Toward an Explanation of the Genesis of Ketamine ... - Springer Link

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Brain and Mind 4: 307–326, 2003. ° C 2003 Kluwer Academic Publishers. Printed in the Netherlands.

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Toward an Explanation of the Genesis of Ketamine-Induced Perceptual Distortions and Hallucinatory States ALFREDO PEREIRA JR.1 and GENE JOHNSON2 University of S˜ao Paulo (UNESP), Institute of Biosciences, 18618-000 Botucatu, S˜ao Paulo, Brazil, e-mail: [email protected] 2 Brain-Behavioral Sciences Research Consultant, 927 Manchester Ct, Charlottesville, Virginia, 22901, USA, e-mail: [email protected]

1 State

(Received: October 31, 2002; Final: June 9, 2003) Abstract. The NMDA receptor (NMDAR) channel has been proposed to function as a coincidence-detection mechanism for afferent and reentrant signals, supporting conscious perception, learning, and memory formation. In this paper we discuss the genesis of distorted perceptual states induced by subanesthetic doses of ketamine, a well-known NMDA antagonist. NMDAR blockage has been suggested to perturb perceptual processing in sensory cortex, and also to decrease GABAergic inhibition in limbic areas (leading to an increase in dopamine excitability). We propose that perceptual distortions and hallucinations induced by ketamine blocking of NMDARs are generated by alternative signaling pathways, which include increase of excitability in frontal areas, and glutamate binding to AMPA in sensory cortex prompting Ca++ entry through voltage-dependent calcium channels (VDCCs). This mechanism supports the thesis that glutamate binding to AMPA and NMDARs at sensory cortex mediates most normal perception, while binding to AMPA and activating VDCCs mediates some types of altered perceptual states. We suggest that Ca++ metabolic activity in neurons at associative and sensory cortices is an important factor in the generation of both kinds of perceptual consciousness. Key words: consciousness, hallucination, ketamine, NMDA receptor, perception.

1. Introduction Distorted perceptual states and hallucinations are varieties of conscious experience, which cannot be exclusively explained by changes in sensory stimuli. Some mechanism internal to the brain should be invoked, in order to account for the changes in conscious experience that are not generated by changes in sensory stimuli. William James (1890) argued that external stimulation is not absent in hallucination, but “the secondary cerebral reaction is out of the normal proportion to the peripheral stimulus which occasions the activity.” Therefore, “an hallucination is a strictly sensational form of consciousness, as good and true a sensation as if there were a real object there.” Therefore, according to James, the content of ordinary conscious perception is proportionally related to a stimulus, while in the case of hallucinations stimulation is also present but the brain reacts differently to the stimulus. How does the brain generate perceptual distortions and hallucinations? Ketamine, as well as other hallucinatory drugs, have been used as scientific tools to investigate the mechanisms

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ALFREDO PEREIRA AND GENE JOHNSON

involved in these processes. Ketamine is a specific noncompetitive antagonist of the NMDA neuronal glutamate receptor that is widely distributed in the brain. It is a powerful anesthetic drug used in veterinary medicine to sedate big animals. For this anesthetic property and other effects on consciousness (like the effects we will study here), the NMDA receptor (NMDAR) is regarded as having a relevant role in conscious sensory processing (Oye et al., 1992; Flohr, 1995; Rocha et al., 2001; Philips and Silverstein, 2002). When used in humans (as an illegal recreational drug, or legally in scientific experimentation with consent of subjects), a subanesthetic dose of ketamine can elicit perceptual distortions and hallucinatory states similar to those reported by schizophrenic subjects. For this reason, the usage of this drug is considered to provide an experimental model of schizophrenia (see Lahti et al.,1995; Newcomer et al., 1999, Abi-Saab et al., 1998; Lahti et al., 1999, 2001; Breese et al., 2002). It is also used in experimental animals, in combination with invasive methods as microdialysis, to study its effects in several brain areas. In this paper we review neurochemical systems directly and indirectly affected by subanesthetic doses of ketamine, and propose an explanation of complex interactions among several brain areas underlying the genesis of ketamine-induced perceptual distortions and hallucinatory states. Our reasoning is developed in the following sections: (a) an epistemological discussion of the concept of reliable perception, exemplified with a neural network model of conscious perception proposed by Grossberg (1999); (b) discussion of the putative role of NMDARs in reliable perception; (c) review of direct effects of a subanesthetic dose of ketamine in mammals; (d) review of indirect effects of a subanesthetic dose of ketamine in human subjects; (e) proposal of a NMDAR-substitutive mechanism generating nonreliable perceptual consciousness; (f) conclusion: the contribution of this work to a neurobiological theory of sensory consciousness. In the first section we briefly develop the epistemological claim that reliable and unreliable percepts can be pragmatically distinguished. The following sections review and discuss neurobiological issues that may present some difficulty for the philosophical reader. In order to avoid an excessive length of the paper, we didn’t elaborate on tutorials about neurotransmitters, neuromodulators, and neuronal membrane receptors, which can be easily found in illustrated textbooks (see Stahl, 1996) or review papers (Bliss and Collingridge, 1993; Riedel et al., 2003). However, we made our best efforts to make sure that the technical language used in the middle sections will not become an insurmountable obstacle for the readers who are seriously interested in the transdisciplinary approach to the brain/mind.

2. Reliable Perception, and Ketamine-Induced Perceptual Distortions and Hallucinations A problem with the Jamesian concept of hallucination is that it assumes the possibility of independently knowing the properties of a stimulus that elicits a conscious perceptual

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state, and then evaluating the degree of proportionality between such properties and the properties of the conscious content. However, it is a well-known philosophical problem the impossibility of a completely objective determination of the properties of stimuli, since every observation is made by somebody who stands from a particular perspective. In other words, a mind-independent observation of reality is impossible. If the distinction between ordinary and hallucinatory contents depends on the possibility of determining the objective (metaphysical/ontological) properties of reality, it is faded to failure. However, there is another solution for the problem, one that is adopted by modern science. Instead of discussing the hypothetical objective properties of things, scientists look for intersubjective agreement in their observations of systems. If the broad majority of scientists agree about the outcome of a measurement process, they consider that the corresponding content of their conscious perception is reliable. Of course, this concept of reliability is based on a mental construction that happens to be common to several subjects, possibly because of a similarity among their perceiving apparatus. Using this pragmatic concept, scientists are able to get rid of the difficulties of holding metaphysical realism, while retaining a consensual sense of reality. Similarly, in order to characterize the difference between ordinary perception and hallucination, we use a pragmatic concept. We consider that a conscious perceptual state X about a stimulus Y is reliable if there is broad intersubjective agreement that the observation of Y elicits a conscious X. For instance, consider a group of human subjects who share a definitional consensus about what is a cat and what is a dog. Now introduce one animal to this group. If there is a secure consensus that observing that animal elicits the conscious percept of a dog, then the dog percept is considered to be reliable. If one of the subjects observes the same animal in the same conditions and see a cat, then this perceptual content is considered to be unrealiable. Eventually, if a perceptual consensus is not formed, then (a) the stimulus may be ambiguous, as the famous Gestalt unstable figures. In the following discussion we will not consider these cases, since the distinction between reliable and unrealiable perceptions doesn’t apply to ambiguous stimuli; or (b) the observers do not share a common perceptual mechanism. For instance, a group of schizophrenics in acute hallucinatory phase will hardly agree about the animal being a dog or a cat. Even if they form a majority in the group, this majority is not able to form a consensus, so there is no risk that the judgement of reliability would depend on a simple majority criterion. The epistemological discussion about the reliability of percepts can be pursued at deeper levels (see Shanon, 2003), but for the purpose of this paper we simply assume that a fallible but pragmatically strong judgement of reliability can be established. This strategy is based on the same kind of empirical procedure used by scientists to construct scientific objectivity from controlled intersubjective agreement. In order to understand the possible difference of brain processes supporting reliable and unreliable perceptions, we will begin with a neural network model proposed by Grossberg (1999).

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In the Adaptive Resonance Theory (ART; see Grossberg, 1999, 2000b), recognition of a stimulus pattern is related to the occurrence of a “resonance” of bottom–up and top–down patterns in a multilayered neuronal network. Such a resonance can be exemplified in sensory cortices by the matching of afferent signals transduced to pyramidal cells in deeper layers and previously learned patterns found in superficial layers. In this context, perceptual distortions may be defined as a partial loss of correlation between the content of conscious perceptions and the afferent patterns that elicit them. As in the Jamesian concept, while the content of distorted perception is still largely determined by the afferent pattern, it presents aspects that are not proportional to the corresponding aspects of the stimulus. The hallucinatory phenomenon involves a step beyond distortion. It may be defined— again, following the Jamesian approach—as a perceptual state where an endogenously generated conscious content is perceived as if corresponding to an external stimulus. Both perceptual distortions and hallucinations imply a loss of reliability of conscious content regarding exteroceptive or interoceptive stimulation of peripheral sensory receptors. Although perceptual distortions and hallucinatory processes may be useful in the homeostasis of the central nervous system (CNS), for adaptive reasons such processes were avoided along evolutionary lines, since they elicit behaviors that frequently are not in tune with the environment. They can be considered a modality of perceptual consciousness, but not a reliable one. According to Jansen (2000), ketamine can produce features of near-death experiences, including out-of-body experiences and mystical states: “important features of NDE’s include a sense that what is experienced is “real” and that one is actually dead, a sense of ineffability, timelessness, and feelings of calm and peace, although some cases have been frightening. There may be analgesia, apparent clarity of thought, a perception of separation from the body, and hallucinations of landscapes, beings such as “angels,” people including partners, parents, teachers and friends (who may be alive at the time), and religious and mythical figures. Transcendent mystical states are commonly described. Memories may emerge into consciousness, and are rarely organized into a “life review.” Grinspoon and Bakalar (1981; reproduced in Jansen, 2000) wrote, “becoming a disembodied mind or soul, dying and going to another world. Childhood events may also be re-lived. The loss of contact with ordinary reality and the sense of participation in another reality are more pronounced and less easily resisted than is usually the case with LSD. The dissociative experiences often seem so genuine that users are not sure that they have not actually left their bodies.” The neurobiological genesis of such perceptual distortions and hallucinations involves complex perceptual mechanisms. Baseline activity or maintained discharges throughout the sensory pathways, from the periphery to the supramodal areas of the prefrontal cortex, can play an important role in the genesis of perceptual states. Grossberg (2000a) proposes that “normal learning and memory are stabilized through the use of learned top–down expectations. These expectations learn prototypes that are capable of focusing attention upon the combinations of features that comprise conscious perceptual experiences.” Such a

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baseline activity is constantly tuned and biased by short- and long-term potentiation toward what has been perceived in the past. In the case of a mental disorder, “phasic volitional signals can shift the balance between excitation and inhibition to favor net excitatory activation. Such a volitionally mediated shift enables top–down expectations, in the absence of supportive bottom–up inputs, to cause conscious experiences of imagery and inner speech and thereby to enable fantasy and planning activities to occur . . . the top–down expectations can give rise to conscious experiences in the absence of bottom–up inputs and volition” (Grossberg, 2000a). Similarly, Hammer and Herkenham (1983) concluded “the ketamine-induced shift in the laminar focus of sensory cortical metabolism may reflect a functional disconnection from peripheral sensory input and/or enhanced internal (corticocortical) processing.” Perceptual distortions and hallucinations also can mix with, or be projected onto, exteroceptive or interoceptive-stimulated sensations. Mixing or superimposition is a function of the interaction between sensory memory-related predicted afferent flow and ongoing stimulation from peripheral sensory receptors. A lowered threshold of baseline activity or an unusual pattern of sensory stimulation can contribute to such phenomena. Dynamic recurrent interaction between the cortex, sensory thalamic nuclei, and nonspecific thalamic nuclei determine the mixing or superimposition of sensation and memory. These circuits, in turn, are modulated by the motivational and emotional centers of the hypothalamus and associated endocrine/paracrine circuits, the hippocampus, the amygdala, and the basal ganglia. The cingulate cortex, sharing connections with prefrontal cortices, has been proposed (Baev et al., 2002) to control motivational and emotional brain circuits involved in the larger emotional–cognitive loop that generates consciousness (Grossberg, 2000b). The cingulate system may provide an error detection/correction function (as the “comparator function” proposed by Gray, 1995; originally this proposal was related to the subiculum, acting through monoaminergic ascending fibers and tuned by hippocampal theta rhythm) that compares episodic memory contexts with ongoing contexts sensed from polymodal environmental stimuli. Therefore, one interesting target for research on perceptual disorders is to understand the mechanisms by which the cingulate controls activity of sensory cortices, making possible the emergence of distorted and hallucinatory perceptions.

3. The Putative Role of the NMDA Receptor Channel in Perceptual Processing Glutamate (Glu) conveys afferent information to sensory cortices through thalamocortical connections, by binding to two classes of membrane ionotropic receptors (and also to Glu metabotropic receptors, which will not be considered in this review). Glu binding to AMPA and kainate (KA) receptors depolarizes the membrane and eventually prompts Ca++ entry through voltage-dependent calcium channels (VDCCs). Glu binding to N -methyl-DAspartate receptors (NMDARs) in depolarized states (mediated by AMPA/KA receptors activity) opens the channel to Ca++ entry. According to the LTP model of memory formation, a first signal arriving over the AMPA/kainate receptors depolarizes the membrane and removes Mg from the NMDA

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channel, such that if another signal arrives over this channel while the membrane is still depolarized, it may trigger Ca entrance (Bliss and Collingridge, 1993). The putative role of the NMDA receptor in perception is a consequence of its property of working as a coincidence detection mechanism, allowing the entrance of calcium ions in the postsynaptic neuron only if there is a matching between afferent and reentrant signals in a definite time interval in the millisecond scale, which is compatible with the timing of perceptual processes (Rocha et al., 2001). A brief examination of ART principles reveal that they operate similarly to the physiology of the NMDA channel in the cerebral cortex. Grossberg (1999) discusses several cognitive processes and shows that they can be fully explained by ART’s four principles. Here are the principles and the corresponding membrane mechanisms: 1. Bottom–up automatic activation: corresponds to thalamic-cortical input to pyramidal neurons at layer IV, that reaches the proximal region of their apical dendrites, promoting Glu-AMPA/kainate binding, cell depolarization and removal of Mg from the NMDA channel; 2. Top–down priming: corresponds to reentrant signaling from higher cortical associative areas reaching the distal region of the same apical dendrites above, that promotes GluNMDA binding and calcium ions entrance; 3. Match: at this stage resonant states appear at the network, corresponding to the activation of intracellular transduction processes which, among other functions, keep neurons active by means of Ca++ diffusion, activation of retrograde messengers as nitric oxide (promoting vasodilation that increases blood supply) or modulation by allosteric interaction between metabotropic aminergic and ionotropic receptors; 4. Mismatch: if AMPA/kainate depolarization is not followed in a definite time interval by a top–down reinforcement to the same pyramidal neurons, activation of interneurons possibly inhibit them through GABAergic synapses. The Ca moved into the cell activates several signal transduction pathways, by binding to calmodulin (CaM) to activate certain types of kinases as calmodulin kinase II (CaMKII). This kinase, in turn, may control the action of many other types of molecules including retrograde messengers as nitric oxide (NO) and arachidonic acid (AA). The importance of NMDA channel function for consciousness was initially proposed by Flohr’s hypothesis (Flohr, 1995), who also suggested a central role to nitric oxide in the formation of neuronal assemblies supporting conscious processes. Rocha et al. (2001) proposed that calcium ion entrance activates several signal transduction pathways (STPs) inside the pyramidal cortical neuron, triggering quantum computational processes supporting perceptual consciousness. During arousal, the balance of aminergic and cholinergic modulation of excitability in sensory areas defines a baseline level that favors a cooperative activation of NMDARs by afferent and reentrant signals controlling a major portion of Ca++ entry. Such mechanism guarantees the reliability of perception, i.e., that the content of conscious perception correlates with the afferent signal, an important requirement for adaptive behavior. Our

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hypothesis (see later) is that in the genesis of unreliable perceptual states, afferent signals can be present, but there is a perturbation of NMDA function together with a transient hyperglutamatergic state and a change in baseline activity, allowing endogenous patterns to become conscious. The conjunction of the above factors is proposed to increase Ca++ entry through VDCCs while NMDARs are blocked. While the NMDAR is a coincidence-detection mechanism for perceptual processing, VDCCs can be opened by simple membrane depolarization and therefore cannot perform the matching operation required by ART. VDCCs activated by a transient hyperglutamatergic state can compensate NMDARs in the role of supplying Ca++ entry, generating a kind of perceptual consciousness that is not fully correlated to the afferent signal. Therefore NMDA channel activation, although supporting reliable conscious perception, would not be always necessary for the generation of sensory content, since its blockage still allows the existence of unreliable conscious perceptions.

4. Direct Effects of a Subanesthetic Dose of Ketamine The mechanism of action of ketamine has been an object of debate for more than 30 years. While a high dose of ketamine is anesthetic, a weak dose has been proved to generate visual and auditory distortions and hallucinations, similar (in form but not always in content) to those reported as positive symptoms in schizophrenia. The effect of subanesthetic ketamine on perception implies that the drug reach sensory cortices, among several other brain areas. The NMDA-antagonist experimental model of schizophrenia is based on the usage of subanesthetic doses of ketamine and other NMDA antagonists (PCP, MK-801) in healthy subjects, to produce reversible positive and negative symptoms of schizophrenia (Lahti et al., 1995, 1999, 2001; Abi-Saab et al., 1998; Jentsch and Roth, 1999; Newcomer et al., 1999, Breese et al., 2002). The main effect of a subanesthetic dose of ketamine has been thought to be the blocking of NMDA channels and a consequent hypoglutamatergic functioning (Olney et al., 1999; Goff and Coyle, 2001). Recently evidence has been gathered that hypoglutamatergic states, frequently associated with schizophrenia, are preceded by a hyperglutamatergic transient and dose-dependent state (Moghaddam et al., 1997; Farber et al., 1998; Anand et al., 2000; Krystal et al., 2002; Olney et al., 2002). Furthermore, some experiments have suggested that the distorted perception and hallucinatory effects, as well as prefrontal function impairment, would depend on the action of glutamate on non-NMDA receptors. Before considering this cascade of events triggered by ketamine, we will focus on the direct effects. The injection of a subanesthetic dose of ketamine acts directly upon NMDA receptors by crossing the blood-brain barrier. All other consequences of ketamine are usually believed to depend on the perturbation of NMDA functions, although the nonexistence of parallel primary effects hasn’t been proved. Ketamine effects are closely related to the dosage: low doses (e.g., 0.3 mg/kg for human subjects) generate euphoria and perceptual distortions; a subhypnotic dose (5 mg/kg) causes a 20% average increase of glucose utilization in most brain areas (Davis et al., 1988); higher but still subanesthetic doses (5–30 mg/kg) generate increase of activity in limbic and frontal

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areas, hallucinations and cognitive impairments; stronger doses (50–200 mg/kg or higher) produce anesthesia and coma. Vollenweider et al. (1997) showed that two forms of ketamine, called S-ketamine and S/R ketamine, have different effects on regional glucose metabolism. Given the different forms of ketamine, the different dosage levels used, the different modes of administration, and the different sensory stimulation conditions under which it is administered, a wide range of possible effects is possible. Duncan et al. (1998) report that ketamine, at a subanesthetic dose of 35 mg/kg, substantially increased 2-DG (a metabolic marker) uptake in limbic regions, including medial prefrontal, ventrolateral orbital, cingulate, and retrosplenial cortices, the hippocampal formation, select thalamic nuclei, and basolateral amygdala. Earlier studies of brain effects of ketamine tended to focus on limbic excitability combined with sensory inhibition. For instance, studying the effect of subanesthetic (25–75 mg/kg) ketamine in the rat, Nelson et al. (1980) concluded that “inhibition of the regions associated with sensory systems (medial geniculate and inferior colliculus) may account in part for the anesthetic action of ketamine, while the intense activity of the hippocampus may be related to the excitatory manifestations.” Other studies have pointed to a complex pattern of effects. Our review supports a distinction of direct and indirect effects of subanesthetic ketamine. The direct effects are considered to be (a) blockage of NMDA channels in GABAergic neurons in limbic areas, generating an increase of metabolic activity and excitation in the cingulate and frontal areas, and (b) blockage of NMDA channels and a transient increase of Glu-AMPA activity in sensory areas, causing a perturbation of perceptual processing. The indirect effects are considered to be cognitive phenomena observed in human subjects, which follow from the direct effects: (a) an emotional state in limbic/frontal areas, leading to the reactivation of previously learned patterns (that eventually may become the content of hallucinations, by means of top–down signaling to sensory areas), and to changes in cholinergic modulation of thalamocortical connections (eventually changing baseline activity in sensory cortices); (b) increased opening of VDCCs in sensory areas, leading to perceptual distortions and hallucinations. The direct effects have been studied with invasive methods, as microdialysis, in nonhuman animals. The rat medial frontal cortex is directly affected by ketamine, which inhibits NO retrograde signaling by blocking NMDARs (Mueller and Hunt, 1998; Bulutcu, 2002). This cortex controls autonomic function via a projection (Terreberry and Neafsey, 1983) to the nucleus tractus solitarius (NTS). The NTS controls areas in the brainstem medulla related to vagal stimulation (Wang et al. 1998). Regional hyperglycemia effects of ketamine are supported by inhibition of K(ATP) channels, which increases brain glucose transport (Peters et al., 2002). Hypothalamic arginine

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vasopressin (AVP) is released when NO is inhibited, also contributing to hyperglycemia and a resulting increase in glucose metabolism. These results suggest that metabolic activation of the sympathetic system and cingulate cortex plays an important role in the response to ketamine (Eintrei et al., 1999). Holcomb et al. (2001) showed in PET-scanning experiments that an intravenous dose of ketamine in human subjects caused regional cerebral blood flow activation in the anterior cingulate, medial frontal and inferior frontal cortices, with peak changes at 6–16 minutes that tended to correlate with its psychological effects. Yettefti et al. (1997) suggested that glycemia-sensitive neurons in the nucleus tractus solitarii (NTS) act as glucose sensors transmitting information about nutritional states toward hypothalamic structures involved in feeding and metabolic regulation. As a counterregulatory response to hyperglycemia, the release of insulin rapidly lowers blood glucose. However, insulin-induced hypoglycemia does not occur, since central excitatory amino acids contribute to the modulation of the glucoregulatory response through activation of NMDA receptors (Molina and Abumrad, 2001). As the NMDA channels are blocked, this “counter-counterregulatory” response is not completely effective, although some responses to hypoglycemia may be observed. A norepinephrine (NE) release mechanism triggered in the locus coeruleus by hypoglycemia probably is part of the reaction to ketamine. Brain glucose uptake is controlled by NE, rather than directly via insulin, as in other organs and the body in general. This NE release “counter-counterregulation” response fits well with the increase in blood pressure associated with low to medium doses of ketamine. At higher doses, a hypotensive autonomic reversal seems to occur. This type of autonomic reversal protects against stroke. Therefore, the dose-response effects of ketamine are quite nonlinear in a number of areas. They affect fundamental brain homeostasis and signaling systems simultaneously. The blocking of NMDARs generates signals in a pathway that leads from the NTS to several autonomic effector areas in the brainstem medulla. The blood pressure increase because of ketamine is stimulated via AMPA receptors (Chen et al., 1997). Glutamate release is reduced via the post- to presynaptic retrograde negative feedback mechanism because of NMDArelated decrease of NO release, but there should be sufficient glutamate and aspartate release for AMPARs to be major players in the ketamine reaction. Blood pressure increase, vasodilation, and brain glucose stimulation via the norepinephrine and dopamine systems can be accounted as possible responses to a subanesthetic dose of ketamine. Acute systemic administration of ketamine (20 mg/kg) was reported to increase ACh release in the medial prefrontal cortex of the rat 250% above baseline for 40 min (Nelson et al., 2002a,b). This reaction possibly leads to ACh increase in the cingulate (Everitt and Robbins, 1997). An important direct effect is the inhibition of GABA(B) and other GABA receptors (Manocha et al., 2001), but not GABA(A) (Nelson et al., 2002a,b). Decrease of GABAergic inhibition as well as increase in glucose metabolism may underlie the ketamine-induced increase of dopaminergic excitability in frontal areas. Li et al. (2002) used MK-801 to test the effect of NMDA antagonists on inhibition of GABAergic inhibition, concluding that in some areas NMDA receptors mediate excitatory drive onto inhibitory interneurons,

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and, then, “NMDA receptor/channel antagonists may reduce inhibition (i.e., produce “disinhibition”) . . . This region-specific reduction in inhibitory input to pyramidal cells could underlie the region-specific neurotoxicity of NMDA antagonists.” The same reasoning appears in Olney et al. (2002). Vollenweider et al. (1997) report that subanesthetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex, including the anterior cingulate, parietal, and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena, so they concluded that “the (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.” The increased metabolism in the cingulate area could be due to a decrease of GABAergic interneuron metabolism under conditions of less NMDAR glutamatergic drive, leading to increased excitation of pyramidal cells. Since ACh release is partially controlled by the cingulate, the increased metabolism could be due to increased vasodilation and blood flow delivery of glucose. NE could play a role in increasing glucose transport. The adding of diazepam, a GABA agonist, could reduce all of these processes (Eintrei et al., 1999), but since metabolism is reduced, the metabolic requirements to increase inhibition seem to be much less than driving to hyperexcitation. Several studies have shown that subanesthetic ketamine causes a decrease of metabolic activity in sensory cortices, probably by blocking NMDARs and inhibiting NO and AA retrograde excitation. However, inhibition of metabolic and electrical activity in sensory cortices is not absolute; on the contrary, an interesting combination of inhibition and excitation has been observed by several researchers. Patel and Chapin (1990) detected two separable effects of ketamine: a strong inhibition of all somatosensory responsiveness and a tonic excitatory influence expressed heterogeneously on a subgroup of neurons, concluding that “this coexistence of cortical neuronal excitation and sensory suppression in the same cortical region may explain in part the mechanism of dissociative anesthesia and hallucinatory side effects observed in humans during emergence from ketamine anesthesia.” Hammer and Herkenham (1983) noted that subanesthetic ketamine in rats caused increased metabolism in limbic regions and “produced a reduction of 2DG uptake in layers I–IV of granular somatosensory cortex while sparing uptake in layer Va . . . In the primary visual cortex, this dose of ketamine decreased 2DG uptake relative to secondary visual cortex. Alteration of 2DG uptake in various cortical regions might be the consequence of a ketamine-induced activation of specific neuronal pathways with special neurochemical features.” Such results are in accord with recent data suggesting a combination of inhibitory and excitatory effects of ketamine in sensory cortex. One must consider that the blocking effect of NMDA antagonists is dependent on initial sensory stimulation that is strong enough to open the channel so the ligand can lodge in the intrachannel PCP receptor site. According to Muir and Lees (1995), “in order to reach its binding site, a noncompetitive NMDA receptor antagonist requires an ion channel to be opened up and the voltage-dependent Mg2+ block to be released by postsynaptic membrane

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depolarization. As such drugs can only bind in an open ion channel, they accumulate in regions where the concentration of glutamate is highest.” This factor might create some interesting effects on body image-related sensing, which would depend on recent movement patterns. This effect might be called ‘temporary activity-dependent neglect’. For example, the awareness that a limb is one’s own might depend on recent movement to activate some receptor-based coincidence detection between the activation feedback and the feedback signal from actually sensing the moving limb (visual, kinesthetic, proprioceptive). That brief period of activation might be sufficient to lead to ketamine ligand blocking of the PCP channel in enough NMDARs, so that neglect and/or perceptual distortion would occur soon after. Slight variations in limb movement dynamics would likely activate (partially) different sets of NMDARs, so variations from distortion to complete neglect would be predicted.

5. Indirect Effects of a Subanesthetic Dose of Ketamine in Human Subjects Indirect effects, as stated earlier, are considered to be those mediated by DA excitability and transient Glu increase. Glycine and GABA amino acid inhibitory transmitters and their receptors are frequently located on interneurons. Each of these systems is associated with intracellular second messenger signaling involving calcium, calcium associated enzymes, adenylyl cyclase (AC), and cAMP, and a number of effectors such as protein kinases and phospholipids. These transmitter systems are in turn controlled by neuromodulator systems. Wellcontrolled homeostatic regulation of these systems define normal NMDA activity supporting reliable perception. Abnormal changes in dopamine, serotonin, norepinephrine, acetylcholine, endoopiate, and sigma systems and their associated receptors have all been linked to the genesis of perceptual distortions and hallucinations. Many psychotropic drugs and recreational drugs/drugs of abuse have either facilitative or suppressive effects on one or more of these neuromodulators. Both facilitative and suppressive effects can lead to distortions and hallucinations. GABA transporter changes have been linked to the activity of prefrontal pyramidal neurons and to dopamine: “the chandelier class of GABA neurons, especially those located in the middle layers of the prefrontal cortex (PFC), have been hypothesized to be preferentially involved in schizophrenia because they (1) receive direct synaptic input from dopamine axons, (2) exert powerful inhibitory control over the excitatory output of layer 3 pyramidal neurons” (Lewis et al., 1999). An increase in DA release in the nucleus accumbens, by influence of NMDAR antagonists like ketamine, has been reported (Rahman and McBride, 2002). A blocked NMDAR, which was exciting a GABAergic interneuron to inhibit a dopamine terminal, would release DA because of inhibition reduction. In normal conditions, this circuit produces phasic release of DA coordinated with ACh release in thalamocortical connections, biasing sensory cortex toward incoming sensory signals. Increased DA could be related to the learned/remembered reward value of the sensory stimulus. Under conditions of high DA release, the cortical bias in favor of sensory input would be reduced and DA-triggered sensory memory would be amplified.

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The increase of DA may influence the intracellular Ca++ system, leading to Glu release. Lezcano and Bergson (2002) identified “a population of neurons in primary cultures of hippocampus and neocortex which respond to D1/D5 dopamine receptor agonists with a marked increase in intracellular calcium (Ca++ i ) levels. The D1/D5 receptor stimulated responses occurred in the absence of extracellular Ca++ indicating the rises in Ca++ involve i release from internal stores. In addition, the responses were blocked by D1/D5 receptor antagonists.” In conclusion, they propose that “D1-like dopamine receptors likely modulate as well neocortical and hippocampal neuronal excitability and synaptic function via Ca++ i as cAMP-dependent signaling.” Moghaddam et al. (1997) proposed that increase of DA release would be the link between subanesthetic ketamine and transient hyperglutamatergic states in the neocortex. A study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, while ketamine at 30 mg/kg also increased the release of dopamine in the PFC. Wang and O’Donnell (2001) found that DA can potentiate NMDA-mediated excitability in prefrontal pyramidal neurons, while on the other hand NMDA receptors can alter the balance between D1 and D2 receptors. The results indicate the presence of a dopamine–glutamate interaction in the prefrontal cortex, by which D1 receptors maintain NMDA-mediated responses in prefrontal cortical pyramidal neurons. The cingulate circuit involving the hypothalamus, the hippocampus, and the anterior thalamic nuclei, is likely to be very important to the genesis of perceptual distortions, hallucinations and function impairment, by increasing excitatory drive. One of the critical structures regarded as responsible for “keeping information in and out of mind” (Bunge et al., 2001) is the anterior cingulate. From the connectivity of the cingulate cortex to the autonomic nervous system and to its central integrative role in the hypothalamus, anterior thalamus, basal ganglia loop (ventral striatum), and to its powerful anterior dopaminergic innervation, it can be inferred a situation-dependent metabolic stimulation and blood flow control system. Devinsky et al. (1995) point that excessive cingulate activity in seizures can impair consciousness, alter affective state and expression, and influence skeletomotor and autonomic activity: “the anterior cingulate cortex appears to play a crucial role in initiation, motivation, and goal-directed behaviors.” Corticocortical connections between frontal and temporal/parietal associative cortex can transport the ketamine-induced excitability to the sensory cortex through reentrant signaling to superficial layers, then reaching the pyramidal neurons where NMDARs are blocked but not AMPAs, which can respond to an increase in Glu transmission. This mechanism allows the formulation of a new explanatory hypothesis for the genesis of ketamine-induced altered perceptual states.

6. Hypothesis of a AMPA/VDCC Alternative Glutamate Transmission Supporting Unreliable Sensory Consciousness In this section we advance and discuss the evidence for a new hypothesis to account for human subanesthetic ketamine indirect effects. The hypothesis has four steps:

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(a) ketamine impairs the functioning of GABAergic neurons that inhibit DA production and release to frontal areas, then leading to an increase of excitability; (b) frontal signaling to posterior cortical areas generate AMPA-mediated excitability at the sensory (e.g. primary visual) cortex, while NMDARs are still blocked by ketamine: (c) AMPA-mediated depolarization activates voltage-dependent calcium channels (VDCC), allowing Ca++ entry, compensating the absence of Ca++ entry through NMDARs; (d) mnemonic patterns retrieved through frontal excitability reach sensory cortex and provide the content for hallucinatory states, which become relatively independent of afferent patterns. Another possibility, compatible with this hypothesis, is that intracellular Ca ions (Ca++ i ) are released in frontal and/or sensory cortex through G-protein-coupled receptor (GPCR) pathways activation by dopamine (DA) receptors (Lezcano and Bergson, 2002), an alternative way to increase the participation of Ca++ in neuronal metabolism, independent of Ca++ entry through NMDARs or VDCCs. Another possible explanation is based on changes in Ach cortical excitability. A complementary hypothesis may be drawn from the result obtained by Kitsikis and Steriade (1981) through an injection of kainic acid in the midbrain reticular core of cats, inducing a hallucinatory-type behavior. Steriade et al. (1990) also found that ponto-geniculo-occipital (PGO) spikes could be produced in the waking state by activation of pedunculopontine tegmental cholinergic neurons. These results sugests the possibility that a chemical imbalance as produced by ketamine may excite or disinhibit such cholinergic neurons to trigger PGO spikes during the waking state, then generating hallucinatory content by means of a mechanism similar to dreaming. On the other hand, Vollenweider’s proposal of hallucinatory states emerging from overload of information in thalamocortical pathways (Vollenweider and Geyer, 2001) is not consistent with the reviewed mechanisms of subanesthetic ketamine action, that alter mainly limbic, prefrontal, and sensory areas, apparently not producing an overload of information in thalamocortical pathways. Recent results have brought support for our hypothesis, indicating that besides the wellknown limbic excitability and blockage of afferent information in sensory areas, also a transient hyperglutamatergic state leading to AMPA/KA excitability is involved in the genesis of ketamine-induced unreliable perceptual states. This possibility could also help to “reconcile the conflicting hyperdopaminergic and hypoglutamatergic hypotheses of schizophrenia” (Scott et al., 2002). An important result suggests a role for VDCCs in the generation of hallucinations. Krupitsky et al. (2001) discovered that when VDCCs are antagonized the hallucinatory effects of ketamine are reduced: “the L-type VDCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/h) in 26 ethanoldependent inpatients who were sober for at least 1 month prior to testing . . . nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception,

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dysphoria, verbal fluency impairment, and learning deficits . . . These data suggest that antagonism of L-type VDCCs attenuates the behavioral effects of NMDA antagonists in humans.” Using microdialysis, Moghaddam et al. (1997) clarified the link between subanesthetic ketamine and transient hyperglutamatergic states in the rat neocortex: “low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at nonNMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels.” More important, the transient glutamate increase was blocked by intraapplication of AMPA antagonist, suggesting a role for AMPA in the neocortical response to ketamine. Glutamate release-inhibiting drugs as lamotrigine also reduce perceptual abnormalities while the NMDA channel is blocked (Farber and Olney, 1999; Anand et al., 2000; Mechri et al., 2001a), presumably by reducing AMPA-mediated depolarization that opens VDCCs (Krystal et al., 2002). Serotonin (5-HT) receptor stimulation increases the release of glutamate in the prefrontal cortex, and also control excitation/inhibition in layer 2/3 of the cerebral cortex. The effect of NMDA antagonists as ketamine may also involve such receptor (Aghajanian and Marek, 2000, Breese et al., 2002), thus adding to the evidence of a transient hyperglutamatergic state following the injection of ketamine. Clozapine has been reported to reduce the psychotic effects of subanesthetic ketamine (Mechri et al, 2001a,b), although this result was not replicated by Adams and Moghaddam (2001). Positive modulators of AMPA receptors have been proposed to be coadministered with clozapine, to avoid positive and negative simptoms of schizophrenia (Danysz, 2002). One possibility of explaining the antihallucinatory effect of 5-HT agonists administered with ketamine is their action on AMPA/VDCCs. Day et al. (2002) reported that “bath application of 5-HT(2) agonists inhibited voltage-dependent Ca(2+) channel currents. L-type Ca(2+) channels were a particularly prominent target of this signaling pathway.” Similar conclusions regarding the role of VDCCs may be drawn from studies with gabapentin, a GABA enhancer and VDCC blocker (Czuczwar and Patsalos, 2001). Complete remission of complex visual hallucinations related to Charles Bonnet syndrome was obtained in patients treated by gabapentin (Paulig and Mentrup, 2001). Nicholson (2000) claims that gabapentin “may have a unique effect on voltage-dependent Ca2+ channel currents at postsynaptic dorsal horn neurons. Thus, gabapentin may interrupt an entire series of [APJ/GJ]), not just a single process, that lead to the development events (triggered by Ca++ i of neuropathic pain.” The link between VDCCs and pain was recently clarified in a research by Cain et al. (2002); VDCCs are required to overcome fear but play no role in becoming fearful or expressing fear. The evidence leads to the suggestion that increased VDCC opening may compensate for NMDAR blockage in perceptual processing. This process would be facilitated by a change in baseline activity controlled by thalamocortical cholinergic input. The NMDAR coincidencedetection mechanism in normal functioning makes endogenous patterns matched by afferent signals the usual “winners” to reach consciousness. During arousal, the baseline for a neural

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pattern to become a conscious content guarantees that perception is reliable, since the winners are mostly resonant patterns (in Grossberg’s sense), i.e., the result of matching afferent and reentrant patterns. When NMDA is blocked by subanesthetic ketamine, the baseline is changed. In this condition, endogenous patterns, which are usually “losers” in the awake state, can become conscious as in dreaming. AMPA increased activity generates higher depolarization eliciting Ca++ entry through VDCCs, possibly interacting with DA excitation that increases Ca++ levels. As VDCCs and GPCRs are not coincidence-detectors i promoting the matching of endogenous to afferent patterns, the resulting perception is unreliable. This hypothesis is consistent with the idea that ketamine-induced increase of ACh in limbic areas is counterbalanced by a decrease of striatal-thalamic release of ACh to sensory areas. Hallucinations that occur during emergence from anesthetic ketamine are possibly related to low ACh levels (Schneck and Rupreht, 1989). Increased release of ACh has also been reported with the injection of NMDAR antagonists (Olney et al., 1991) but excessive Ach is balanced by GABAergic inhibition (Kim et al., 1999). Therefore, release of ACh in the ventral striatum-cingulate loop could coexist with decrease in peripheral ACh release. DA inhibits Ach release in the striatum through the activity of D2 receptors (Stoof and Kebabian, 1982; Lehmann and Langer, 1983; Drukarch et al., 1990). The decrease of ACh levels in striatum–thalamic–cortical pathways may be a result of a negative feedback loop, involving activation of DA receptors in frontal areas. Baldwin et al. (2002) studied the role of dopaminergic D1 and glutamatergic NMDA receptors within the prefrontal cortex of the rat during the development of adaptive instrumental learning, suggesting that “coincident detection of D1-NMDA receptor activation and its transcriptional consequences, within multiple sites of a distributed corticostriatal network, may represent a conserved molecular mechanism for instrumental learning.” This may be a major control mechanism for cerebral metabolism, sending negative feedback signals to ACh centers once the learning process is finished. As ketamine leads to an increase of activity in frontal areas, it may trigger the negative feedback control that leads to a decrease of ACh release to sensory areas. Another possibility is that ketamine indirectly activates physostigmine, that inhibits acetylcholinesterase, the enzyme which breaks down ACh and terminates its action. Nystagmus and blurred vision, which followed ketamine anesthesia, disappeared more rapidly when physostigmine was given. (Toro-Matos et al., 1980). In any case, a ketamine-induced cholinergic imbalance may be related to the production of PGO spikes during the waking state, contributing to the generation of hallucinations. Therefore our hypothesis about the genesis of hallucinations is complementary to the hypothesis that attributes a role to PGO spikes in the waking state, since ketamine is likely to perturb pedunculopontine tegmental cholinergic neurons.

7. Conclusion Understanding some of the interactions of the many substrate levels, circuits, and brain areas involved in control of ketamine-induced hallucinatory behavior directly impacts the understanding of normal perception and how the content of consciousness is determined.

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In reliable perception one of the inputs must be an afferent one (e.g., glutamatergic input from the thalamus to visual pyramidal neurons). When ketamine blocks NMDA channels, sensory conscious content does not match afferent patterns, so in this situation conscious sensory processes are supported by an alternative mechanism orchestrated by a broad network, possibly controlled by the cingulate. When sensory mechanisms are perturbed and the processing of afferent signals is blocked, the cingulate error detection/correction system triggers a process by which mnemonic patterns become the content of perceptual consciousness. Once an imbalance occurs the system detects it and sends a controlling signal to the striatum, that changes baseline levels in thalamocortical pathways, while excitatory signals are sent from associative to sensory areas. The dopamine system activation by subanesrelease in associative thetic ketamine compensate for NMDA blockage, inducing Ca++ i areas that convey mnemonic patterns to the sensory cortex, as well as triggering a transient hyperglutamatergic state leading to the opening of VDCCs. Rocha et al., (2001) proposed NMDARs to have a central role in the generation of conscious perceptions (see also Philips and Silverstein, 2002). However, in this case the blockage of Ca++ entry would be expected to generate a loss of consciousness (corresponding to the anesthetic effect of ketamine) but not distorted perception and hallucination, which are two kinds of conscious states. The explanation is that Ca++ entry may also occur through VDCCs while NMDARs are blocked, and DA receptors may activate Ca++ release, thus i generating distorted perceptual states and hallucinations. As all these mechanisms involve the participation of Ca++ ions, then the general conclusion that follows is that Ca++ activity (but not NMDARs alone) should play a central role in all kinds of perceptual consciousness. A complex mechanism, including the interaction of several excitatory and inhibitory transmitters, receptors, and modulators, and several brain systems, operates in the genesis of subanesthetic ketamine-induced perceptual distortions and hallucinations. The dynamics of Ca++ populations is closely related to the processing of perceptual functions in a variety of conditions, but other mechanisms besides changes in Ca++ concentration and fluxes are also likely to operate in the genesis of reliable and unreliable perceptual states. Our future work is intended to focus on the shaping of action potentials in a neuronal population by a diversity of transmitters, receptors, and modulators, composing a spatiotemporal wavelike pattern able to encode the conscious content.

Acknowledgments CNPq/Brasil (APJ). Process No. 300028/00-8 (NV).

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