ArticlePDF Available

The serotonin 2A receptor agonist 25CN-NBOH increases murine heart rate and neck-arterial blood flow in a temperature-dependent manner

Authors:
  • Beckley Foundation

Abstract and Figures

Background Serotonin 2A receptors, the molecular target of psychedelics, are expressed by neuronal and vascular cells, both of which might contribute to brain haemodynamic characteristics for the psychedelic state. Aim Aiming for a systemic understanding of psychedelic vasoactivity, here we investigated the effect of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine – a new-generation agonist with superior serotonin 2A receptor selectivity – on brain-supplying neck-arterial blood flow. Methods We recorded core body temperature and employed non-invasive, collar-sensor based pulse oximetry in anesthetised mice to extract parameters of local blood perfusion, oxygen saturation, heart and respiration rate. Hypothesising an overlap between serotonergic pulse- and thermoregulation, recordings were done under physiological and elevated pad temperatures. Results N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (1.5 mg/kg, subcutaneous) significantly increased the frequency of heart beats accompanied by a slight elevation of neck-arterial blood flow. Increasing the animal-supporting heat-pad temperature from 37°C to 41°C enhanced the drug’s effect on blood flow while counteracting tachycardia. Additionally, N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine promoted bradypnea, which, like tachycardia, quickly reversed at the elevated pad temperature. The interrelatedness of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine’s respiro-cardiovascular effects and thermoregulation was further corroborated by the drug selectively increasing the core body temperature at the elevated pad temperature. Arterial oxygen saturation was not affected by N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine at either temperature. Conclusions Our findings imply that selective serotonin 2A receptor activation modulates systemic cardiovascular functioning in orchestration with thermoregulation and with immediate relevance to brain-imminent neck (most likely carotid) arteries. As carotid branching is a critical last hub to channel cardiovascular output to or away from the brain, our results might have implications for the brain haemodynamics associated with psychedelia.
Content may be subject to copyright.
For Peer Review
The 5-HT2AR agonist 25CN-NBOH increases murine heart
rate and neck-arterial blood flow in a temperature-
dependent manner
Journal:
Journal of Psychopharmacology
Manuscript ID
JOP-2019-4055.R1
Manuscript Type:
Original Paper
Date Submitted by the
Author:
n/a
Complete List of Authors:
Buchborn, Tobias; Imperial College London, Medicine
Lyons, Taylor; Imperial College London, Medicine
Song, Chenchen; Imperial College London, Medicine
Feilding, Amanda; The Beckley Foundation, .
Knöpfel, Thomas; Imperial College London, Medicine
Please list at least 3 keywords
which relate to your
manuscript::
25CN-NBOH, selective 5-HT<sub>2A</sub> agonist, psychedelic,
carotid artery, thermoregulation
Abstract:
Background: Serotonin 2A receptors (5-HT2ARs), the molecular target of
psychedelics, are expressed by neuronal and vascular cells, both of
which might contribute to the brain haemodynamics characteristic for the
psychedelic state.
Aim: Aiming for a systemic understanding of psychedelic vasoactivity, we
here investigated the effect of 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-
dimethoxy-4-cyanophenylethylamine) —a new-generation agonist with
superior 5-HT2AR selectivity— on brain-supplying neck-arterial blood
flow.
Methods: We recorded body core temperature and employed non-
invasive, collar-sensor based pulse oximetry in anesthetised mice to
extract parameters of local blood perfusion, oxygen saturation, heart and
respiration rate. Hypothesising an overlap between serotonergic pulse-
and thermoregulation, recordings were done under physiological and
elevated pad temperature.
Results: 25CN-NBOH (1.5 mg/kg, s.c.) significantly increased the
frequency of heart beats accompanied by a slight elevation of neck-
arterial blood flow. Increasing the animal-supporting heat-pad
temperature from 37 to 41˚C enhanced the drug’s effect on blood flow
while counteracting tachycardia. Additionally, 25CN-NBOH promoted
bradypnea, which like tachycardia quickly reversed at elevated pad
temperature. The interrelatedness of 25CN-NBOH’s respiro-
cardiovascular effects to thermoregulation was further corroborated by
the drug selectively increasing body core temperature at elevated pad
temperature. Arterial oxygen saturation at neither temperature was
affected by 25CN-NBOH.
Conclusions: Our findings imply that selective 5-HT2AR activation
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
For Peer Review
modulates systemic cardiovascular functioning in orchestration with
thermoregulation, and with immediate relevance to brain-imminent neck
(most likely carotid) arteries. As carotid branching is a critical last hub to
channel cardiovascular output to or away from the brain, our results
might have implications for the brain haemodynamics associated with
psychedelia.
Page 1 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
1
The 5-HT2AR agonist 25CN-NBOH increases murine heart rate and neck-
arterial blood flow in a temperature-dependent manner
Buchborn T1,3,#, Lyons T1,3, Song C1, Feilding A4, Knöpfel T1,2
1Laboratory for Neuronal Circuit Dynamics, Department of Medicine, Imperial College, London, UK
2Centre for Neurotechnology, Institute of Biomedical Engineering, Imperial College, London, UK
3Centre for Psychedelic Research, Department of Medicine, Imperial College, London, UK
4The Beckley Foundation, Beckley Park, Oxford, UK
#Corresponding Author:
Tobias Buchborn, t.buchborn@imperial.ac.uk
Short title: 25CN-NBOH on neck-arterial blood flow
Page 2 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
2
Abstract
Background: Serotonin 2A receptors (5-HT2ARs), the molecular target of psychedelics, are
expressed by neuronal and vascular cells, both of which might contribute to the brain
haemodynamics characteristic for the psychedelic state.
Aim: Aiming for a systemic understanding of psychedelic vasoactivity, we here investigated
the effect of 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine)
—a new-generation agonist with superior 5-HT2AR selectivity— on brain-supplying neck-
arterial blood flow.
Methods: We recorded body core temperature and employed non-invasive, collar-sensor
based pulse oximetry in anesthetised mice to extract parameters of local blood perfusion,
oxygen saturation, heart and respiration rate. Hypothesising an overlap between serotonergic
pulse- and thermoregulation, recordings were done under physiological and elevated pad
temperature.
Results: 25CN-NBOH (1.5 mg/kg, s.c.) significantly increased the frequency of heart beats
accompanied by a slight elevation of neck-arterial blood flow. Increasing the animal-
supporting heat-pad temperature from 37 to 41˚C enhanced the drug’s effect on blood flow
while counteracting tachycardia. Additionally, 25CN-NBOH promoted bradypnea, which like
tachycardia quickly reversed at elevated pad temperature. The interrelatedness of 25CN-
NBOH’s respiro-cardiovascular effects to thermoregulation was further corroborated by the
drug selectively increasing body core temperature at elevated pad temperature. Arterial
oxygen saturation at neither temperature was affected by 25CN-NBOH.
Conclusions: Our findings imply that selective 5-HT2AR activation modulates systemic
cardiovascular functioning in orchestration with thermoregulation, and with immediate
relevance to brain-imminent neck (most likely carotid) arteries. As carotid branching is a
critical last hub to channel cardiovascular output to or away from the brain, our results might
have implications for the brain haemodynamics associated with psychedelia.
Declaration of conflicting interests: Amanda Feilding is the director of the Beckley
Foundation, one of the sponsors of the study.
Funding: This study was supported by the European Commission (TB [MSCA], TK), The
Beckley Foundation (TB, TK), and funds provided by Imperial College (TK), NIH (TK), and
by MRC (TL).
Page 3 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
3
Keywords: 25CN-NBOH, selective 5-HT2AR agonist, psychedelic, carotid artery, vasoactive.
hypertension, tachycardia, haemodynamics, thermoregulation, bradypnea
Page 4 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
4
Introduction
Psychedelics (i.e., serotonergic hallucinogens) are psychoactive drugs, whose effects show
strong manifestation in human psychological functioning as well as in various somatic
alterations across mammals. Lysergic acid diethylamide (LSD) in humano, for instance, has
been shown to induce pupil dilatation, patellar hyperreflexia, temperature dysregulation, as
well as increases in breath rate, heart rate, and blood pressure (Isbell, 1959; Schmid et al.,
2015). In animals, stereotypical movements, including head twitches and wet dog shakes
(e.g., Corne and Pickering, 1967; Buchborn et al., 2015) as wells as other motor symptoms
taken together referred to as serotonin syndrome have been described (Sloviter et al., 1980).
Beyond neuro-summative EEG and MEG recordings, our knowledge of the
neurophysiological correlates of the human psychedelic brain state largely feeds from BOLD-
fMRI and PET based research. As the given methods indirectly measure neuronal activity by
extraction of blood-flow related parameters, the vasoactivity intrinsic to psychedelics
deserves particular experimental scrutiny when interpreting such correlates. Psychedelics are
thought to primarily mediate their psychedelic effect by activation of serotonin 2A receptors
(5-HT2ARs) (Kraehenmann et al., 2017; Preller et al., 2017), with glutamatergic pyramidal
cells within the cerebral cortex proposed as one of the key sites of their action (Vollenweider
and Kometer, 2010; Muthukumaraswamy et al., 2013; Nichols, 2016; Marek, 2017). 5-
HT2ARs —apart from neuronal expression in the brain (see GPCR database; Regard et al.,
2008; Andrade and Weber, 2010)— are widely expressed across the vascular system (Cohen,
1988; Ullmer et al., 1995), and there is ongoing controversy as to how a direct interaction
between psychedelics and the vessels might contribute to the overall corticodynamics
associated with the psychedelic state (Lewis et al., 2017; Muller et al., 2018). Psychedelics
are likely to interfere with cerebral blood flow by targeting 5-HT receptors within the brain’s
microcirculation itself (Cohen et al., 1996). Despite autoregulatory shielding of brain blood
flow from the caprioles of the periphery (Yang and Liu, 2017), heart rate and systemic blood
pressure have a clear effect on cerebral haemodynamics, too (Kalisch et al., 2005; Ma et al.,
2016; Terem et al., 2018). BOLD-fMRI based brain functioning studies, thought to mainly
reflect neuronal activity, might therefore partially be confounded by local and/or
cardiovascular bottom-up effects (e.g., de Munck et al., 2008; van‘t Ent et al., 2014).
Although there is general effort to control for these complex interactions in brain imaging
studies on psychedelics (Carhart-Harris et al., 2012; Müller et al., 2018), it appears essential
to learn how 5-HT2AR activation influences the brain’s supply of blood when disentangling
Page 5 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
5
neuro- and haemodynamic mechanisms involved in the psychedelic brain state.
Cardiovascular receptors of the 5-HT2 family (5-HT2Rs) have been subject to extensive
research (rev. McCall and Clement, 1994; Ramage, 2001; Nagatomo et al., 2004; Kermorgant
et al., 2018), yet our understanding of how they regulate systemic circulation has largely been
occluded by the unavailability of selective agonists. The phenylaminergic psychedelics DOI
and DOM (2,5-dimethoxy-4-iodo-/methyl-amphetamine) for instance, which so far have been
the state-of-the-art drugs for delineation of 5-HT2R specific cardiovascular functioning, do
not seem to well discriminate 5-HT2ARs from 5-HT2B and/or 5-HT2C receptors (e.g., Sanders-
Bush et al., 1988; Porter et al., 1999). Also, it has been suggested that they might have
confounded affinity for adrenergic receptors (Ray, 2010), making an appraisal of 5-HT2AR
specific vasoactive effects difficult.
Here, we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-
cyanophenylethylamine), a recently developed selective 5-HT2AR agonist with 100-fold
preference for 5-HT2ARs over a plethora of non-5-HT2R targets (Jensen et al., 2017). We
tested 25-CN-NBOH with regard to its effects on heart rate, blood flow, blood oxygenation,
and respiratory rate in mice, monitored by non-invasive pulse oximetry drawn from the
animals’ brain-imminent neck arteries. In both animals and humans, psychedelics are known
to strongly exalt emotions (e.g., Katz et al., 1968; Adams and Geyer, 1985). To avoid
cardiovascular effects associated with emotional arousal (Prkachin et al., 1999; Hoyt et al.,
2007), experiments were performed under anaesthesia. Furthermore, as 5-HT2AR related
vasoconstriction is thought to be a main effector site of serotonergic thermoregulation (e.g.,
Ootsuka et al., 2004), we expected environmental temperature to be critical for psychedelic
haemodynamics. We therefore explored the drug’s cardiovascular effects by varying the
temperature of the heat-pad supporting the animal.
Methods
Animals
All experimental procedures performed at Imperial College London were in accordance with
the UK Animal Scientific Procedures Act (1986) under Home Office Personal and Project
licenses (I5B5A6029, IA615553C; PPL 70/7818), following appropriate ethical review.
Adult mice of both sexes and with mixed (non-inbred) genetic background (stock of mainly
C57BL/6JxB6CBAF1 background; N=41) were bred in-house at the Central Biomedical
Page 6 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
6
Services (CBS) of Imperial College London. They were housed in individually ventilated
cages with a 12:12 h light/dark cycle and maintained at an ambient temperature of 21±2˚C at
55±10% humidity. Mice were provided with standard rodent-chow pellets (Special Diet
Services, #RM1) and water ad libitum.
Drugs
25CN-NBOH hydrochloride (a kind gift from Jesper L. Kristensen, University of
Copenhagen) was dissolved in isotonic saline and applied subcutaneously (<10ml/kg). The
dose used (i.e., 1.5 mg/kg) was found optimal for a 5-HT2AR specific effect, as determined by
a dose-response curve for 25CN-NBOH induced head twitches (Buchborn et al., 2018).
Experiments were performed under general anaesthesia using isoflurane (IsoFlo; Zoetis, UK)
delivered in 100% oxygen, as detailed below.
Pulse oximetry and body core temperature measurements
Pulse oximetry was performed in anaesthetised mice using the rodent-specific MouseOx Plus
collar-sensor system (STARR Life Sciences Corp., Oakmont, PA). Anaesthesia was induced
in an anaesthesia chamber (VetTech Solutions, Cheshire, UK) at 2-2.5% isoflurane, and
following the loss of the righting reflex maintained via two-port mask supply at 1.5-2.0%
concentration. Body temperature was maintained by a feedback-loop controlled heat-pad
(TR-200 Fine science tools, USA), which drew input from a thermosensor attached to the
heat-pad’s surface, controlling for physiological and elevated (37 and 41˚C) pad temperature,
respectively. The collar-sensor was placed around the shaved necks of the animals to read out
oxygen saturation (% of functional arterial haemoglobin), heart rate (beats per minute [bpm]),
respiration rate (breaths per minute [brpm]), and pulse distention of carotid arteries (Figure
1(a)). Pulse distention reflects changes in light absorption by haemoglobin and via Beer’s law
provides the length of the optical path through the blood (Hete et al., 2013). All parameters
were calculated by the MouseOx system and read out at 1 Hz, with a 20-minutes baseline
period, followed by injection of 25CN-NBOH and saline, respectively, and a 20-minutes
post-injection period. Body core temperature was monitored via a digital thermometer and
rectal probe and registered at 2-minutes intervals.
Statistics
Page 7 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
7
Pulse oximetry 1-Hz readouts –as aggregated in 5-min bins– and body core temperature
measurements were analysed via SPSS-implemented 3-factorial repeated measures ANOVA
(with group and pad temperature as between-subject factors, and time as within-subject
factor), and analysed for main effects, interaction, and contrast, respectively. Significant
interactions were followed up on by Bonferroni-corrected multiple comparisons. For cross-
parameter comparability, results were normalised to their respective baseline average and
depicted as -fold baseline.
Results
Pulse distention
For isoflurane-anaesthetised control animals at both 37 and 41 ˚C pad temperature (n= 8 and
14, resp.), pulse distention remained relatively stable throughout the 40-minutes recording
period. This contrasts with 25CN-NBOH treated mice (Figure 1; repeated measures ANOVA,
significant differences as a function of time (F(2.52, 93.27) = 3.51, p=.001), group (F(1, 37) =
3.51, p.001), time x group (F(2.52, 16.37) = 16.37, p≤.001), as well as time x group x
temperature (F(2.52, 93.27) = 4.99, p=.005): Bonferroni-corrected post-hoc analysis revealed
significant group differences from 25CN-NBOH treated animals (n=9 and 10, resp.) at any of
the four post-injection measurements for both temperature conditions (control vs. NBOH
[mean±SEM, fold change] for 37˚C: 0.98±0.017 vs. 1.05±0.03 [5 min], p=.021; 0.97±0.019
vs. 1.04±0.026 [10 min], p=.036; 0.96±0.019 vs. 1.04±0.026 [15 min], p=.022; 0.96±0.021
vs. 1.049±0.026 [20 min], p=.028; for 41˚C: 0.97±0.01 vs. 1.05±0.015 [5 min], p=.005;
0.97±0.012 vs. 1.15±0.027 [10 min], p≤.001; 0.96±0.012 vs. 1.15±0.024 [15 min], p≤.001;
0.96±0.013 vs. 1.15±0.037 [20 min], p≤.001). At increased pad temperature, 25CN-NBOH
induced increase in arterial distension was much more pronounced (NBOH 37˚C vs. 41˚C:
p=.026 [5 min]; p=.031 [10 min]; p=.029 [15 min]; p=.036 [20 min]). For the saline treated
control mice, as opposed, no such temperature effect could be found (control 37˚C vs. 41˚C:
p=.93 [5 min]; p=.85 [10 min]; p=.92 [15 min]; p=.99 [20 min]). Mean absolute values of
arterial distension for the pre- vs. post-injection intervals (given in μm) are presented in
Tables 1 and 2.
[insert Figure 1] [insert Table 1 and 2]
Heart rate
Page 8 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
8
Isoflurane-anesthetised mice overall exhibited a tendency for an increase of heart rate over
time (Figure 2; repeated measures ANOVA, significant main effect time: F(1.77, 65.40) =
65.76, p≤.001). Furthermore, a significant time x group interaction (F(1.77, 65.40) = 4.59,
p≤.001) and a significant time x treatment x temperature interaction (F(1.77, 65.40) = 3.93,
p=.029) indicated that the temporal changes in heart rate differed between both groups in a
temperature dependent manner. Bonferroni-corrected post-hoc comparisons revealed that the
significant time x group interaction was due to an 25CN-NBOH induced tachycardia at all
four post-injection measurements for the 37˚C condition (control vs. NBOH [mean±SEM, -
fold change]: 1.05±0.018 vs. 1.12±0.018 [5 min], p=.041; 1.07±0.02 vs. 1.18±0.027 [10 min],
p≤.001; 1.08±0.026 vs. 1.19±0.031 [15 min], p=.01; 1.08±0.03 vs. 1.19±0.032 [20 min],
p=.016) and at the first post-injection measurement for the 41˚C condition, respectively
(control vs. NBOH [mean±SEM, -fold change]: 1.07±0.016 vs. 1.13±0.026 [5 min], p=.044).
Accordingly, temperature-dependent heart rate differences in 25CN-NBOH treated animals
could be detected at the 15- and 20-minutes measurements, respectively, and as trend for the
10-minutes measurement (NBOH 37 vs. 41˚C: p=.095 [10 min]; p=.015; 40 min [15 min]:
p=.029; p=.014 [20 min]). Mean absolute values for the pre- vs. post-injection intervals
(given in bpm) are shown in Tables 1 and 2.
[insert Figure 2]
Respiration rate
Isoflurane-anesthetised mice overall exhibited a tendency for a decrease of respiration rate
over time (Figure 3; repeated measures ANOVA, significant main effect time F(2.72,100.58)
= 47.46, p≤.001). There was a significant main effect group (F(1, 37) = 8.27, p=.007) and a
significant time x group interaction (F(2.72,100.58) = 3.21, p=.03). Following up on the time
x group interaction, 25CN-NBOH significantly decreased respiration rate at all four post-
injection measurements of the 37˚C condition (control vs. NBOH [mean±SEM, -fold
change]: 0.96±0.041 vs. 0.88±0.038 [5 min], p=.01; 0.91±0.041 vs. 0.78±0.053 [10 min],
p=.014; 0.87±0.048 vs. 0.72±0.046 [15 min], p=.025; 0.87±0.051 vs. 0.7±0.048 [20 min],
p=.01), but only as a trend at the 5-minutes post-injection measurement of the 41˚C condition
(0.94±0.015 vs. 0.86±0.025 [5 min], p=.073). Mean absolute values for the pre- vs. post-
injection intervals (given in brpm) are listed in Tables 1 and 2.
[insert Figure 3]
Page 9 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
9
Oxygenation
Overall, there was a slight tendency for blood oxygenation to decrease during anaesthesia, as
implied by a significant main effect time in the repeated measures ANOVA (F(1.81,66.96) =
3.24, p=.05) (Figure 4). Main effect group and time x group (x temperature) interactions
turned out insignificant, though, indicating that blood oxygenation was not affected by 25CN-
NBOH nor its interaction with the pad temperature. Mean absolute values for the pre- vs.
post-injection intervals (given in % saturation) are presented in Tables 1 and 2.
[insert Figure 4]
Body core temperature
For a subpopulation of animals (n=6-9 per group), body core temperature was quantified via
rectal probe. Over the 40-minutes observation period, rectal temperature was noted to slightly
increase across study groups (time, F(1, 25) = 36.53, p≤.001). Time x treatment interaction
likewise turned out significant (F(1, 25) = 9.13, p=.006), with a marginal contribution from
pad temperature (time x group x temperature F(1, 25) = 1.85, p=.095). Follow-up analysis
revealed that the time x group interaction was driven by 25-NBOH favouring body warming
during the last intervals of recording at 42˚C (control vs. NBOH [mean±SEM, -fold change]:
1.006±0.0019 vs. 1.014±0.005 [16 min], 1.0053±0.003 vs. 1.014±0.005 [18 min], and
1.005±0.002 vs. 1.02±0.005 [20 min], each p≤.05) (Figure 5). Mean absolute values for the
pre- vs. post-injection intervals (given in ˚C) can be extracted from Tables 1 and 2.
[insert Figure 5]
Discussion
Serotonin secreted into the blood stream is a major tissue hormone with a variety of actions
on the cardiovascular system and, when released from the brain stem’s raphe nuclei,
additionally mediates neuronal regulation of blood pressure (Côté et al., 2004; Watts et al.,
2012). Assuming that the serotonergic vasoactivity of psychedelics might contribute to their
overall brain dynamics, we here used the selective 5-HT2AR agonist 25CN-NBOH and
investigated its effect on parameters of neck-arterial blood flow.
Page 10 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
10
At physiological pad temperature, 25CN-NBOH induced a slight increase in neck-arterial
pulse distention, a measure of local tissue perfusion that parallels changes in mean arterial
blood pressure (Olivera et al., 2010; Hete et al., 2013). Pulse oximetry is largely driven by
strong-pulse arteries. Being the most dominant neck arteries with immediate pulse from the
heart-imminent aortic arch (Ruberte et al., 2017), our collar-clip based pulse distention
measurement most likely reflects haemodynamics of the carotid arteries. The effect of 25CN-
NBOH on neck-arterial blood flow is in line with diverse reports on psychedelics increasing
blood pressure (Wolbach et al., 1962; Huang and Ho, 1972; Dedeoğlu and Fisher, 1991;
Dolder et al., 2017), possibly resulting from increased total peripheral resistance (Chaouche-
Teyara et al., 1994) due to vasoconstriction (Cohen, 1988). The rise in arterial distension was
more pronounced, when 25CN-NBOH was applied at elevated pad temperature. Similarly,
the 25CN-NBOH induced rise in body temperature only occurred at 41, not at 37 ˚C.
Psychedelics evoke hyperthermia (e.g., Jacob and Lafille, 1963), particularly when primed by
environmental heat load (Buchborn et al., 2016). That both the effects on body core
temperature and on pulse distention were temperature-dependent, suggests a close
relationship. Indeed, psychedelic induced hyperthermia (like hypertension) is thought to
engage 5-HT2AR related vasoconstriction in the cutaneous bed, which interferes with heat
dissipation (Blessing and Seaman, 2003). Increased body temperature might affect how
common carotid blood flow is distributed across external vs. internal branches in relation to
the brain’s thermoregulatory needs (Baker et al., 1982). 25CN-NBOH furthermore evoked
tachycardia, which at physiological pad temperature sustained but quickly reversed at
elevated pad temperature. Mirroring this observation, psychedelics have been demonstrated
to increase heart rate both in humans (Wolbach et al., 1962; Strassman and Qualls, 1994;
Dolder et al., 2017) and anaesthetised animals (Friedman et al., 1978; Anderson et al., 1995;
Knowles and Ramage, 1999); as to the latter, results appear more controversial, with several
reports of bradycardia (Tadepalli et al., 1975; Chaouche-Teyara et al., 1994), inconsistent or
lack of effects (Dabiré et al., 1989; Dedeoğlu and Fisher, 1991). The controversy in literature
might partially arise from possible adrenergic pharmacodynamics of the earlier-generation
selective 5-HT2R agonists used (Ray, 2010). Indeed, bradycardia and the carotid-pressor
effect of DOM show sensitivity to adrenergic antagonism (Huang and Ho, 1972; Tadepalli et
al., 1975). Although there is other evidence pointing to a potential interaction of DOM and
DOI with the adrenergic system (e.g., Buckholtz et al., 1988; Alper, 1990; Koskinen et al.,
2003), 5-HT2R-comparable binding to adrenergic receptors has also been put in question
(Leysen et al., 1989; Pierce and Peroutka, 1989). Adrenergic effects might alternatively be
Page 11 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
11
secondary to 5-HT2R related adrenaline secretion from adrenal glands (Saxena and Villalón,
1990); thus, additional research, preferentially using functional assays, is needed to solidly
clarify these issues. Beyond unselectivity, however, conflicting results on animal heart rate
might also be reconciled with regard to two opponent counterforces downstream of 5-
HT2ARs. As to this, tachycardia might be due to 5-HT2AR mediated sympathetic cardiac
nerve output (McCall and Harris, 1988; Anderson et al., 1995). Bradycardia, by contrast,
might result from 5-HT2AR mediated hypertension inviting the baroreceptor reflex to cancel
out the sympathetically driven chronotropy (Ramage et al., 1993; N'Diaye et al., 2001). That
the tachycardic effect of 25CN-NBOH at increased pad temperature quickly was reversed as
pulse distention rose, would be in line with the proposed opponency. Apart from its effect on
pulse distention and heart rate, 25CN-NBOH facilitated the development of bradypnea,
which mirrors findings for DOI (KhaterBoidin et al., 1999; Cayetanot et al., 2001) and might
be due to 5-HT2R mediated inhibition of phrenic nerve activity (King and Holtman, 1990).
Interestingly, phrenic inhibition induced by the psychedelic 5-MeO-DMT could be overcome
by ambient heat (Lalley, 1982), which fits wells with the rapid reversal of 25CN-NBOH’s
bradypneic effect at increased pad temperature. Blood oxygen saturation was not significantly
altered by 25CN-NBOH; the observed respiro-/cardiovascular effects of the drug thus do not
seem to reflect changes in functional arterial haemoglobin availability.
In summary, our results show that 25CN-NBOH induces a temperature-dependant increase in
heart rate, decrease in respiration rate, and increase in arterial blood flow, as measured by
pulse oximetry drawn from brain-supplying (most likely carotid) arteries. 25CN-NBOH is the
most selective 5-HT2R agonist at present, with robust preference for 5-HT2AR over 5-HT2B
and 5-HT2C receptors and lack of appreciable affinity for adrenergic receptors (Hansen, 2010;
Halberstadt et al., 2016; Jensen et al., 2017). Given the primary relevance of 5-HT2ARs for
the psychedelic principle along with the immediacy of neck-arterial blood flow to the brain’s
metabolic demands, our results might contribute to a more systemic understanding of how
psychedelic-5-HT2AR interactions translates into the brain (haemo-)dynamics characteristic
for psychedelia.
Acknowledgements
The authors would like to thank Jesper L. Kristensen, University of Copenhagen, for the kind
gift of 25CN-NBOH; Gemma Oliver for help with animal husbandry; all members of the
Page 12 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
12
Knöpfel lab for critical comments and encouragement; as well as Robin Carhart-Harris and
his team for advice and inspiration.
Declaration of conflicting interests
Amanda Feilding is the director of the Beckley Foundation, one of the sponsors of the study.
Funding
This study was supported by the European Commission (TB [MSCA], TK), The Beckley
Foundation (TB, TK), and funds provided by Imperial College (TK), NIH (TK), and by MRC
(TL).
.
Page 13 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
13
Reference
Adams LM and Geyer MA (1985) A proposed animal model for hallucinogens based on LSD's effects
on patterns of exploration in rats. Behav Neurosci 99: 881.
Alper RH (1990) Hemodynamic and renin responses to (±)-DOI, a selective 5-HT2 receptor agonist,
in conscious rats. Eur J Pharmacol 175: 323-332.
Anderson IK, Martin GR and Ramage AG (1995) Evidence that activation of 5HT2 receptors in the
forebrain of anaesthetized cats causes sympathoexcitation. Br J Pharmacol 116: 1751-1756.
Andrade R and Weber ET (2010) Htr2a gene and 5-HT2A receptor expression in the cerebral cortex
studied using genetically modified mice. Front Neurosci 4: 36.
Baker M, Hawkins M and Rader R (1982) Thermoregulatory influences on common carotid blood
flow in the dog. J Appl Physiol 52: 1138-1146.
Blessing WW and Seaman B (2003) 5-Hydroxytryptamine2A receptors regulate sympathetic nerves
constricting the cutaneous vascular bed in rabbits and rats. Neuroscience 117: 939-948.
Buchborn T, Lyons T and Knöpfel T (2018) Tolerance and tachyphylaxis to head twitches induced by
the 5-HT2A agonist 25CN-NBOH in mice. Front Pharmacol 9: 17.
Buchborn T, Schröder H, Dieterich DC, et al. (2015) Tolerance to LSD and DOB induced shaking
behaviour: differential adaptations of frontocortical 5-HT2A and glutamate receptor binding
sites. Behav Brain Res 281: 62-68.
Buchborn T, Schroeder H, Koch T, et al. (2016) Differential tolerance to lysergic acid diethylamide
(LSD) and dimethyltryptamine (DMT)-A matter of serotonin (5-HT) 2A receptor
downregulation? Naunyn Schmiedebergs Arch Pharmacol 389: S63.
Buckholtz NS, Zhou D and Freedman DX (1988) Serotonin2 agonist administration down-regulates
rat brain serotonin2 receptors. Life Sci 42: 2439-2445.
Carhart-Harris RL, Erritzoe D, Williams T, et al. (2012) Neural correlates of the psychedelic state as
determined by fMRI studies with psilocybin. PNAS 109: 2138-2143.
Cayetanot F, Gros F and Larnicol N (2001) 5-HT 2A/2C Receptor–Mediated Hypopnea in the
Newborn Rat: Relationship to Fos Immunoreactivity. Pediatr Res 50: 596.
Chaouche-Teyara K, Fournier B, Safar M, et al. (1994) Systemic and Regional Haemodynamic
Effects of 1–(2, 5–Dimethoxy-4–IODO-Phenyl)-2–Aminopropane (DOI) and α-Methyl-5
HT, in the Anaesthetised Rat. Clin Exp Hypertens 16: 779-798.
Cohen ML (1988) Serotonin receptors in vascular smooth muscle. In Sanders-Bush E (ed) The
Serotonin Receptors. New Jersey: Springer, 295-316.
Cohen Z, Bonvento G, Lacombe P, et al. (1996) Serotonin in the regulation of brain microcirculation.
Prog Neurobiol 50: 335-362.
Corne S and Pickering R (1967) A possible correlation between drug-induced hallucinations in man
and a behavioural response in mice. Psychopharmacologia 11: 65-78.
Côté F, Fligny C, Fromes Y, et al. (2004) Recent advances in understanding serotonin regulation of
cardiovascular function. Trends Mol Med 10: 232-238.
Dabiré H, Chaouche-Teyara K, Cherqui C, et al. (1989) DOI is a mixed agonist-antagonist at
postjunctional 5-HT2 receptors in the pithed rat. Eur J Pharmacol 170: 109-111.
de Munck JC, Gonçalves SI, Faes TJ, et al. (2008) A study of the brain's resting state based on alpha
band power, heart rate and fMRI. Neuroimage 42: 112-121.
Dedeoğlu A and Fisher L (1991) Central and peripheral injections of the 5-HT2 agonist, 1-(2, 5-
dimethoxy-4-iodophenyl)-2-aminopropane, modify cardiovascular function through different
mechanisms. J Pharmacol Exp Ther 259: 1027-1034.
Dolder PC, Schmid Y, Steuer AE, et al. (2017) Pharmacokinetics and pharmacodynamics of lysergic
acid diethylamide in healthy subjects. Clin Pharmacokinet 56: 1219-1230.
Friedman E, Lambert GA and Buchweitz E (1978) 2, 5-dimethoxy-4-methylamphetamine (DOM)—A
central component of its cardiovascular effects in rats; involvement of serotonin. Eur J
Pharmacol 49: 157-161.
Halberstadt AL, Sindhunata IS, Scheffers K, et al. (2016) Effect of 5-HT2A and 5-HT2C receptors on
temporal discrimination by mice. Neuropharmacology 107: 364-375.
Hansen M (2010) Design and synthesis of selective serotonin receptor agonists for positron emission
tomography imaging of the brain. PhD thesis. University of Copenhagen, Denmark.
Page 14 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
14
Hete BF, Starr EW and Ayers EJ (2013) Pulse oximetry system and techniques for deriving cardiac
and breathing parameters from extra-thoracic blood flow measurements. Google Patents.
Hoyt RE, Hawkins JV, St Clair MB, et al. (2007) Mouse physiology. In Fox JG, Barthold S, Davisson
M, et al. (eds) The mouse in biomedical research. Amsterdam: Elsevier, 23-90.
Huang JT and Ho BT (1972) The pressor action of 2, 5dimethoxy4methylamphetamine in rats. J
Pharm Pharmacol 24: 656-657.
Isbell H (1959) Comparison of the reactions induced by psilocybin and LSD-25 in man.
Psychopharmacology (Berl) 1: 29-38.
Jacob J and Lafille C (1963) Charactérisation et detection pharacologiques des substances
hallucinogènes. Arch Int Pharmacodyn Ther 145: 528-545.
Jensen AA, McCorvy JD, Leth-Petersen S, et al. (2017) Detailed characterization of the in vitro
pharmacological and pharmacokinetic properties of N-(2-hydroxybenzyl)-2, 5-dimethoxy-4-
cyanophenylethylamine (25CN-NBOH), a highly selective and brain-penetrant 5-HT2A
receptor agonist. J Pharmacol Exp Ther 361: 441-453.
Kalisch R, Delfino M, Murer MG, et al. (2005) The phenylephrine blood pressure clamp in
pharmacologic magnetic resonance imaging: reduction of systemic confounds and improved
detectability of drug-induced BOLD signal changes. Psychopharmacology (Berl) 180: 774-
780.
Katz MM, Waskow IE and Olsson J (1968) Characterizing the psychological state produced by LSD.
J Abnorm Psychol 73: 1-14.
Kermorgant M, Pavy-Le Traon A, Senard J, et al. (2018) Serotonergic Receptor 5-HT 2A in the
Cardiosympathovagal System. In Guiard B and Di Giovanni G (eds) 5-HT2A Receptors in the
Central Nervous System. Springer, 137-145.
KhaterBoidin J, Rose D, Glérant JC, et al. (1999) Central effects of 5HT on respiratory rhythm in
newborn rats in vivo. Eur J Neurosci 11: 3433-3440.
King K and Holtman J (1990) Characterization of the effects of activation of ventral medullary
serotonin receptor subtypes on cardiovascular activity and respiratory motor outflow to the
diaphragm and larynx. J Pharmacol Exp Ther 252: 665-674.
Knowles ID and Ramage AG (1999) Evidence for a role for central 5HT2B as well as 5HT2A
receptors in cardiovascular regulation in anaesthetized rats. Br J Pharmacol 128: 530-542.
Koskinen T, Haapalinna A and Sirvi J (2003) αAdrenoceptorMediated Modulation of 5HT2
Receptor Agonist Induced Impulsive Responding in a 5Choice Serial Reaction Time Task.
Pharmacol Toxicol 92: 214-225.
Kraehenmann R, Pokorny D, Vollenweider L, et al. (2017) Dreamlike effects of LSD on waking
imagery in humans depend on serotonin 2A receptor activation. Psychopharmacology (Berl)
234: 2031-2046.
Lalley PM (1982) Inhibition of phrenic and sympathetic vasomotor neurons in cats by the serotonin
analog 5-methoxy-N, N-dimethyltryptamine. J Pharmacol Exp Ther 220: 39-48.
Lewis CR, Preller KH, Kraehenmann R, et al. (2017) Two dose investigation of the 5-HT-agonist
psilocybin on relative and global cerebral blood flow. Neuroimage 159: 70-78.
Leysen JE, Janssen PF and Niemegeers CJ (1989) Rapid desensitization and down-regulation of 5-
HT2 receptors by DOM treatment. Eur J Pharmacol 163: 145-149.
Ma Y, Shaik MA, Kim SH, et al. (2016) Wide-field optical mapping of neural activity and brain
haemodynamics: considerations and novel approaches. Philos Trans R Soc Lond B Biol Sci
371.
Marek GJ (2017) Interactions of hallucinogens with the glutamatergic system: permissive network
effects mediated through cortical layer V pyramidal neurons. In Halberstadt A, Vollenweider
F and Nichols D (eds) Behavioral Neurobiology of Psychedelic Drugs. Heidelberg: Springer,
107-135.
McCall RB and Clement ME (1994) Role of serotonin1A and serotonin2 receptors in the central
regulation of the cardiovascular system. Pharmacol Rev 46: 231-243.
McCall RB and Harris LT (1988) 5-HT2 receptor agonists increase spontaneous sympathetic nerve
discharge. Eur J Pharmacol 151: 113-116.
Müller F, Dolder PC, Schmidt A, et al. (2018) Altered network hub connectivity after acute LSD
administration. NeuroImage: Clinical 18: 694-701.
Page 15 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
15
Muller F, Liechti ME, Lang UE, et al. (2018) Advances and challenges in neuroimaging studies on
the effects of serotonergic hallucinogens: Contributions of the resting brain. Prog Brain Res
242: 159-177.
Muthukumaraswamy SD, Carhart-Harris RL, Moran RJ, et al. (2013) Broadband cortical
desynchronization underlies the human psychedelic state. J Neurosci 33: 15171-15183.
N'Diaye A, Sévoz-Couche C, Nosjean A, et al. (2001) Stimulation of 5-HT2 receptors in the nucleus
tractus solitarius enhances NMDA receptor-mediated reflex-evoked bradycardiac responses in
the rat. Auton Neurosci 92: 45-55.
Nagatomo T, Rashid M, Muntasir HA, et al. (2004) Functions of 5-HT2A receptor and its antagonists
in the cardiovascular system. Pharmacol Ther 104: 59-81.
Nichols DE (2016) Psychedelics. Pharmacol Rev 68: 264-355.
Olivera A, Eisner C, Kitamura Y, et al. (2010) Sphingosine kinase 1 and sphingosine-1-phosphate
receptor 2 are vital to recovery from anaphylactic shock in mice. J Clin Invest 120: 1429-
1440.
Ootsuka Y, Nalivaiko E and Blessing WW (2004) Spinal 5-HT2A receptors regulate cutaneous
sympathetic vasomotor outflow in rabbits and rats; relevance for cutaneous vasoconstriction
elicited by MDMA (3, 4-methylenedioxymethamphetamine,“Ecstasy”) and its reversal by
clozapine. Brain Res 1014: 34-44.
Pierce PA and Peroutka SJ (1989) Hallucinogenic drug interactions with neurotransmitter receptor
binding sites in human cortex. Psychopharmacology (Berl) 97: 118-122.
Porter R, Benwell K, Lamb H, et al. (1999) Functional characterization of agonists at recombinant
human 5HT2A, 5HT2B and 5HT2C receptors in CHOK1 cells. Br J Pharmacol 128: 13-
20.
Preller KH, Herdener M, Pokorny T, et al. (2017) The fabric of meaning and subjective effects in
LSD-induced states depend on serotonin 2A receptor activation. Curr Biol 27: 451-457.
Prkachin KM, Williams-Avery RM, Zwaal C, et al. (1999) Cardiovascular changes during induced
emotion: An application of Lang's theory of emotional imagery. J Psychosom Res 47: 255-
267.
Ramage A (2001) Central cardiovascular regulation and 5-hydroxytryptamine receptors. Brain Res
Bull 56: 425-439.
Ramage AG, Shepheard SL, Jordan D, et al. (1993) Can the 5-HT2/1c agonist DOI cause differential
sympatho-excitation in nerves supplying the heart in anaesthetized cats? J Auton Nerv Syst
42: 53-62.
Ray TS (2010) Psychedelics and the human receptorome. PLoS One 5: e9019.
Regard JB, Sato IT and Coughlin SR (2008) Anatomical profiling of G protein-coupled receptor
expression. Cell 135: 561-571.
Ruberte J, Navarro M, Carretero A, et al. (2017) Circulatory system. In Ruberte J, Carretero A and
Navarro M (eds) Morphological Mouse Phenotyping: Anatomy, Histology and Imaging.
Amsterdam: Elsevier, 269-347.
Sanders-Bush E, Burris KD and Knoth K (1988) Lysergic acid diethylamide and 2, 5-dimethoxy-4-
methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide
hydrolysis. J Pharmacol Exp Ther 246: 924-928.
Saxena PR and Villalón CM (1990) Cardiovascular effects of serotonin agonists and antagonists. J
Cardiovasc Pharmacol 15: 17-34.
Schmid Y, Enzler F, Gasser P, et al. (2015) Acute effects of lysergic acid diethylamide in healthy
subjects. Biol Psychiatry 78: 544-553.
Sloviter RS, Drust EG, Damiano BP, et al. (1980) A common mechanism for lysergic acid,
indolealkylamine and phenethylamine hallucinogens: serotonergic medication of behavioral
effects in rats. J Pharmacol Exp Ther 214: 231-238.
Strassman RJ and Qualls CR (1994) Dose-response study of N, N-dimethyltryptamine in humans: I.
Neuroendocrine, autonomic, and cardiovascular effects. Arch Gen Psychiatry 51: 85-97.
Tadepalli AS, Friedman E and Gershon S (1975) Cardiovascular actions of 2, 5-dimethoxy-4-
methylamphetamine (DOM) in the cat. Eur J Pharmacol 31: 305-312.
Terem I, Ni WW, Goubran M, et al. (2018) Revealing subvoxel motions of brain tissue using
phasebased amplified MRI (aMRI). Magn Reson Med 80: 2549-2559.
Page 16 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
16
Ullmer C, Schmuck K, Kalkman HO, et al. (1995) Expression of serotonin receptor mRNAs in blood
vessels. FEBS Lett 370: 215-221.
van‘t Ent D, Den Braber A, Rotgans E, et al. (2014) The use of fMRI to detect neural responses to
cognitive interference and planning: Evidence for a contribution of task related changes in
heart rate? J Neurosci Methods 229: 97-107.
Vollenweider FX and Kometer M (2010) The neurobiology of psychedelic drugs: implications for the
treatment of mood disorders. Nat Rev Neurosci 11: 642.
Watts SW, Morrison SF, Davis RP, et al. (2012) Serotonin and blood pressure regulation. Pharmacol
Rev 64: 359-388.
Wolbach A, Isbell H and Miner E (1962) Cross tolerance between mescaline and LSD-25 with a
comparison of the mescaline and LSD reactions. Psychopharmacology (Berl) 3: 1-14.
Yang SH and Liu R (2017) Cerebral Autoregulation. In Caplan LR, Biller J, Leary MC, et al. (eds)
Primer on Cerebrovascular Diseases. San Diego: Academic Press, 57-60.
Page 17 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
Figure 1. Effect of 25CN-NBOH (1.5 mg/kg, s.c.) on arterial distension of isoflurane-anaesthetised mice. (a)
Schematic depiction of the major carotid branches of the mouse with area of neck-arterial pulse oximetry
indicated. Infrared (IR) light from a light emitting diode (LED) is detected by an IR light detector after
passing the perfused tissue. Recordings at (b) physiological and (c) elevated pad temperature. Mean±SEM
(-fold change of baseline, μm); n = 8-14 per group. Repeated measures ANOVA comparison to saline,
*p≤.05 and **p≤.01. (d) Temperature-dependency of 25CN-NBOH’s effect on pulse distension, depicted in
1-Hz resolution. Vertical dotted lines in (b-d) indicate time of drug injection.
242x170mm (300 x 300 DPI)
Page 18 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
Figure 2. Effect of 25CN-NBOH (1.5 mg/kg, s.c.) on the heart rate of isoflurane-anaesthetised mice at (a)
physiological and (b) elevated pad temperature. Mean±SEM (-fold change of baseline bpm); n = 8-14 per
group. Repeated measures ANOVA comparison to saline, *p≤.05 and **p≤.01. (c) Temperature-dependency
of 25CN-NBOH’s effect on heart rate, depicted in 1-Hz resolution. Vertical dotted lines indicate time of drug
injection.
238x169mm (300 x 300 DPI)
Page 19 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
Figure 3. Effect of 25CN-NBOH (1.5 mg/kg, s.c.) on respiration rate of isoflurane-anaesthetised mice at (a)
physiological and (b) elevated pad temperature. Mean±SEM (-fold change of baseline brpm); n = 8-14 per
group. Repeated measures ANOVA comparison to saline, *p≤.05, **p≤.01, and (NS) p≤.1 (Trend). Vertical
dotted lines indicate time of drug injection.
235x84mm (300 x 300 DPI)
Page 20 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
Figure 4. Effect of 25CN-NBOH (1.5 mg/kg, s.c.) on blood oxygenation of isoflurane-anaesthetised mice at
(a) physiological and (b) elevated pad temperature. Mean±SEM (-fold change of baseline % oxygen
saturation); n = 8-14 per group. Repeated measures ANOVA comparison to saline, not significant. Vertical
dotted lines indicate time of drug injection.
234x82mm (300 x 300 DPI)
Page 21 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
Figure 5. Effect of 25CN-NBOH (1.5 mg/kg, s.c.) on body core temperature of isoflurane-anaesthetised mice
at (a) physiological and (b) elevated pad temperature. Mean±SEM (-fold change of baseline ˚C); n = 6-9
per group. Repeated measures ANOVA, post-hoc comparison to saline, *p≤.05. Vertical dotted lines indicate
time of drug injection.
237x85mm (300 x 300 DPI)
Page 22 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
Table 1. Effect of 25CN-NBOH (1.5 mg/kg, s.c.) on autonomic functioning of isoflurane-
anaesthetised mice at 37 ˚C pad temperature. Mean (SEM) absolute values of 20-minutes
baseline vs. 20-minutes post-injection period. N = 6-14 per group.
Saline
NBOH
37˚C
Baseline
Post-injection
Baseline
Post-injection
Pulse distention
(μm)
478 (36)
464 (38)
497 (24)
508 (25)
Heart rate
(bpm)
459 (19)
492 (24)
430 (17)
511 (15)
Respiration rate
(brpm)
69 (6)
63 (7)
76 (5)
59 (15)
Oxygenation (%)
99 (0.1)
99 (0.1)
99 (0.1)
99 (0.1)
Temperature
(˚C)
37 (0.2)
37 (0.2)
37 (0.2)
37 (0.2)
Page 23 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For Peer Review
Table 2. Effect of 25CN-NBOH (1.5 mg/kg, s.c.) on autonomic functioning of isoflurane-
anaesthetised mice at 41 ˚C pad temperature. Mean (SEM) absolute values of 20-minutes
baseline vs. 20-minutes post-injection period. N = 6-14 per group.
Saline
NBOH
41˚C
Baseline
Post-injection
Baseline
Post-injection
Pulse distention
(μm)
484 (37)
468 (35)
462 (30)
517 (30)
Heart rate
(bpm)
466 (16)
509 (16)
474 (18)
523 (15)
Respiration rate
(brpm)
81 (7)
70 (7)
84 (10)
67 (8)
Oxygenation (%)
99 (0.06)
99 (0.06)
99 (0.07)
99 (0.07)
Temperature
(˚C)
37 (0.2)
37 (0.2)
37 (0.2)
38 (0.3)
Page 24 of 23
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
... In recent years medicinal chemistry explorations of the phenethylamine scaffold of mescaline has yielded agonists characterized by substantially higher degrees of 5-HT 2A R-selectivity [24,25]. We have developed series of potent 5-HT 2A R-agonists based on the N-benzylphenethylamine (NBOMe) scaffold [26] in the search for PET imaging and pharmacological tools for the receptor, which most notably have yielded the analogs N-(2-methoxybenzyl)-2,5-dimethoxy-4-bromophenylethylamine (25B-NBOMe, Cimbi- 36), and N-(2-hydroxybenzyl)-2,5dimethoxy-4-cyanophenylethyl-amine (25CN-NBOH (1), Fig. 1) [24,25]. [ 11 C]Cimbi-36 has seen use as a tool in in vivo imaging studies of 5-HT 2A R distribution and serotonin release in the primate brain [27][28][29][30]. ...
... [ 11 C]Cimbi-36 has seen use as a tool in in vivo imaging studies of 5-HT 2A R distribution and serotonin release in the primate brain [27][28][29][30]. As one of the most 5-HT 2A R-selective agonists published to date, 25CN-NBOH has been used in several recent studies of 5-HT 2A R functions in vivo [31][32][33][34][35][36]. ...
... The present study builds on the increasing interest that 5-HT 2A R activation has gained in recent years as a novel promising approach for treatment of depression and other cognitive/psychiatric disorders [15] and on the emergence of 25CN-NBOH as a frequently applied pharmacological tool for this receptor [31][32][33][34][35][36]. In this work, we have probed a structural hotspot in the 25CN-NBOH molecule in our continuous search for analogs with distinct and potentially optimized pharmacological properties as 5-HT 2A R agonists, investigated the in vivo efficacy of 25CN-NBOH and its even more 5-HT2AR-selective analog 25CN-NBMD in behavioural assays, and performed an in-depth characterization of the binding properties of [ 3 H]25CN-NBOH to recombinant and native 5-HT 2 Rs in order to qualify the radioligand as another potentially useful pharmacological tool for 5-HT 2A R studies. ...
... 5HT2 receptor influence data on body temperature in mice (Table 5) serve as evidence for absence of hyperthermic effect of 5-HT2 agonists in these animals, except the experiments of Buchborn et al. [178]. Moreover, the hypothermic effects of 5-HT2 receptor agonists were also described [174,176]. ...
... Attention should also be paid to the temperature conditions of the experiments. Thus, Buchborn et al. [178] conducted their studies on anesthetized animals placed on a heat-pad. The authors discovered the hyperthermic effect of the agonist when they raised the temperature of the heat-pad from 37 to 41 °C: after the injection of the agonist, body temperature of an animal rose by one degree compared to the injection of the solvent. ...
Article
Full-text available
The present review summarizes the data concerning the influence of serotonin (5-HT) receptors on body temperature in warm-blooded animals and on processes associated with its maintenance. This review includes the most important part of investigations from the first studies to the latest ones. The established results on the pharmacological activation of 5-HT1A, 5-HT3, 5-HT7 and 5-HT2 receptor types are discussed. Such activation of the first 3 type of receptors causes a decrease in body temperature, whereas the 5-HT2 activation causes its increase. Physiological mechanisms leading to changes in body temperature as a result of 5-HT receptors’ activation are discussed. In case of 5-HT1A receptor, they include an inhibition of shivering and non-shivering thermogenesis, as well simultaneous increase of peripheral blood flow, i.e., the processes of heat production and heat loss. The physiological processes mediated by 5-HT2 receptor are opposite to those of the 5-HT1A receptor. Mechanisms of 5-HT3 and 5-HT7 receptor participation in these processes are yet to be studied in more detail. Some facts indicating that in natural conditions, without pharmacological impact, these 5-HT receptors are important links in the system of temperature homeostasis, are also discussed.
... Serotonin also exerts chronotropic effects on the heart (Stoyek et al., 2017). Due to the undeniable effects of serotonin on cardiovascular system, studies were designed to measure the effect of each subtype of 5HT receptors on cardiovascular system (Buchborn et al., 2020). ...
Article
Sumatriptan is the first available medication from triptans family that was approved by the U.S. Food and Drug Administration for migraine attacks and cluster headaches in 1991. Most of its action is mediated by selective 5‐HT1B/1D receptor agonism. Recent investigations raised the possibility of repositioning of this drug to other indications beyond migraine, as increasing evidence suggests for an anti‐inflammatory property of sumatriptan. We performed a literature search using PubMed, Web of Science, Scopus, and Google Scholar using “inflammation AND sumatriptan” or “inflammation AND 5HT1B/D” as the keywords. Then, articles were screened for their relevance and those directly discussing the correlation between inflammation and sumatriptan or 5HT1B/D were included. Total references reviewed or inclusion/exclusion were 340 retrieved full‐text articles (n = 340), then based on critical assessment 66 of them were included in this systematic review. Our literature review indicates that at low doses, sumatriptan can reduce inflammatory markers (e.g., interleukin‐1β, tumor necrosis factor‐α, and nuclear factor‐κB), affects caspases and changes cells lifespan. Additionally, nitric oxide synthase and nitric oxide signaling seem to be regulated by this drug. It also inhibits the release of calcitonin gene‐related peptide. Sumatriptan protects against many inflammatory conditions including cardiac and mesenteric ischemia/reperfusion, skin flap, pruritus, peripheral, and central nervous system injuries such as spinal cord injury, testicular torsion‐detorsion, oral mucositis, and other experimental models. Considering the safety and potency of low dose sumatriptan compared to corticosteroids and other immunosuppressive medications, it is worth to take advantage of sumatriptan in inflammatory conditions.
Article
The 2,5-dimethoxyphenethylamine (2, 5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the seroto-nin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as mesca-line, TMA-2, DOM, DOI, DOB, 2C-B and 2C-I, and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized and their pharmacological profiles evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of Head Twitch Response in mice. Elimination of either the 2- or 5-methoxy leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pro-nounced upon removal of the 5-methoxy. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the compounds ability to induce the Head Twitch Response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.
Thesis
Full-text available
Serotonin (5‐HT) is an important neurotransmitter that is responsible for the regulation of a number of behavioral effects such as mood, appetite and sleep. Abnormalities in the serotonin system are associated with a broad range of disorders in the central nervous system (CNS) such as schizophrenia, depression, anxiety and migraine. The 5‐HT2A receptor is the primary excitatory 5‐HT receptor in the human brain and mediates the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD) and is the target of atypical antipsychotics. Positron emission tomography (PET) is a powerful technique to study receptors in the living brain and is widely used for investigating 5‐HT receptors in both human and animal studies. Currently, only antagonist PET tracers are in use for the 5‐HT2A receptor. Agonist PET tracers could selectively label 5‐HT2A receptors in the high‐affinity state and thereby serve as a better functional measure of 5‐HT2A receptor function. Furthermore, agonist PET tracers are potentially more sensitive to changes in endogenous neurotransmitter levels than antagonist tracers. The aims of this project were: 1) To design and synthesize new 5‐HT2A agonists with the aim to increase affinity and selectivity for 5‐HT2A receptor. 2) To synthesize, radiolabel and evaluate a number of 5‐HT2A agonists for use as PET tracers. These were based on some known 5‐HT2A agonists from the literature as well as newly designed compounds. We synthesized four groups of compounds derived from the N‐benzylphenethylamine scaffold. Group 1, 2 and 4 compounds were synthesized by a general strategy comprising reductive amination of the appropriate phenethylamine and benzaldehyde building blocks. The more complicated Group 3 compounds were synthesized by a variety of methods. Group 1 compounds focused on the 4‐position of the phenethylamine‐moiety with minor variations in the N‐benzyl moiety. We found that most compounds had high affinity for the 5‐HT2A, 5‐HT2B and 5‐HT2C receptors. Compounds containing a cyano‐group in the 4‐position showed high selectivity towards the 5‐HT2A receptor, a property that has previously been elusive. Group 2 compounds were designed with the aim to further investigate the 2’‐ and 3´‐ position of the N‐benzyl moiety and many of these were designed as benzo‐fused heterocycles. When necessary, the required aldehydes were synthesized de novo. The preliminary biological screening showed a mix of good and passable compounds. Some of these compounds have the highest affinity for the 5‐HT2A receptor when compared to known compounds from the literature. Group 3‐compounds were designed as conformationally restricted analogues of the known agonists 25B‐NBOMe and 25B‐NB. Most of the compounds had significantly lower binding affinity at the 5‐HT2A when compared to group 2 or 3 compounds, but the study gave valuable information on the binding conformation of N‐benzylphenethylamines. One compound (4.7) showed good selectivity for the 5‐HT2A receptor as well as high affinity. IV Group 4 compounds were designed using a homology model of the 5‐HT2A receptor made using a template from an in silico‐activated model of the human β2‐adrenergic receptor. The predicted compounds were synthesized and submitted for biological evaluation. The results obtained so far, however, show that the predicted affinity does not correlate well with the experimental results, necessitating further refinement of the model. A total of nine compounds were selected for in vivo evaluation as PET‐tracers in pigs. 6.1 ([11C]‐CIMBI‐5) was able to label 5‐HT2A receptors in the brain and the cortical binding of 6.1 was blocked by treatment with the antagonist ketanserin. 6.1 had a non‐displaceable binding potential (BPND) in the pig brain comparable to [18F]‐altanserin. Using 6.1 as the lead compound, eight other compounds as well as the 6.1 isotopomer 6.2, were synthesized and tested. Compound 6.7 ([11C]‐CIMBI‐36) showed both better brain uptake and higher targetto‐ background ratio than 6.1. The cortical BPND of 6.7 was decreased by ketanserin, indicating high selectivity for 5‐HT2A receptors.
Article
Full-text available
Purpose Amplified magnetic resonance imaging (aMRI) was recently introduced as a new brain motion detection and visualization method. The original aMRI approach used a video‐processing algorithm, Eulerian video magnification (EVM), to amplify cardio‐ballistic motion in retrospectively cardiac‐gated MRI data. Here, we strive to improve aMRI by incorporating a phase‐based motion amplification algorithm. Methods Phase‐based aMRI was developed and tested for correct implementation and ability to amplify sub‐voxel motions using digital phantom simulations. The image quality of phase‐based aMRI was compared with EVM‐based aMRI in healthy volunteers at 3T, and its amplified motion characteristics were compared with phase‐contrast MRI. Data were also acquired on a patient with Chiari I malformation, and qualitative displacement maps were produced using free form deformation (FFD) of the aMRI output. Results Phantom simulations showed that phase‐based aMRI has a linear dependence of amplified displacement on true displacement. Amplification was independent of temporal frequency, varying phantom intensity, Rician noise, and partial volume effect. Phase‐based aMRI supported larger amplification factors than EVM‐based aMRI and was less sensitive to noise and artifacts. Abnormal biomechanics were seen on FFD maps of the Chiari I malformation patient. Conclusion Phase‐based aMRI might be used in the future for quantitative analysis of minute changes in brain motion and may reveal subtle physiological variations of the brain as a result of pathology using processing of the fundamental harmonic or by selectively varying temporal harmonics. Preliminary data shows the potential of phase‐based aMRI to qualitatively assess abnormal biomechanics in Chiari I malformation.
Article
Full-text available
LSD is an ambiguous substance, said to mimic psychosis and to improve mental health in people suffering from anxiety and depression. Little is known about the neuronal correlates of altered states of consciousness induced by this substance. Limited previous studies indicated profound changes in functional connectivity of resting state networks after the administration of LSD. The current investigation attempts to replicate and extend those findings in an independent sample. In a double-blind, randomized, cross-over study, 100 μg LSD and placebo were orally administered to 20 healthy participants. Resting state brain activity was assessed by functional magnetic resonance imaging. Within-network and between-network connectivity measures of ten established resting state networks were compared between drug conditions. Complementary analysis were conducted using resting state networks as sources in seed-to-voxel analyses. Acute LSD administration significantly decreased functional connectivity within visual, sensorimotor and auditory networks and the default mode network. While between-network connectivity was widely increased and all investigated networks were affected to some extent, seed-to-voxel analyses consistently indicated increased connectivity between networks and subcortical (thalamus, striatum) and cortical (precuneus, anterior cingulate cortex) hub structures. These latter observations are consistent with findings on the importance of hubs in psychopathological states, especially in psychosis, and could underlay therapeutic effects of hallucinogens as proposed by a recent model.
Article
Full-text available
The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion. 25CN-NBOH evoked HTRs with an inverted u-shape-like dose-response curve and highest efficacy at 1.5 mg/kg, i.p. HTR occurrence peaked within 5 min after agonist injection, and exponentially decreased to half-maximal frequency at ~11 min. Thorough habituation to the experimental procedures (including handling, saline injection, and exposure to the observational boxes 1 day before the experiment) facilitated the animals' response to 25CN-NBOH. 25CN-NBOH (1.5 mg/kg, i.p.) induced HTRs were blocked by the 5-HT2A antagonist ketanserin (0.75 mg/kg, 30 min pre), but not by the 5-HT2C antagonist SB-242084 (0.5 mg/kg, i.p., 30 min pre). SB-242084 instead slightly increased the number of HTRs occurring at a 3.0-mg/kg dose of the agonist. Apart from HTR induction, 25CN-NBOH also modestly increased locomotor activity of the mice. Repeated once-per-day injections (1.5 mg/kg, i.p.) led to reduced occurrence of 25CN-NBOH induced HTRs. This intermediate tolerance was augmented when a second (higher) dose of the drug (3.0 mg/kg) was interspersed. Short-interval tolerance (i.e., tachyphylaxis) was observed when the drug was injected twice at intervals of 1.0 and 1.5 h at either dose tested (1.5 mg/kg and 0.75 mg/kg, respectively). Inducing ketanserin-sensitive HTRs, which are dependent on environmental valences and which show signs of tachyphylaxis and tolerance, 25CN-NBOH shares striking features common to serotonergic hallucinogens. Given its distinct in vitro selectivity for 5-HT2A over non5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity.
Chapter
Full-text available
Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or μ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.
Article
Full-text available
RationaleAccumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming. Objectives This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects. Methods Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire. ResultsLSD, compared with placebo, significantly increased cognitive bizarreness (p < 0.001). The LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control (p < 0.05). Both LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin. ConclusionsLSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.
Chapter
Abstract The effects of hallucinogenic drugs on the human brain have been studied since the earliest days of neuroimaging in the 1990s. However, approaches are often hard to compare and results are heterogeneous. In this chapter, we summarize studies investigating the effects of hallucinogens on the resting brain, with a special emphasis on replicability and limitations. In previous studies, similarities were observed between psilocybin, LSD, and ayahuasca, with respect to decreases in cerebral blood flow and increases in global functional connectivity in the precuneus and thalamus. Additionally, LSD consistently decreased functional connectivity within distinct resting state networks. Little convergence was observed for connectivity between networks and for blood flow in other brain regions. Although these studies are limited by small sample sizes and might be biased by unspecific drug effects on physiological parameters and the vascular system, current results indicate that neuroimaging could be a useful tool to elucidate the neuronal correlates of hallucinogenic effects.
Chapter
The serotonin receptor 5-HT2A is widely expressed throughout the central nervous system. While abundant evidence exits implicating 5-HT2A receptors in regulating central nervous system, in particular stress responses and that their expression levels or signaling can contribute to stress-related disorders such as anxiety, depression and aggression; the 5-HT2A receptors is also gaining importance in regulating the activity of the autonomic nervous system. Elucidating the functional specificity and significance of the 5HT2A receptor in autonomic function is a challenge given the existence and often co-localization of other 5HT2 receptor subtypes, the central and peripheral expression pattern of the 5HT2A receptor, and the relative poor selectivity of the pharmacological agents used to identify their function. Data has long been accumulated indicating that the 5-HT2A receptor-induced regulation of the autonomic nervous system function appears to be mediated, at least in part, through the regulation of the serotoninergic afferents and efferents to the nucleus tractus solitarius. In this article, we review the role of 5-HT2A receptor function in the modulation of cardiac sympathovagal balance with special emphasis on the networks by which 5-HT2A receptors modulate the function of the nucleus tractus solitarius in regulating the baroreflex and autonomic function.
Article
Psilocybin, the active compound in psychedelic mushrooms, is an agonist of various serotonin receptors. Seminal psilocybin positron emission tomography (PET) research suggested regional increases in glucose metabolism in frontal cortex (hyperfrontality). However, a recent arterial spin labeling (ASL) study suggests psilocybin may lead to hypo-perfusion in various brain regions. In this placebo-controlled, double-blind study we used pseudo-continuous ASL (pCASL) to measure perfusion changes, with and without adjustment for global brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose: 0.215 mg/kg) in two groups of healthy controls (n = 29 in both groups, total N = 58) during rest. For all neuroimaging analyses we controlled for sex and age and used family-wise error corrected p values. Both dose groups reported profound subjective drug effects as measured by the Altered States of Consciousness Rating Scale (5D-ASC) with the high dose inducing significantly larger effects in four out of the 11 scales. After adjusting for global brain perfusion, psilocybin increased relative perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Whereas, psilocybin significantly reduced absolute perfusion in frontal, temporal, parietal, and occipital lobes, and bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampus. Our analyses demonstrate consistency with both the hyperfrontal hypothesis of psilocybin and the more recent study demonstrating decreased perfusion, depending on analysis method. Importantly, our data illustrate that relative changes in perfusion should be understood and interpreted in relation to absolute signal variations.