sex, the experience of pleasure itself exhibits no tolerance, even though our innumerable objects of desire certainly do. Thus we can eventually get bored of anything - with a single exception. Stimulation of the pleasure-centres of the brain never palls. Fire them in the right way, and boredom is neurochemically impossible. Its substrates are missing. Electrical stimulation of the mesolimbic dopamine system is more intensely rewarding than eating, drinking, and love-making; and it never gets in the slightest a bit tedious. It stays exhilarating. The unlimited raw pleasure conjured up by wirehead bliss certainly inspires images of monotony in the electrode-naive outsider; but that's a different story altogether.

       Yet are wireheading or supersoma really the only ways to ubiquitous ecstasy? Or does posing the very question reflect our stunted conception of the diverse family of paradise-engineering options in prospect?

       This question isn't an exercise in idle philosophising. As molecular neuroscience advances, not just boredom, but pain, terror, disgust, jealousy, anxiety, depression, malaise and any form of unpleasantness are destined to become truly optional. Their shifting gradients played a distinct information-theoretic role in the lives of our ancestors in the ancestral environment of adaptation. But their individual textures (i.e. "what it feels like", "qualia") can shortly be either abolished or genetically shifted to a more exalted plane of well-being instead. Our complicity in their awful persistence, and ultimately our responsibility for sustaining and creating them in the living world, is destined to increase as the new reproductive technologies mature and the revolution in post-genomic medicine unfolds. The biggest obstacles to a cruelty-free world - a world cured of any obligate suffering - are ideological, not technical. Yet whatever the exact time-scale of its replacement, in evolutionary terms we are on the brink of a Post-Darwinian Transition.

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