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Michael Rule (M, 27)
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    Salvia Divinorum
    What follows is a paper by Klaus M. Stiefel which summarizes the latest studies into the mechanisms of the salvia divinorum induced hallucinogenic experience. This paper is reproduced here in full WITHOUT permission or knowledge of the original author.

    [begin paper : ]

    The consciousness-altering effects of Salvia Divinorum are likely due to its action on the claustrum and cortex.

    Klaus M. Stiefel

    Theoretical and Experimental Neurobiology Unit, Okinawa Institute of Science and Technology,
    Uruma, Okinawa, Japan. stiefel@oist.jp Tel. +81-98-921-3927 Fax. +81-98-921-4021

    This theoretical article aims to bring together three findings and ideas relevant for the understanding of human consciousness: (1) Crick's and Koch's ideas on the central role of the claustrum as a directing center crucial for subjective conscious experience. (2) The wealth of subjective reports describing the severely consciousness-altering effects of salvinorin A, a κ- opioid receptor agonist and the active ingredient of the plant Salvia divinorum. (3) The high density of κ-opioid receptors in the claustrum. Taken together, these facts lead me to hypothesize that the consciousness-altering effects of salvinorin A, the main active compound of Salvia divinorum, are due to a κ-opioid receptor mediated inhibition of primarily the claustrum and, additionally, the deep layers of the (mainly prefrontal) cortex. The high consciousness-altering potency of salvinorin A and the high density of its target, the κ-opioid receptors, in the claustrum give added weight to the ideas emphasizing the role of this brain area in human consciousness. I discuss opportunities for experimental consciousness research arising from the proposed role of salvinorin A in modulating claustral function.

    Keywords: Claustrum, consciousness, Salvia divinorum, salvinorin A, κ opioid receptor

    Introduction and Results
    Crick and Koch's ideas on the role of the claustrum
    The late Francis Crick proposed the idea that human subjective consciousness is brought about by the activity of a limited number (~105) of neurons (Crick, 1995). These neurons need to fulfill a number of criteria: 1. They must be central in the connection-scheme of the human brain, not to close to primary sensory or motor areas. 2. They must involve a number of sensory areas, since consciousness integrates several sensory modalities. 3. Their activity must be correlated with conscious experience, even in situations where it is dissociated from direct sensory input (for instance during the perception of visual illusions). The identity of these neural populations will change with changing contents of the conscious experience. Possibly a brain region acting as a “director” of this process is needed. In Crick's very last paper, he and Koch argued that the claustrum is an ideal candidate for this role (Crick & Koch, 2005). The claustrum, is a layered brain region in-between the insular cortex, piriform cortex and the caudate-putamen (Crick & Koch, 2005; Franklin & Paxinos, 2007). It is highly connected to a number of cortical areas in a non-trivial, mostly reciprocal manner. This strong and complex interconnectivity with the cortex makes it a prime candidate for the role of the “director” of the “conscious field” (Searle, 2004), “dynamical core” (Tononi & Edelman, 1998a; Tononi & Edelman, 1998b) or “neuronal workspace” (Dehaene & Changeux, 2004). Ways to test this hypothesis fall in two groups: One would be to conduct recordings of claustral activity in conscious humans. This possible, but challenging due to the small size of the claustrum, which presents difficulties for interpreting the results obtained with non-invasive imaging methods (functional magnetic resonance imaging, positron emission tomography). Invasive recordings in non-human primates and other mammals are possible, but in this case it is impossible to obtain verbal reports of the subjects’ experiences during the recordings.
    An alternative approach would be a selective pharmacological manipulation of the claustrum. I argue that salvinorin A, the active compound of the psychoactive plant Salvia divinorum, provides the opportunity for such a manipulation.

    Consciousness-altering effects of salvinorin A

    Salvia divinorum is a plant native to the Oxaca region in southern Mexico which is traditionally used in the Mazatec culture as inebriate in religious and spiritual contexts (Cheyene, 2006; Siebert, 2008). It is smoked or orally ingested. Its active compound, salvinorin A, is the substance with the lowest known effective concentration for mind-altering effects (Siebert, 1994). Salvinorin A is a κ-opioid receptor agonist (Ansonoff et al., 2006; Chavkin et al., 2004; Roth et al., 2002). Subjective effects at low doses are described as disorienting, confusing, even frightening or alternatively also as subtly calming and meditative. The unpredictability of the effects is one of their prominent and most interesting features. Subjective effects at higher doses are often described as dissociative to an extreme degree. Subjects often report a loss of the awareness of their current surroundings and, while fully conscious, believe that they are in different locations which they remember, sometimes from decades in the past. Space is often distorted and subject sometimes experience states which are described as complete non-spatial
    existence. These experiences are described as interesting, even life-altering, but typically as unpleasant. They are clearly distinct from the experiences brought about by classical, serotroninergic, psychedelics like LSD and psilocybin. In general, verbal reports of experiences induced by the consumption of high doses of Salvia divinorum describe a most profound alteration of consciousness, even more fundamental than those induced by these classical psychedelics (Arthur, 2008; Siebert, 2008). How does this effect arise from the action of salvinorin A in the brain?

    The effects of κ-opioid receptors and their distribution in the primate brain
    The κ-opioid receptor, the target of salvinorin A, is a g-protein coupled neurotransmitter receptor. Upon agonist binding, it activates phospholipase C, which then sets off an intracellular IP3 and cAMP based 2nd messenger cascade (Law et al., 2000). This second messenger cascade couples the agonist binding to downstream cellular effects (Law et al., 2000). Known effects are the reduction of presynaptic neurotransmitter release, via a reduction in N-type calcium current (Tallent et al., 1994), and a decrease of cellular excitability, via an increase of the inward rectifier potassium currents (Henry et al., 1995). The effects of κ-opioid receptors are thus inhibitory, both by reducing the amount of input a neuron is receiving and by reducing the response to that input.
    In human brains, κ-opioid receptor expression was measured by mRNA in situ hybridization (Peckys & Landwehrmeyer, 1999). High densities were found in the striatum, hippocampal dentate gyrus, deep cortical layers (V and VI, with more expression in the prefrontal than in the occipital cortex) and, especially, in the claustrum. The claustrum was the only brain region in which nearly all cells were labeled with dense to very dense labeling density. In the macaque monkey brain, κ-opioid receptor activity was measured by monitoring the agonist- induced binding of a radioactively labeled GTP-analogue ([35S]GTPγS). Strong activity was found in the limbic and association cortex, ventral striatum, caudate, putamen, globus pallidus, claustrum, amygdala, hypothalamus and substantia nigra (Sim-Selley et al., 1999). The authors report that “A very high level of κ1-stimulated [35S]GTPγS binding was observed in the claustrum, with an area of especially high stimulation in the ventral claustrum, adjacent to the amygdala.”. While there was evidence for κ-opioid receptor activity in other brain regions as well, the densities were significantly higher in the afro mentioned regions.

    This presents us with a number of candidate brain regions for the consciousness-altering effects of salvinorin A. The inhibition of each of these brain regions alone, or in any combination, could be responsible for its consciousness-altering effects. While all brain regions are important for brain function, and ultimately the survival of the animal, not the activity of all of them might be neural correlates of consciousness. Excluding some regions will be somewhat speculative due to the still incomplete characterization of the complex functions of these brain regions. There is nevertheless a sizeable body of work available in systems neuroscience which makes it possible to narrow the candidate list down. The striatum, caudate, putamen, substantia nigra and globus pallidus are commonly considered to be part of an integrated system involved in action selection, reinforcement learning and motor control, and are not likely neural correlates of consciousness (Wilson, 2004). The hypothalamus is considered to be responsible for the regulation of metabolic processes as part of the autonomous nervous system. It is also an unlikely candidate for a role in consciousness. The amygdala is a brain region thought to be involved in emotional processing, such as fear and fear conditioning (Phelps & LeDoux, 2005). While many subjects report a component of fear in their Salvia divinorum evoked experiences, this is separate from the consciousness-altering effects I am discussing here.
    This leaves us with the deep layers of the (mainly prefrontal) cortex and the claustrum as relevant salvinorin A target areas. Most likely, these are the brain areas which, when inhibited by salvinorin A, give rise to the intense consciousness-altering experiences reported by users of Salvia divinorum. The unusually high κ-opioid receptor density in the claustrum makes it a particularly good candidate target area.

    Discussion
    I hypothesize that the consciousness-altering effects of salvinorin A, the main active compound of Salvia divinorum, are due to a κ-opioid receptor mediated inhibition of primarily the claustrum and, additionally, the deep layers of the (mainly prefrontal) cortex. This hypothesis supports the role of the claustrum in human consciousness as proposed by Crick and Koch. It is a testable hypothesis, by non-invasive and invasive recordings in humans and non-human primates under the influence of salvinorin A, respectively. Furthermore, it opens new avenues for experimental consciousness research. One open question is the exact role of the inhibition of the claustrum and the cortex in bringing about the changes experienced under the influence of salvinorin A. Other open questions are the time course of its action and the difference in neural activity between high and low doses which are experienced in a qualitatively different way. Lastly, if the hypothesis about the claustrum’s role as a “director” of cortical activity is correct, then claustral inhibition by salvinorin A should lead to a massive alteration of cortical synchronization patterns.
    Acknowledgements
    I thank Drs. Charles F. Stevens, Gordon W. Arbuthnott and John Jacobson for helpful discussion and critically reading the manuscript.

    References

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