There is a pervasive issue in the way that animal research is applied to humans, especially with schizophrenia and psychedelics. At least this is the area of research where I was exploring when I become bothered. I’m sure this problem exists quite ubiquitously throughout most domains of animal biopsychology. Though, translating the conscious experience of rats through their behaviors does seem a little bit more absurd than translating genetic research from animals to humans.
One of the studies I was looking at was exploring an chronic LSD induced model of psychosis (1). David E. Nichols and colleagues found that giving chronic doses of LSD to rats for 3 months ended up producing lasting changes to genes and behavior. These changes lasted far after the drug was cleared from the animals systems. In this study, the researchers noted that the rats were not favoring sucrose over water and they conclude that this may be evidence of anhedonia, a common symptom of schizophrenia. The LSD rats also had increased exploratory behavior and locomotor behavior.
“You can tell that the rats were depressed because they did not crave sugar.”
There is a problem here. Anhedonia is typically associated with laziness and depressive behavior, even in rat models (2). It is a symptom of lacking hedonic responses; the inability to feel pleasure. The symptom is often related to apathy, and especially not curiosity and exploration, which are motivated behaviors. The lack of sucrose affection found in the LSD rats may be related to the way LSD-type drugs seem to rapidly abolish addiction (3). Many addiction models have explored how addictive drugs increase the peptide dynorphin (4), which is associated to withdrawal-like symptoms such as anxiety (5), depression (6), stress (6), dysphoria (7), and even psychosis (8). LSD has been shown to attenuate the effects of dynorphin’s main target receptor system, the kappa opioid receptors (KORs) (9).
The way LSD suppresses dynorphin/KOR activity may occur through 5HT2ar-mGlur2 complexes in which 5HT2a receptor agonism leads to suppression of mGlu2 receptor activity (10), since mGlu2 receptors have been found to facilitate dynorphin activity (11). 5HT1a receptor agonism also seems to suppress the increase of dynorphin that usually accompanies L-Dopa administration (12), so this may be another way that LSD attenuates dynorphin activity.
The effects of KOR agonism are much more like anhedonia than what was observed in the rats of the LSD-psychosis study. Dynorphin has been described as an antireward before (13), so its function to induce anhedonia makes sense as the term literally means lack of hedonic response, lack of reward. It makes sense pharmacologically because dynorphin suppresses dopamine (14), opposes the functions of the rewarding opioid systems (15), and seems to induce depressive behavior.
It is possible that the lack of sucrose-preference could be described as ‘anhedonic’ although this may not be like the anhedonic states that those with schizophrenia experience, which may look more like laying in bed, not moving for hours on end. Instead, the rats seem driven to explore for far longer than the control rats, which does not seem schizophrenic. Those with schizophrenia and depression have decreased motor activity and exploration, meanwhile those with bipolar disorder have been characterized as having motor hyperactivity and increased exploratory behavior (41). So LSD may better model mania/bipolar disorder rather than schizophrenia, something I’ve argued in Psychedelics and Schizophrenia.
Amphetamine is often explored as a psychosis model in animals (16). The psychostimulant is known to induce hyperactivity in rats (17), which may be due to dopaminergic effects. As with other rewarding and addictive drugs, amphetamine increases dynorphin activity, which seems to be due to stimulation of D1 dopamine receptors and glutamate NMDA receptors (18). Even sugar increases dynorphin secretion (19), which may be part of how sugar becomes addictive (20). Since LSD is found to attenuate KOR mediated depressive effects (9) and also rapidly attenuates addiction (3), it may be that the LSD rats in the LSD-psychosis study are not developing this addiction response due to lasting changes to the KOR system. The locomotor activity found in amphetamine rats may be sign of increased dopamine activity, meanwhile hallucinogenic effects produced by amphetamine may be a byproduct of increased dynorphin activity, since agonism of KOR is psychotomimetic and hallucinogenic (21).
Drug cravings seem to get induced by dynorphin activity (4), which makes sense as a euphoriant may be able to help relieve or cope with dysphoria and stress. It would make sense if the LSD-rats were not experiencing sensitivity to stress or depressiveness, and thus not reaching for the sugar to cope. Instead, maybe the animals are more motivated towards novelty, thus the exploratory behaviors. To clearly show the distinction of novel-reward seeking and comfort-reward seeking, consider that stress often makes rats express less exploratory behavior (23) and locotomor behavior (22), but it does enhance sugar intake (24). This makes sense, even among humans we see those who are stressed reaching for the sugary delights. Perhaps sugar intake actually measures depressiveness/stress and the rats in the study are experiencing “anhedonia” because they are simply too happy (sarcasm).
It is possible that serotonergic drugs, such as SSRIs and psychedelics, could induce a reduced reward-seeking state. SSRI drugs have been observed to reduce reward and aversion processing (42), meanwhile dynorphin/KOR agonism and stress both seem to be aversive and potentiate the rewarding effects of drugs, and they do so by inducing reuptake of serotonin (43), which is the opposite of effect of SSRI drugs. Keep in mind, KOR agonism and stress also induce behavioral depression (44). Also, it is important to consider that humans and animals may seek out or have enhanced relief from the dysphoria of dynorphin by taking euphoriants. Perhaps dysphoria is like a tolerance break from euphoria or even baseline neutral affect.
Without suffering, perhaps reward is less desirable.
I’ve talked a lot in the past how dynorphin can bind together so many of the schizophrenia hypotheses and even is found to be elevated in the brains of schizophrenics (25, 26). The dynorphin system is also the main target of the hallucinogenic drug Salvia Divinorum (21). Dynorphin isn’t only psychomimetic through KOR agonism, but it also binds to NMDAr directly as an antagonist (27), much like PCP and ketamine, which are both used as models for psychosis. KOR agonism also potentiates dopamine D2 receptor activity (28) and mimics some of the effects of presynaptic dopamine D2 receptors, namely dopamine release inhibition (29, 30). This is significant, as high D2 receptor counts, specifically increased dopamine presynaptic D2 function is implicated in schizophrenia (31).
A new study has even challenged schizophrenic animal research (31). The authors noted that locomotor activity due to psychostimulants such as amphetamine is highly associated with increased limbic striatal dopamine activity, whereas the positive symptoms of schizophrenia, such as hallucinations, is associated with high dopamine in the associative striatum. Despite this, researchers continue to use locomotor activity as evidence of positive symptoms in animal research.
Another important thing to consider is that the positive symptoms and schizophrenia are linked to presynaptic D2 receptors (32), which suppress dopamine release (30), like dynorphin. Amphetamines increase dopamine release largely indiscriminately, so they are not specific to the presynaptic receptor activity. Though, they may increase psychotic-like mechanisms by enhancing dynorphin to potentiate D2 activity and dopamine release suppression, which may disrupt working memory and cognitive abilities by preventing D1-NMDAr complex function (33). This is also evidenced by the fact that dopamine increases and abnormalities exist prior to the onset of psychotic symptoms (31), suggesting that it takes time for psychotic symptoms to emerge.
In contrast, Salvia Divinorum induces radical alterations to perception and consciousness that occur acutely (21). The dynorphin blocking drug buprenorphine also function as a rapid-acting and potent anti-psychotic (34, 35). Though the withdrawals of this drug also produces psychotic effects (36, 37, 38), which suggests that targeting KORs with antagonists is only a temporary solution to schizophrenia that is prone to dependency. Most fascinatingly, there is one case report that reported LSD-like effects from sublingual buprenorphine administration (39), although the subject was addicted to heroin and so this complicates matters.
From that case report (39):
On the second day, patient reported an intense psychologic experience, which he described as an “LSD-like trip.” He described a heightened sense of excitement, intense euphoria, experiencing radiant colors, trance music, and visualizing fairies and goblins playing around him. This lasted for nearly 4 to 6 hours and left the patient feeling intensely happy. After this, buprenorphine was withheld and the patient reported no recurrences after that. After 4 days, when the buprenorphine was restarted, the patient again reported a similar “trip”; however, this time it was less intense.
This effect of buprenorphine may be a kind of ‘psychedelic manic’ state, as opposed to a ‘dysdelic psychotic’ state like the one Salvia produces. This is particularly fascinating because it fits with the ideas proposed in Psychedelics and Schizophrenia, which suggests that there is an inverse relationship between serotonergic and dynorphinergic tone in the brain and that psychedelia is actually mania.
We must consider research on psychedelics and schizophrenia much more carefully than we currently do. There is this frequent assumption that psychedelics induce a state that is like schizophrenia without consideration that there exists multiple altered states that involve broadly similar effects, at least at face value. In reality, Salvia is very distinguishable from psychedelics, even so much that animals are able to distinguish between psychedelics and Salvia (40).
One study (21) actually compared the subjective effect reports of Salvia and psychedelic users:
The inhalation of vaporized salvinorin-A led to very strong psychotropic effects of rapid onset and short duration. Perceptual modifications included the visual domain, and in contrast with 5HT2A agonists, auditory hallucinations were very common. Also in contrast with the classical serotonergic psychedelics, loss of contact with external reality was prominent with the participants being unreactive to external visual and verbal cues, especially after the medium and high doses. While at the low and medium doses there was an increase in bodily sensations, at 1.0mg there was an almost complete loss of body ownership and an increase in out-of-body experiences. These results suggest that the dynorphins – KOR system may play a previously underestimated role in the regulation of sensory perception, interoception, and the sense of body ownership in humans.
It may be that Salvia is a better model for schizophrenia than either dissociatives, psychedelics, or psychostimulants. I’ll refer you to my dynorphin hypothesis of schizophrenia if you are curious to see why I think psychedelics could actually help to treat schizophrenia.
. . .
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