Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity

Rachael Ingram, Heather Kang, Stafford Lightman, David E. Jane, Zuner A. Bortolotto, Graham L. Collingridge, David Lodge, Arturas Volianskis

Neuropharmacology, 2018, 142, 30e40

https://doi.org/10.1016/j.neuropharm.2018.06.008

Abstract

Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects,
which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptors to afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptormediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibition may indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptor mediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation (LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP.We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 mM) IC50 values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC50 value ~ 15 mM). A GluN2D-subunit preferring NMDA receptor antagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory.

Keywords : Psychedelics, Ketamine, Phencyclidine, PCP, NMDA receptors, GluN2D subunit, Short-term potentiation, STP, Long-term potentiation, LTP, Memory, Working memory

Contents

1. Introduction .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2. Sites of action of ketamine and PCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3. Effects of ketamine on central information processing . . . . . . . . . . . . . . . .  . . . . . . . . . 32
3.1. Dopaminergic modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . 32
3.2. Altered sensory inputs . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.3. Changes in synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . 35
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . 37
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 37
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

1. Introduction

Shortly after the synthesis in the 1950s of phencyclidine (PCP), (Maddox et al., 1965) and later of ketamine (McCarthy et al., 1965), it became apparent that these two anaesthetics produced some bizarre central effects in both laboratory animals (Chen et al., 1959) and in man (Greifenstein et al., 1958; Meyer et al., 1959). The drugs produced a state of anaesthesia and analgesia with a good safety margin before lethality but poor muscle relaxation (White et al., 1982). This unusual anaesthetic state was termed ‘dissociative’ after both the disrupted electroencephalographic patterns and the sensory deprivation with detachment from the real world (Domino et al., 1965; see Domino and Luby, 2012). The central effects,
following either PCP or ketamine, include dizziness, nausea, delirium, confusion, disorientation, paranoia, amnesia, dysarthria, dysphoria with agitation, unpredictable aggression and delusions of extreme strength (Allen and Young, 1978; Domino et al., 1965; Luisada, 1978; Siegel, 1978a). Both drugs were known as psychotomimetics from the outset (Luby et al., 1959), and have been used to create animal models of schizophrenia (Cadinu et al., 2017; Frohlich and Van Horn, 2014; Javitt et al., 2012) but can they also be defined as psychedelics? Psychedelics are ‘drugs (especially LSD [lysergic acid diethylamide] that produce hallucinations and apparent expansion of consciousness’ and hallucinations are experiences ‘involving the apparent perception of something not present’ (Oxford English Dictionary). There are hundreds of reports of hallucinations, visual, auditory and somatosensory, following exposure to ketamine and PCP.

For example, a recreational user of ketamine reported: ‘…when I closed my eyes a lot of information started to happen. Colors, patterns, cross-connections in sensory perception. Like sound and inner visions sort of got confused. I got deeper and deeper into this state of realization, until at one point the world disappeared. I was no longer in my body. I didn’t have a body. And I reached a point at which I knew I was going to die …. .And what incredible feelings that evoked! . . . . . .I just yielded. And then I entered a space in which . . .there aren’t any words ….I mean, at-one-with-the-universe, recognizing-your-godhead ….The feeling was: I was home. That’s really the feeling of it. And I didn’t want to go anywhere, and I didn’t need to go anywhere. It was a bliss state. Of a kind I had never experienced before. I hung out there awhile, and then I came back. I didn’t want to come back. I guess in the
deep state it was no longer than half an hour ‘. Stafford (1977), quoted in (Siegel, 1978b) who also quotes Young et al. (1977) likening ‘this state to an LSD trip, only the ketamine tripper “feels as if he is floating
in a dreamlike state while experiencing vivid visual images”’. In fact, there are numerous reports noting similarities between experiences with LSD and ketamine. But ketamine, unlike classical psychedelics
such as LSD, psilocybin, mescaline and dimethyltryptamine (DMT), is not a serotonin receptor agonist and its central effects in man can be distinguished from those of LSD, as described on psychonaut websites. In humans, serotonin-based hallucinogens and dissociative anaesthetics have psychedelic features in common, as well as abuse potential, and their mode of action may be linked by direct or indirect agonism of 5-HT2 receptors (Heal et al., 2018; Sellers et al., 2017). In a standard psychometric
test which scores five separate dimensions of altered states of consciousness (Dittrich, 1998), a classical psychedelic and ketamine showed similarities but clear differences (Vollenweider and Kometer, 2010). The profile following ketamine was skewed toward the dimensions of ‘disembodiment’ and ‘experience of
unity’. Furthermore, in behavioural studies in laboratory animals, the effects of LSD and PCP/ketamine are easily discriminated, suggesting a quite different mode of action (Carroll, 1990; Jones and Balster, 1998; West et al., 2000).

Drug discrimination studies in rats, monkeys, pigeons, etc, have, however found many drugs that do generalize to the PCP and ketamine cues. In the early 1980s, it became apparent that PCP and ketamine provided similar cues to other arylcyclohexylamines such as tiletamine, to benzomorphan sigma opiates such as SKF10,047 and cyclazocine, to dioxalanes such as dexoxadrol and etoxadrol, to morphinans such as dextrorphan and dextromethorphan, to benz(f)isoquinolines and to propanolamines such as 2-MDP (Brady and Balster, 1981; Brady et al., 1982a, 1982b; Herrling et al., 1981; Holtzman, 1982, 1980; Mendelsohn et al., 1984; Shannon, 1982a, 1982b; 1981; Tang et al., 1984; White and Holtzman, 1982). Such a list of compounds coincides with those also shown to displace PCP binding from rat brain tissue (Hampton et al., 1982; Murray and Leid, 1984; Quirion et al., 1981; Sircar and Zukin, 1983; Vincent et al., 1979; Zukin and Zukin, 1981; Zukin, 1982; Zukin et al., 1984; Zukin and Zukin, 1979).

Several of these compounds were already known to have similar bizarre subjective effects in man including hallucinations and were generally known as psychotomimetics (see Lodge and Mercier, 2015 for many of the chemical structures). Thus, beside arylcyclohexylamines PCP and ketamine (see above), the morphinans, dextromethorphan and dextrorphan, were originally described as producing ‘toxic symptoms (dizziness, diplopia, etc)’ (Isbell and Fraser, 1953). Benzomorphans including the ‘sigma agonists’, SKF 10.047 (Keats and Telford, 1964) and cyclazocine produce ‘doserelated scores on the LSD scale’ (Haertzen, 1970 quoted by Jasinski et al.,1967) and fuzzy thinking, illusions, dysphoria and frank visual hallucinations like LSD (Freedman and Fink, 1968; Jasinski et al., 1967); such features were considered to be mediated by the sigma opiate receptor (Martin et al., 1976). The dioxalanes, dexoxadrol
(Lasagna and Pearson, 1965), and etoxadrol, induced ‘dreams and/or visions that were pleasing.’ (Frederickson et al., 1976).

Further contemporary support for this psychedelic effect of such compounds comes from a cursory examination of the web sites frequented by so-called psychonauts. This reveals that drugs such as ketamine, dextromethorphan, 2-MDP and compounds related to them are still frequently being used by humans. To avoid legal issues associated with ketamine use, new drugs for example, methoxetamine and arylethylamines, such as ephenidine, have come on to the market (Kang et al., 2016; Morris andWallach, 2014; Wallach et al., 2016). During the last two weeks of January 2018, for example on one website, there were 35 reports of experiences with these and similar drugs (https://erowid.org/experiences/exp.cgi? New).

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