ArticlePDF Available

Abstract and Figures

A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.
Content may be subject to copyright.
For Peer Review
Repeated lysergic acid diethylamide (LSD) in an a
nimal
model of depression: Normalisation of learning behaviour
and hippocampal 5-HT
2
signalling
Journal:
Journal of Psychopharmacology
Manuscript ID:
JOP-2013-2161.R1
Manuscript Type:
Original Paper
Date Submitted by the Author:
09-Feb-2014
Complete List of Authors:
Buchborn, Tobias; Otto-von-Guericke University, Institute of Pharmacology
and Toxicology
Schröder, Helmut; Otto-von-Guericke University, Institute of Pharmacology
and Toxicology
Höllt, Volker; Otto-von-Guericke University, Institute of Pharmacology and
Toxicology
Grecksch, Gisela; Otto-von-Guericke University, Institute of Pharmacology
and Toxicology
Please list at least 3 keywords
which relate to your
manuscript::
Serotonergic hallucinogen, 5-HT2A receptor, Animal model of depression,
LSD, Hippocampus
Abstract:
A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an
increase in 5-HT
1A
and a decrease in 5-HT
2(A)
signalling, is a final common
pathway multiple antidepressants share. Given that the 5-HT
1A/2A
agonist
lysergic acid diethylamide (LSD), when repeatedly applied, selectively
downregulates 5-HT
2(A)
, but not 5-HT
1A
receptors, one might expect LSD to
similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea,
we use an animal model of depression specifically responding to repeated
antidepressant treatment (olfactory bulbectomy), and test the
antidepressant-like properties of repeated LSD (0.13 mg/kg/d, 11d). In
line with former findings, we observe that bulbectomised rats show marked
deficits in active avoidance learning. These deficits, similar as we earlier
noted with imipramine, are largely reversed by repeated LSD. Additionally,
bulbectomised rats exhibit distinct anomalies of monoamine receptor
signalling in hippocampus and/or frontal cortex; from these, only the
hippocampal decrease in 5-HT
2
related [
35
S]-GTP-gamma-S binding is
normalised by LSD. Importantly, the sham-operated rats do not profit from
LSD, and exhibit reduced hippocampal 5-HT
2
signalling. As behavioural
deficits after bulbectomy respond to agents classified as antidepressants
only, we conclude that LSD’s effect in this model can be considered
antidepressant-like, and discuss it in terms of a re-balance of hippocampal
5-HT
2
/5-HT
1A
signalling.
http://mc.manuscriptcentral.com/jop
Journal of Psychopharmacology
For Peer Review
Page 1 of 26
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
Repeated LSD in an animal model of depression
Abstract
A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT
1A
and a
decrease in 5-HT
2(A)
signalling, is a final common pathway multiple antidepressants share. Given that the
5-HT
1A/2A
agonist
lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates
5-HT
2(A)
, but not 5-HT
1A
receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT
signalling. Challenging this idea, we use an animal model of depression specifically responding to
repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of
repeated LSD treatment (0.13 mg/kg/d, 11d). In line with former findings, we observe that bulbectomised
rats show marked deficits in active avoidance learning. These deficits, similar as we earlier noted with
imipramine, are largely reversed by repeated LSD. Additionally, bulbectomised rats exhibit distinct
anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the
hippocampal decrease in 5-HT
2
related [
35
S]-GTP-gamma-S binding is normalised by LSD. Importantly,
the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT
2
signalling. As
behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude
that LSD’s effect in this model can be considered antidepressant-like, and discuss it in terms of a re-
balance of hippocampal 5-HT
2
/5-HT
1A
signalling.
Keywords
Serotonergic hallucinogen, LSD, 5-HT
2(A)
receptor, antidepressant, animal model, olfactory bulbectomy,
avoidance learning, hippocampus
Page 2 of 26
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
Repeated LSD in an animal model of depression
Introduction
Lysergic acid diethylamide (LSD) is a serotonergic hallucinogen known to induce profound alterations of
the human consciousness (Hintzen and Passie, 2010). When abused in an unsupervised context,
hallucinogens can have detrimental effects to the individual (Cohen, 1960; Strassman, 1984), when used
in a controlled environment, however, they might be of medical value (Winkelman and Roberts, 2007; De
Lima Osório et al., 2011; Grob et al., 2011). Although early and extensively recognised for their ability to
facilitate certain strategies of psychotherapy (Unger, 1964; Passie, 1997), notably in the context of
anxiety neuroses and/or depressive reactions (Mascher, 1967; Savage et al., 1973), the therapeutic
potential of serotonergic hallucinogens has hardly been considered pharmacologically, i.e. in terms of
their mere receptor profile (Riedlinger and Riedlinger, 1994; Montagne, 2007; Vollenweider and
Kometer, 2010). Sharing the indolethylamine moiety of the serotonin molecule (Kang and Green, 1970),
LSD is a suitable ligand for a variety of monoaminergic, notably serotonergic (5-HT) receptors; with low-
nanomolar affinity, for instance, it binds to 5-HT
1A
and 5-HT
2A
receptors (Roth et al., 2002). Both
receptor subtypes regulate a variety of functions critically involved in the pathogenesis of depression; the
pyramidal integration of excitatory input to the prefrontal cortex (PFC) (Araneda and Andrade, 1991), the
hypothalamic-pituitary-adrenal axis (Zhang et al., 2002; Osei-Owusu et al., 2005), as well as the
hippocampal neurogenesis and/or cell proliferation (Banasr et al., 2004). In accordance with their
functional relevance, long-term treatment with diverse-class antidepressants has been shown to
downregulate 5-HT
2A
receptors in the frontal cortex, and to increase the responsiveness of hippocampal 5-
HT
1A
receptors in a time frame consistent with their delayed therapeutic onset (Haddjeri et al., 1998; Gray
and Roth, 2001; Szabo and Blier, 2001). As repeated LSD, acting as an agonist at both receptor subtypes,
also downregulates 5-HT
2A
, but not 5-HT
1A
receptors (in areas, such as the frontal cortex or the
hippocampus) (Buckholtz et al., 1985, 1990; Gresch et al., 2005), one might expect it to re-balance the
postsynaptic 5-HT signalling in a way similar to antidepressants. And indeed, given that cross-tolerance
Page 3 of 26
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
Repeated LSD in an animal model of depression
between hallucinogens and antidepressant-class drugs develops (Lucki and Frazer, 1982; Goodwin et al.,
1984; Bonson et al., 1996), a mechanistic overlap seems plausible. Challenging this idea of a mechanistic
overlap, we here evaluate whether LSD exerts antidepressant-like effects within an established animal
model of depression. In the forced swim test, an animal model that responds to one-time antidepressant
application, LSD fails (Gorka et al., 1979). Thus, in line with our assumption that 5-HT
2(A)
regulation
(which requires a repeated LSD regimen) (Buckholtz et al., 1985, 1990) is important for an
antidepressant-like effect to occur, an animal model responding to repeated antidepressant treatment
might be of more validity. From the few animal models, which meet such a criterion, we here decide for
the olfactory bulbectomy because it is the only one considered highly reliable and specific (Jesberger and
Richardson, 1985; Cryan et al., 2002). Following the bilateral dissection of the olfactory bulbs, rodents
show a variety of behavioural disturbances, such as stress-associated hyperlocomotion or avoidance
learning deficits, which reliably ameliorate in response to the (sub-)chronic, but not acute application of
drugs specified as antidepressants (Kelly et al., 1997; Song and Leonard, 2005). The bulbectomy induced
hyperlocomotion is considered to be of dopaminergic origin (Masini et al., 2004) and might model
symptoms of the agitated depression. Avoidance learning deficits, on the other hand, involve the
serotonin system (Cairncross et al., 1979; Garrigou et al., 1981; Ögren 1986) and appear to have more
general implications for the human situation. According to the cognitive theory, depression primarily
arises from biases in cognitive processing, including attention and memory, which as a consequence
corrupt emotional integrity (e.g. Mathews and MacLeod, 2004). As (serotonergic) antidepressants are
thought to act on these biases, rather than on mood itself (Harmer, 2008; Harmer et al., 2009), avoidance
learning deficits of bulbectomised rats seem to be an optimal proxy for depressive-like cognition biases
and their responsiveness to serotonin related action of antidepressant-class drugs.
Thus, for evaluating the antidepressant-like action of LSD, we here repeatedly apply the hallucinogen to
bulbectomised rats and investigate its effect on avoidance learning and forebrain 5-HT
1A
/5-HT
2
Page 4 of 26
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
Repeated LSD in an animal model of depression
signalling. As LSD, despite having high affinity, is not selective for 5-HT
1A
and 5-HT
2(A)
receptors (Roth
et al., 2002), we additionally investigate its effect on beta, overall 5-HT, dopamine and noradrenaline
signalling. Methodologically, we use the conditioned pole-jumping paradigm and radioligand binding
techniques, respectively.
Methods and Materials
Animals and housing
For experiments, male Wistar rats 400 g) (HsdCpb:WU; Harlan Winkelmann, Germany) were used.
The animals were housed in groups of five each cage, and held under controlled laboratory conditions
(temperature 20 ± 2 °C, air humidity 55-60%, light/dark cycle 12:12 [light on at 6 a.m.]) with standard
food pellets (TEKLAD Global Diet, Harlan-Teklad, UK) and tap water ad libitum. All experiments
conducted comply with the regulations of the National Act on the Use of Experimental Animals
(Germany), as approved by the Tierschutzkommission Sachsen-Anhalt.
Bilateral olfactory bulbectomy
At the age of seven weeks, rats were bulbectomised as described by Grecksch et al. (1997). In brief,
animals were anaesthetised with pentobarbital (40 mg/kg i.p. [10 ml/kg injection volume]) and fixed in a
stereotactic instrument. The scalp was incised at the midline, and two holes (Ø 2 mm) were drilled into
the skull (one above each olfactory bulb [6.5 mm anterior to bregma, 2 mm lateral to midline]). The bulbs
were cut and gently removed by aspiration. The resulting cavities were filled with haemostatic sponges
(Gelitaspon®, Gelita Medical, The Netherlands), and the skin was closed by tissue adhesive
(Histoacryl®, Braun Aesculap AG, Germany). Extent and adequacy of the surgical ablation were assessed
after decapitation at end of the behavioural experiments. Sham-operated rats were treated alike (including
piercing of dura mater), except that their bulbs were not removed.
Page 5 of 26
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
Repeated LSD in an animal model of depression
Behavioural experiments
Treatment.
Lysergide[(R,R)-tartrate]-anhydrate (THC Pharm, Germany) was applied for a period of 11
days, once every 24 hours (0.13 mg/kg, s.c., dissolved in isotonic saline, 10 ml/kg). Treatment started five
days before the behavioural experiments, and continued till 24 hours before decapitation. The dose
chosen was extrapolated from literature as adequate for activation of 5-HT
2A
receptors (as indexed by the
occurrence of wet dog shakes) (Bedard and Pycock, 1977). The five days beforehand regimen was chosen
so to allow 5-HT
2A
(down-)regulation to precede the behavioural experiments (Buckholtz et al., 1990). To
avoid interference from LSD’s acute effects (Taeschler et al., 1960; Schmidt, 1963; Domino et al., 1965;
Bignami, 1972), administration was performed two hours after each test session (Castellano, 1979).
Control animals received saline injections without LSD.
Assignment of rats to conditions (sham/saline vs. sham/LSD; bulb/saline vs. bulb/LSD) occurred in a
randomised fashion.
One-way active avoidance learning (pole-jumping test).
Eight weeks after surgery, on the
sixth day of subchronic treatment, pole-jumping experiments set in. On five days in a row, within ten
trials each day, rats had to learn to actively avoid electrical foot stimuli (unconditioned stimulus [US]) by
jumping onto a pole. Every trial started with a sound from a buzzer (80 dB) (conditioned stimulus [CS]),
which –from second four on– was accompanied by the electrical foot stimulation (delivered through
stainless steel rods of the test apparatus’ floor, and adjusted to the rat’s individual pain sensitivity [0.2-0.4
mA]). A trial was restricted to 20 seconds, but stopped earlier when a rat successfully jumped onto the
pole. CS and US overlapped and were co-terminated. The intertrial-interval was stochastically varied (30-
90 s). All five sessions were performed at about the same time during the light period. On the first day,
rats were allowed five minutes for exploration of the test apparatus, on the following days only one
Page 6 of 26
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
Repeated LSD in an animal model of depression
minute was granted. For evaluation of learning, the number of successful escapes (instrumental reactions,
≤ 20 s) and avoidances (conditioned reactions, ≤ 4 s) was recorded.
Neurochemical experiments
5-HT
2A
receptor binding.
Twenty-four hours after the last treatment, rats were decapitated, brain
regions of interest (frontal cortices and hippocampi) were removed and frozen in liquid nitrogen. For
measuring ketanserin-sensitive [
3
H]spiroperidol binding to 5-HT
2A
receptors, thawed tissue was
homogenised. Cell membranes were pelleted by centrifugation (10 min, 50,000 x g, 4 °C), washed in Tris
buffer (pH 8.0), and resuspended in incubation buffer (50 mM Tris-HCI, containing 120 mM NaCl, 5 mM
KCl, 2.5 mM CaCl
2
, 1 mM MgCl
2
, and 50 nM d-butaclamol [D
2
receptor mask] [Sigma-Aldrich,
Germany], pH 8.0). Aliquots of the crude membrane suspension (150-250 µg protein) were incubated for
30 minutes at 37 °C with [
3
H]spiroperidol (specific activity: 800 GBq/mM [Perkin-Elmer, USA]). The
membrane fraction was then collected on GF/A glass-fibre filters, washed with buffer (50 mM Tris-HCl,
pH 8.0), and a taken for liquid scintillation counting in a toluene containing scintillation cocktail. Specific
binding was calculated by subtracting non-specific binding (as seen in presence of 0.25 nM
[
3
H]spiroperidol and 1 µM unlabelled ketanserin [Sigma-Aldrich, Germany]) from total binding (obtained
with 0.25 nM [
3
H]spiroperidol alone), and expressed in fmol per mg of protein (as determined by Lowry
Method).
[
35
S]-GTP-gamma-S binding.
For measuring G-protein coupling by 5-HT
(1A/2)
, dopamine, and (beta)
adrenergic receptors, tissue was homogenised in Tris buffer (50 mM Tris-HCl, 1 mM EGTA, 10 mM
EDTA, pH 7.4) and pelleted by centrifugation. After resuspension in assay buffer (50 mM Tris-HCl, 3
mM MgCl
2
, 0.2 mM EGTA, 100 mM NaCl, pH 7.4), aliquots containing 15-20 µg protein were incubated
with 3 µM GDP and 0.05 nM [
35
S]-GTP-gamma-S (specific activity: 46.3 TBq/mM [Perkin-Elmer,
Page 7 of 26
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
Repeated LSD in an animal model of depression
USA]) in presence and absence of the relevant agonist (1h, 30 °C) (10 µM alpha-methylserotonin [alpha-
MS for 5-HT
2
], 100 µM 8-hydroxy-2-[di-n-propylamino] tetralin [8-OH-DPAT for 5-HT
1A
], 100 µM
isoprenaline [for beta], 10 µM serotonin, 100 µM dopamine, and 10 µM noradrenaline [Sigma-Aldrich,
Germany]). Incubation was terminated by rapid filtration, filters were rinsed in washing buffer (50 mM
Tris-HCl, 3 mM MgCl
2
, 1 mM EGTA, pH 7.4), and taken for liquid scintillation counting of bound
radioactivity. Total [
35
S]-GTP-gamma-S binding was corrected for unspecific binding (in presence of 10
µM unlabelled GTP-gamma-S), and expressed as E
max
, percent stimulation over basal specific binding.
All determinations were performed at least in duplicate.
Statistical analysis
A two-factor ANOVA with repeated measures on one factor (mixed model) was conducted to assess main
effects and interaction of time and group in avoidance learning, and followed by pairwise contrast
analysis. Intergroup differences in specifically bound radioactivity were analysed using nonparametric
Mann-Whitney U-tests (a-priori planned comparisons). Calculations were carried out by SPSS and
GraphPad Prism software. Statistical significance was assumed if the null hypothesis could be rejected at
.05 probability level.
Results
Behavioural experiments
The omnibus F-test revealed significant main effects for both factors, time (F
[4, 124]
= 69.04, p =.000
[conditioned]; F
[4, 124]
= 43.22, p =.000 [instrumental]) and group (F
[3, 31]
= 6.39, p = .002 [conditioned];
F
[3, 31]
= 2.93, p = .049 [instrumental]), and a significant time x group interaction for conditioned reactions
(F
[12, 124]
= 2.62, p = .004). Results were further probed by pairwise comparison with a-priori specified
contrasts. As can be seen in Figure 1, sham-operated rats showed good progress in learning instrumental
Page 8 of 26
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
Repeated LSD in an animal model of depression
and conditioned avoidance behaviour. Irrespective of treatment, they rapidly learnt to avoid and/or to
escape from the aversive foot stimuli (sham/saline vs. sham/LSD: F
[1, 17]
= .08, p = .78 [conditioned]; F
[1,
17]
= .963, p = .34 [instrumental]). Saline treated bulbectomised rats failed to achieve the level of
performance shown by the sham-operated controls; the acquisition of both, the conditioned and
instrumental reactions, was disturbed (sham/saline vs. bulb/saline: F
[1, 14]
= 13.15, p = .003 [conditioned];
F
[1, 14]
= 4.85, p = .045 [instrumental]). The repeated administration of LSD, however, led to a
normalisation of conditioned avoidance learning: LSD treated bulbectomised rats caught up with the
sham-operated controls (sham/saline vs. bulb/LSD: F
[1, 16]
= 2.16, p = .16), and significantly differed from
their saline treated counterparts (bulb/saline vs. bulb/LSD: F
[4, 56]
= 2.6, p = .045) (Figure 1 [a]). As to the
instrumental reactions, LSD treated bulbectomised rats did not significantly differ from the sham-
operated controls (sham/saline vs. bulb/LSD: F
[1, 16]
= .813, p = .38), the difference from the saline treated
bulbectomised animals, however, failed to achieve statistical significance (see Figure 1 [b]) (bulb/saline
vs. bulb/LSD: F
[4, 56]
= .766, p = .55).
[Figure 1 near here]
Neurochemical experiments
5-HT
2A
receptor binding.
As shown in Figure 2, bulbectomy slightly increased the ketanserin-
sensitive [
3
H]spiroperidol binding in hippocampus. This trend of increase (sham/saline vs. bulb/saline: u
= 4, p = .095) was partially counteracted by the repeated LSD treatment. Although the difference between
LSD and saline treated bulbectomised rats fell short of significance (bulb/saline vs. bulb/LSD: u = 6, p =
.063), the difference between LSD treated bulbectomised rats and saline treated, sham-operated controls
was not significant either (sham/saline vs. bulb/LSD: u = 11, p = .46). As opposed to its decreasing effect
in bulbectomised rats, repeated LSD treatment did not affect the hippocampal [
3
H]spiroperidol/ketanserin
Page 9 of 26
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
Repeated LSD in an animal model of depression
binding of the sham-operated animals (sham/saline vs. sham/LSD: u = 11, p = .46). In the frontal cortex,
bulbectomy had no significant effect on the ketanserin-sensitive [
3
H]spiroperidol binding (sham/saline vs.
bulb/saline: u = 9, p = .27); LSD, however, induced a significant increase (sham/saline vs. sham/LSD: u =
0, p = .002) (Figure 2).
[Figure 2 near here]
[
35
S]-GTP-gamma-S binding.
In the hippocampus, bulbectomy led to a significant reduction in
alpha-MS stimulated guanine nucleotide exchange (sham/saline vs. bulb/saline: u = 5, p = .041) which
was reversed by subchronic LSD (bulb/saline vs. bulb/LSD: u = 6, p = .032) (Figure 3). In contrast to its
resensitising effect in bulbectomised rats, LSD caused a desensitisation of alpha-MS stimulated [
35
S]-
GTP-gamma-S binding in the hippocampus of the sham-operated animals (sham/saline vs. sham/LSD: u
= 3, p = .0015). Other significant effects and/or trends of bulbectomy, such as the hippocampal decrease
in isoprenaline and noradrenaline stimulated receptor signalling (sham/saline vs. bulb/saline: u = 0, p =
.004; u = 2, p = .057), or the fronto-cortical increase in alpha-MS, 8-OH-DPAT, and isoprenaline induced
[
35
S]-GTP-gamma-S binding (sham/saline vs. bulb/saline: u = 4, p = .026; u = 2, p = .016; u = 1, p = .036)
were not reversed by LSD (Figure 3 and 4). The hippocampal signalling stimulated by 8-OH-DPAT,
serotonin, and dopamine was neither influenced by bulbectomy (sham/saline vs. bulb/saline: u = 15, u =
18, and u = 8, respectively, n. s.), nor by its interaction with repeated LSD (bulb/saline vs. bulb/LSD: u =
14.5, u = 15.5, and u = 16, n. s.) (Figure 3). Finally, in the frontal cortex of the sham-operated animals,
LSD led to a sensitisation of all receptors investigated, including 5-HT
2
(sham/saline vs. sham/LSD: u =
3.5, p = .022) (Figure 4).
[Figure 3 near here] [Figure 4 near here]
Page 10 of 26
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
Repeated LSD in an animal model of depression
Discussion
Exploratory evidence suggests that serotonergic hallucinogens –when psychotherapeutically embedded–
might be assistant to the treatment of neurotic-type depression (Mascher, 1967; Savage et al., 1973), or
emotional distress associated with advanced stages of cancer (Kurland et al., 1973; Grob et al., 2011). As
their acute effects on affection are highly fluctuant and critically dependent on the pre-existing mood,
though (Metzner et al., 1963; Katz et al., 1968), hallucinogens should not be (mis-)conceptualised as
acute mood-enhancers or antidepressants in a literal sense. Instead, they might rather be seen as a tool for
psychotherapy to facilitate access to emotion-salient cognitions (e.g. memory) and work on the inherent
biases that negatively prime the patient’s affective mindset (compare Kurland et al., 1973; Harmer, 2008;
Carhart-Harris et al., 2012). Here, we refer to the idea that hallucinogens –similar as hypothesised
relevant for repeated antidepressant treatment (Gray and Roth, 2001; Harmer, 2008; Savitz et al., 2009)–
might affect mood-relevant cognitive biases by regulation of 5-HT
1A/2(A)
receptors. We repeatedly apply
LSD to bulbectomised rats, and test its effect on depressive-like avoidance learning deficits and forebrain
5-HT
1A/2
signalling. In keeping with former findings (Marks et al., 1971; Thomas, 1973; Cairncross et al.,
1979; Gebhardt et al., 2013), we confirm that bulbectomised rats are deficient in active avoidance
learning. Similar as we earlier noted with imipramine under comparable experimental conditions
(Grecksch et al., 1997), or as noted by other labs with amitriptyline or trazodone (Cairncross et al., 1973;
Otmakhova et al., 1992), repeated LSD treatment –in dosing known to induce 5-HT
2A
related wet dog
shakes (Bedard and Pycock, 1977)– largely reverses this deficiency. As the avoidance learning deficits
after bulbectomy are reversible by drugs classified as antidepressant only (Kelly et al., 1997), we infer
that LSD’s behavioural effect in this model can be considered antidepressant-like. Our inference is
strengthened by the fact that LSD specifically helps bulbectomised, but not sham-operated rats.
In addition, we show that bulbectomised rats exhibit various anomalies of monoamine receptor signalling,
with 5-HT
1A
, 5-HT
2
and beta signalling being sensitised in the frontal cortex, and the latter two being
Page 11 of 26
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
Repeated LSD in an animal model of depression
desensitised in the hippocampus. From the given anomalies, the desensitisation of hippocampal 5-HT
2
signalling, as indicated by a decrease in alpha-MS stimulated [
35
S]-GTP-gamma-S binding, is the only to
be normalised by subchronic LSD. Despite alpha-MS being a mixed 5-HT
1/2
agonist (Ismaiel et al., 1990)
rather than selective for 5-HT
2
receptors, we think 5-HT
2
receptors might be more implicated, because
neither bulbectomy nor its interaction with LSD significantly influences hippocampal 5-HT
1A
signalling.
Also, the relevance of hippocampal 5-HT
2(A)
receptors might be inferred from our finding that bulbectomy
is associated with trends for increased ketanserin-sensitive [
3
H]spiroperidol binding, and LSD to
counteract it. Although these trends should be interpreted with caution, they yet are reminiscent on former
findings about bulbectomy upregulating, and/or antidepressants downregulating hippocampal 5-HT
2
receptors (Gurevich et al., 1993; Earley et al., 1994). Hippocampal 5-HT
2(A)
anomalies might be a
consequence of the bulbectomy induced raphe degeneration (Nesterova et al., 1997), and the (associated)
reduction in local serotonin (van der Stelt et al. 2005). Remarkably, similar as seen for the avoidance
learning deficiency, LSD’s (counter-)regulatory action on 5-HT
2(A)
receptors
is specific for the
pathological condition; in sham-operated animals, it desenitises alpha-MS signalling, and leaves
ketanserin-sensitive [
3
H]spiroperidol binding unaffected.
LSD exhibits high 5-HT
1A
and
2A
affinity, but it is not selective for these receptors. In fact, it binds to a
variety of monoamine receptors (Roth et al., 2002), with beta and D
4
, for instance, complementing 5-
HT
2A
in LSD’s behavioural profile (Mittman and Geyer, 1991; Marona-Lewicka et al., 2009). As neither
bulbectomy nor its interaction with LSD, however, affects overall dopamine signalling, and LSD
normalises hippocampal 5-HT
2
, but not beta signalling, we think it is reasonable to discuss the LSD
induced normalisation of avoidance learning in terms of a re-balance of hippocampal 5-HT
2
(vs.
1A
)
signalling. Deficits in avoidance learning as well as their reversal by antidepressants have been linked to
5-HT
2(A)
receptors (Broekkamp et al. 1980; Gurevich et al. 1993; Ögren 1986), and LSD is known to
affect learning via hippocampal 5-HT
2A
regulation (Romano et al., 2010). Bulbectomy leads to deficient
Page 12 of 26
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
Repeated LSD in an animal model of depression
hippocampal neurogenesis, and to an upregulation of brain-derived neurotrophic factor (BDNF) (Jaako-
Movits and Zharkovsky, 2005; Hellweg et al., 2007). Although generally considered antidepressant-like,
too much BDNF might be detrimental and compromise avoidance learning (Croll et al., 1999). As a
model of LSD’s antidepressant-like activity one could, therefore, hypothesise that LSD (by activating 5-
HT
1A
and resensitising 5-HT
2
signalling) might re-balance the anti-BDNF effect of 5-HT
2A
against the
neurotrophic effect of 5-HT
1A
receptors (Vaidya et al., 1999; Santarelli et al., 2003). Consequently, a
more coordinated turnover of hippocampal neurons might occur, allowing the stress-integration system of
bulbectomised rats to more effectively meet the demands of avoidance learning (compare Sairanen et al.,
2005; Surget et al., 2011). This model is speculative, however, and needs further investigation. Also, to
more clearly establish the role of 5-HT
2(A)
and
1A
receptors, future research might co-apply selective
antagonists with LSD, combine a selective 5-HT
1A
with a selective 5-HT
2(A)
agonist, or use selective dual
agonists instead. As the latter seem sparse (Ray, 2010), the repeated combination of two agents will raise
pharmacokinetic problems, and 5-HT
2(A)
antagonists act antidepressant-like themselves (e.g. Otmakhova
et al., 1992), such a study might be complicated, though.
Intriguingly in the frontal cortex of the sham-operated rats, LSD significantly increases all binding
parameters investigated (including those of 5-HT
2[A]
), which in bulbectomised animals –for the most
part– cannot be found. Likewise in hippocampus, the desensitisation of 5-HT
2
and dopamine signalling
specifically occurs in the sham rats. Our results contrast with the notion that LSD selectively
downregulates 5-HT
2(A)
receptors (Buckholtz et al., 1985, 1990). Yet, possibly varying with application
scheme, strain, and/or embedding of the rats into behavioural procedures, hallucinogens might provoke a
more or less complex pattern of receptor regulation (e.g. 5-HT
1A
downregulation for psilocybin, alpha
1
upregulation for DOI, or regional 5-HT
2A
down- vs. upregulation for DOM) (Buckholtz et al., 1988,
1990; Doat-Meyerhoefer et al., 2005). The fact that LSD –despite regulating their neurochemistry– does
not affect avoidance learning of the sham rats, underlines that our application scheme was well chosen.
Page 13 of 26
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
Repeated LSD in an animal model of depression
Repeatedly applying LSD –such as noted for antidepressant-class drugs– might have counteracted the
neurochemical imbalance induced by bulbectomy (including hippocampal 5-HT
2
signalling), thus,
normalising the learning capacity (or re-shifting the cognitive bias) of the bulbectomised rats. For the
sham animals, as opposed, there had never been such an imbalance (or bias), and the only (or most likely)
way in which LSD might have affected their avoidance learning would have been by acutely interfering.
Applying LSD two hours after each learning session, however, we minimised the chance of such an
interference (compare Castellano, 1979; Frieder and Allweis, 1982). Therefore, the LSD induced changes
of the sham rats’ neurochemistry might rather be unspecific and (temporally) unrelated to the processes
involved in avoidance learning.
In summary, our data demonstrate that in bulbectomised rats, repeated LSD treatment reverses
depressive-like avoidance learning deficits, possibly engaging a re-balance of hippocampal 5-HT
2
(vs.
1A
)
signalling. Given the postulated interrelation between the reversal of mood-relevant cognitive biases and
5-HT
(2A)
receptor regulation (Harmer, 2008), our findings might have implications for the understanding
of how hallucinogens alleviate emotional distress, such as seen in advanced-stage cancer.
Acknowledgements
The professional technical assistance of Michaela Böx, Petra Dehmel, Doreen Heidemann, and Gabriele
Schulze is gratefully acknowledged.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-
profit sectors.
Conflict of Interest Statement
The authors declare that there is no conflict of interest.
Page 14 of 26
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
Repeated LSD in an animal model of depression
Reference
Araneda R, Andrade R (1991) 5-Hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate
opposing responses on membrane excitability in rat association cortex. Neuroscience 40: 399-412.
Banasr M, Hery M, Printemps R, et al. (2004) Serotonin-Induced Increases in Adult Cell Proliferation and
Neurogenesis are Mediated Through Different and Common 5-HT Receptor Subtypes in the Dentate
Gyrus and the Subventricular Zone. Neuropsychopharmacology 29: 450-460.
Bedard P, Pycock C J (1977) ‘Wet-Dog’ shake behaviour in the rat: A possible quantitative model of
central 5-hydroxytryptamine activity. Neuropharmacology 16: 663-670.
Bignami G (1972) Facilitation of avoidance acquisition by LSD-25. Psychopharmacologia 25: 146-151.
Bonson K R, Buckholtz J W, Murphy D L (1996) Chronic Administration of Serotonergic
Antidepressants Attenuates the Subjective Effects of LSD in Humans. Neuropsychopharmacology
14: 425-436.
Broekkamp C L, Garrigou D, Lloyd KG (1980) Serotonin-mimetic and antidepressant drugs on passive
avoidance learning by olfactory bulbectomised rats. Pharmacol Biochem Behav 13: 643-646.
Buckholtz N S, Freedman D X, Middaugh L D (1985) Daily LSD administration selectively decreases
serotonin2 receptor binding in rat brain. Eur J Pharmacol 109: 421-425.
Buckholtz N. S., Zhou D. F., Freedman D. X. (1988). Serotonin2 agonist administration down-regulates
rat brain serotonin2 receptors. Life Sci, 42, 2439-2445.
Buckholtz N S, Zhou D F, Freedman D X, et al. (1990) Lysergic acid diethylamide (LSD) administration
selectively downregulates serotonin2 receptors in rat brain. Neuropsychopharmacology 3: 137-148.
Cairncross K D, Cox B, Forster C, et al. (1979) Olfactory projection systems, drugs and behaviour: A
review. Psychoneuroendocrinology 4: 253-272.
Cairncross K D, Schofield S, King H G (1973) The Implication of Noradrenaline in Avoidance Learning
in the Rat. Prog Brain Res 39: 481-485.
Carhart-Harris R L, Leech R, Williams T M, et al. (2012) Implications for psychedelic-assisted
psychotherapy: functional magnetic resonance imaging study with psilocybin. Br J Psychiatry 200:
238-244.
Castellano C (1979) Effects of LSD-25 on avoidance behavior and locomotor activity in mice.
Psychopharmacology 62: 145-149.
Cohen S (1960) Lysergic Acid Diethylamide: Side Effects and Complications. J Nerv Ment Dis 130: 30-
40.
Croll S D, Suri C, Compton D L, et al. (1999) Brain-derived neurotrophic factor transgenic mice exhibit
passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the
hippocampus and entorhinal cortex. Neuroscience 93: 1491-1506.
Cryan J F, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments
and future needs. Trends Pharmacol Sci 23: 238-245.
De Lima Osório F, de Macedo L R H, de Sousa J P M, et al. (2011) The therapeutic potential of harmine
and ayahuasca in depression: Evidence from exploratory animal and human studies. In Dos Santos
RG (ed) The Ethnopharmacology of Ayahuasca. Transworld Research Network, Kerala.
Doat-Meyerhoefer M M, Hard R, Winter J C, et al. (2005) Effects of clozapine and 2,5-dimethoxy-4-
methylamphetamine [DOM] on 5-HT2A receptor expression in discrete brain areas. Pharmacol
Biochem Behav 81: 750-757.
Domino E, Caldwell D, Henke R (1965) Effects of psychoactive agents on acquisition of conditioned pole
jumping in rats. Psychopharmacologia 8: 285-289.
Earley B, Glennon M, Lally M, et al. (1994) Autoradiographic distribution of cholinergic muscarinic
receptors and serotonin2 receptors in olfactory bulbectomized (OB) rats after chronic treatment with
mianserin and desipramine. Hum Psychopharmacol 9: 397-407.
Page 15 of 26
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
Repeated LSD in an animal model of depression
Frieder B, Allweis C (1982) Memory consolidation: Further evidence for the four-phase model from the
time-courses of diethyldithiocarbamate and ethacrinic acid amnesias. Physiol Behav 29: 1071-1075.
Garrigou D, Broekkamp C L, Lloyd K G (1981) Involvement of the amygdala in the effect of
antidepressants on the passive avoidance deficit in bulbectomised rats. Psychopharmacology 74: 66-
70.
Gebhardt N, Bär K-J, Boettger M K, et al. (2013) Vagus nerve stimulation ameliorated deficits in one-
way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats.
Brain Stimulat 6: 78-83.
Goodwin G M, Green A R, Johnson P (1984) 5-HT2 receptor characteristics in frontal cortex and 5-HT2
receptor-mediated head-twitch behaviour following antidepressant treatment to mice. Br J
Pharmacol 83: 235-242.
Gorka Z, Wojtasik E, Kwiatek H, et al. (1979) Action of serotoninmimetics in the behavioral despair test
in rats. Commun Psychopharmacol 3: 133-136.
Gray J A, Roth B L (2001) Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and
antagonists. Brain Res Bull 56: 441-451.
Grecksch G, Zhou D, Franke C, et al. (1997) Influence of olfactory bulbectomy and subsequent
imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural
correlates. Br J Pharmacol 122: 1725-1731.
Gresch P J, Smith R L, Barrett R J, et al. (2005) Behavioral Tolerance to Lysergic Acid Diethylamide is
Associated with Reduced Serotonin-2A Receptor Signaling in Rat Cortex.
Neuropsychopharmacology 30: 1693-1702.
Grob C S, Danforth A L, Chopra G S, et al. (2011) Pilot study of psilocybin treatment for anxiety in
patients with advanced-stage cancer. Arch Gen Psychiatry 68: 71-78.
Gurevich E V, Aleksandrova I A, Otmakhova N A, et al. (1993) Effects of bulbectomy and subsequent
antidepressant treatment on brain 5-HT2 and 5-HT1A receptors in mice. Pharmacol Biochem Behav
45: 65-70.
Haddjeri N, Blier P, de Montigny C (1998) Long-term antidepressant treatments result in a tonic
activation of forebrain 5-HT1A receptors. J Neurosci 18: 10150-10156.
Harmer C J (2008) Serotonin and emotional processing: Does it help explain antidepressant drug action?
Neuropharmacology 55: 1023-1028.
Harmer C J, Goodwin G M, Cowen P J (2009) Why do antidepressants take so long to work? A cognitive
neuropsychological model of antidepressant drug action. Br J Psychiatry 195: 102-108.
Hellweg R, Zueger M, Fink K, et al. (2007) Olfactory bulbectomy in mice leads to increased BDNF
levels and decreased serotonin turnover in depression-related brain areas. Neurobiol Dis 25: 1-7.
Hintzen A, Passie T (2010) The pharmacology of LSD: a critical review. Oxford University Press, New
York.
Ismaiel A M, Titeler M, Miller K J, et al. (1990) 5-HT1 and 5-HT2 binding profiles of the serotonergic
agents .alpha.-methylserotonin and 2-methylserotonin. J Med Chem 33: 755-758.
Jaako-Movits K, Zharkovsky A (2005) Impaired fear memory and decreased hippocampal neurogenesis
following olfactory bulbectomy in rats. Eur J Neurosci 22: 2871-2878.
Jesberger J A, Richardson J S (1985) Animal models of depression: Parallels and correlates to severe
depression in humans. Biol Psychiatry 20: 764-784.
Katz M M, Waskow I E, Olsson J (1968) Characterizing the psychological state produced by LSD. J
Abnorm Psychol 73: 1-14.
Kang S, Green J P (1970) Steric and Electronic Relationships among Some Hallucinogenic Compounds.
Proc Natl Acad Sci U S A 67: 62-67.
Kelly J P, Wrynn A S, Leonard B E (1997) The olfactory bulbectomized rat as a model of depression: An
update. Pharmacol Ther 74: 299-316.
Page 16 of 26
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
Repeated LSD in an animal model of depression
Kurland A A, Grof S, Pahnke W N, et al. (1973) Psychedelic Drug Assisted Psychotherapy in Patients
with Terminal Cancer. In Goldberg I K, Malitz S, Kutscher A H (eds), Psychopharmacological
agents for the terminally ill and bereaved. Columbia University Press, London.
Lucki I, Frazer A (1982) Prevention of the serotonin syndrome in rats by repeated administration of
monoamine oxidase inhibitors but not tricyclic antidepressants. Psychopharmacology 77: 205-211.
Marks H E, Remley N R, Seago J D, et al. (1971) Effects of bilateral lesions of the olfactory bulbs of rats
on measures of learning and motivation. Physiol Behav 7: 1-6.
Marona-Lewicka D, Chemel B R, Nichols D E (2009) Dopamine D4 receptor involvement in the
discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI.
Psychopharmacology (Berl) 203: 265-277.
Mascher E (1967) Psycholytic therapy: Statistics and indications. In Brill H, Cole JO (eds), Neuro-
psycho-pharmacology. Proceedings of the 5th international congress. Excerpta medica, Amsterdam.
Masini C V, Holmes P V, Freeman K G, et al. (2004) Dopamine overflow is increased in olfactory
bulbectomized rats: an in vivo microdialysis study. Physiol Behav 81: 111-119.
Mathews A, MacLeod C (2004) Cognitive Vulnerability to Emotional Disorders. Annu Rev Clin Psychol
1: 167-195.
Metzner R, Litwin G, Weil G M (1963) The Relation of Expectation and Mood to Psilocybin Reactions:
A Questionnaire Study. Psychedelic Rev 1:18-26.
Mittman S, Geyer M (1991) Dissociation of multiple effects of acute LSD on exploratory behavior in rats
by ritanserin and propranolol. Psychopharmacology 105: 69-76.
Montagne M (2007) Psychedelic therapy for the treatment of depression. In Winkelman M, Roberts TB
(eds), Psychedelic medicine: new evidence for hallucinogenic substances as treatments. Praeger
Publishers, Westport.
Nesterova I V, Gurevich E V, Nesterov V I, et al. (1997) Bulbectomy-induced loss of raphe neurons is
counteracted bt antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 21: 127-140.
Ogren S O (1986) Serotonin receptor involvement in the avoidance learning deficit caused by
pchloroamphetamine-induced serotonin release. Acta Physiol Scand 126: 449-462.
Osei-Owusu P, James A, Crane J, et al. (2005) 5-Hydroxytryptamine 1A Receptors in the Paraventricular
Nucleus of the Hypothalamus Mediate Oxytocin and Adrenocorticotropin Hormone Release and
Some Behavioral Components of the Serotonin Syndrome. J Pharmacol Exp Ther 313: 1324-1330.
Otmakhova N A, Gurevich E V, Katkov Y A, et al. (1992) Dissociation of multiple behavioral effects
between olfactory bulbectomized C57B1/6J and DBA/2J mice. Physiol Behav 52: 441-448.
Passie T (1997) Psycholytic and psychedelic therapy research 1931-1995: a complete international
bibliography. Laurentius, Hannover.
Ray T S (2010) Psychedelics and the human receptorome. PLoS ONE 5: e9019.
Riedlinger T J, Riedlinger J E (1994) Psychedelic and Entactogenic Drugs in the Treatment of
Depression. J Alt States Conscious 26: 41-55.
Romano A, Quinn J, Li L, et al. (2010) Intrahippocampal LSD accelerates learning and desensitizes the 5-
HT2A receptor in the rabbit. Psychopharmacology 212: 441-448.
Roth B L, Baner K, Westkaemper R, et al. (2002) Salvinorin A: A potent naturally occurring
nonnitrogenous κ opioid selective agonist. Proc Natl Acad Sci U S A 99: 11934-11939.
Sairanen M, Lucas G, Ernfors P, et al. (2005) Brain-Derived Neurotrophic Factor and Antidepressant
Drugs Have Different But Coordinated Effects on Neuronal Turnover, Proliferation, and Survival in
the Adult Dentate Gyrus. J Neurosci 25: 1089-1094.
Santarelli L, Saxe M, Gross C, et al. (2003) Requirement of Hippocampal Neurogenesis for the
Behavioral Effects of Antidepressants. Science 301: 805-809.
Savage C, Mc Cabe O L, Kurland A A, et al. (1973) LSD-assisted psychotherapy in the treatment of
severe chronic neuroses. J Alt States Conscious 1: 31-47.
Page 17 of 26
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
Repeated LSD in an animal model of depression
Savitz J, Lucki I, Drevets W C (2009) 5-HT1A receptor function in major depressive disorder. Prog
Neurobiol 88: 17-31.
Schmidt J (1963) Die Beeinflussung einer bedingten motorischen Fluchtreaktion der Ratte durch
Noradrenalin, Serotonin und Lysergsäurediäthylamid. Acta Biol Med Ger 10: 343-349.
Song C, Leonard B E (2005) The olfactory bulbectomised rat as a model of depression. Neurosci
Biobehav Rev 29: 627-647.
Strassman R J (1984) Adverse Reactions to Psychedelic Drugs. A Review of the Literature. J Nerv Ment
Dis 172: 577-595.
Surget A, Tanti A, Leonardo E D, et al. (2011) Antidepressants recruit new neurons to improve stress
response regulation. Mol Psychiatry 16: 1177-1188.
Szabo S T, Blier P (2001) Effects of the selective norepinephrine reuptake inhibitor reboxetine on
norepinephrine and serotonin transmission in the rat hippocampus. Neuropsychopharmacology 25:
845-857.
Taeschler M, Weidmann H, Cerletti A (1960) The effect of LSD on reaction times in a conditioned
avoidance reaction and in the analgesia test. Helv Physiol Pharmacol Acta 18: 43-49.
Thomas J B (1973) Some behavioral effects of olfactory bulb damage in the rat. J Comp Physiol Psychol
83: 140-148.
Unger S M (1964) LSD and Psychotherapy: A Bibliography of the English-Language Literature. Psych
rev 1: 442-449.
Vaidya V A, Terwilliger R M Z, Duman R S (1999) Role of 5-HT2A receptors in the stress-induced
down-regulation of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett
262: 1-4.
Van der Stelt H M, Breuer M E, Olivier B, et al. (2005) Permanent deficits in serotonergic functioning of
olfactory bulbectomized rats: An in vivo microdialysis study. Biol Psychiatry 57: 1061-1067.
Vollenweider F X, Kometer M (2010) The neurobiology of psychedelic drugs: implications for the
treatment of mood disorders. Nat Rev Neurosci 11: 642-651.
Winkelman M J, Roberts T B (2007) Psychedelic Medicine: New Evidence for Hallucinogenic
Substances As Treatments. Praeger.
Zhang Y, Damjanoska K J, Carrasco G A, et al. (2002) Evidence That 5-HT2A Receptors in the
Hypothalamic Paraventricular Nucleus Mediate Neuroendocrine Responses to (−)DOI. J Neurosci
22: 9635-9642.
Page 18 of 26
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
Repeated LSD in an animal model of depression
Figures and legends
Figure 1. Effect of bulbectomy and repeated LSD administration on conditioned (a) vs. instrumental (b)
pole-jumping learning over five consecutive days (mean +/- standard error of mean [SEM]): Repeated
measures ANOVA with pairwise contrast analysis revealed significant differences between sham/saline
and bulb/saline (F
[1, 14]
= 13.15, p = .003 [a]; F
[1, 14]
= 4.85, p = .045 [b]), bulb/saline and bulb/LSD (F
[4, 56]
= 2.6, p = .045 [a]), but not between sham/saline and bulb/LSD (F
[1, 16]
= 2.16, n. s. [a]; F
[1, 16]
= .813, n. s.
[b]). Sham = sham-operated rats, bulb = bulbectomised rats.
Page 19 of 26
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
Repeated LSD in an animal model of depression
Figure 2. Effect of bulbectomy and repeated LSD treatment on specific ketanserin-sensitive
[
3
H]spiroperidol binding to frontocortical and hippocampal membranes. Note the trends of bulbectomy to
increase hippocampal 5-HT
2A
binding, and of LSD to counteract it. Mean + SEM (n = 4-6); comparison
of groups of interest, * p < .05, (NS) = trend (p < .10). Sham = sham-operated rats, bulb = bulbectomised
rats.
Page 20 of 26
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
Repeated LSD in an animal model of depression
Figure 3. Effect of bulbectomy and repeated LSD application on [
35
S]-GTP-gamma-S binding to
hippocampal membranes stimulated by various agonists (per cent of basal binding). Note that from the
bulbectomy associated anomalies, LSD selectively normalised 5-HT
2
signalling (as induced by alpha-
MS). Mean + SEM (n = 4-6); comparison of groups of interest, * p < .05, (NS) = trend (p < .10). Sham =
sham-operated rats, bulb = bulbectomised rats; alpha-MS = alpha-methylserotonin.
Page 21 of 26
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
Repeated LSD in an animal model of depression
Figure 4. Effect of bulbectomy and repeated LSD application on [
35
S]-GTP-gamma-S binding to
frontocortical membranes stimulated by various agonists (per cent of basal binding). Note that from the
bulbectomy associated anomalies, none was normalised by LSD. Mean + SEM (n = 4-6); comparison of
groups of interest, * p < .05, (NS) = trend (p < .10). Sham = sham-operated rats, bulb = bulbectomised
rats; alpha-MS = alpha-methylserotonin.
Page 22 of 26
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
Effect of bulbectomy and repeated LSD administration on conditioned (a) vs. instrumental (b) pole-jumping
learning over five consecutive days (mean +/- standard error of mean [SEM]): Repeated measures ANOVA
with pairwise contrast analysis revealed significant differences between sham/saline and bulb/saline (F
[1, 14]
= 13.15, p = .003 [a]; F
[1, 14]
= 4.85, p = .045 [b]), bulb/saline and bulb/LSD (F
[4, 56]
= 2.6, p = .045 [a]),
but not between sham/saline and bulb/LSD (F
[1, 16]
= 2.16, n. s. [a]; F
[1, 16]
= .813, n. s. [b]). Sham =
sham-operated rats, bulb = bulbectomised rats.
112x51mm (300 x 300 DPI)
Page 23 of 26
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
Effect of bulbectomy and repeated LSD treatment on specific ketanserin-sensitive [
3
H]spiroperidol binding to
frontocortical and hippocampal membranes. Note the trends of bulbectomy to increase hippocampal 5-HT
2A
binding, and of LSD to counteract it. Mean + SEM (n = 4-6); comparison of groups of interest, * p < .05,
(NS) = trend (p < .10). Sham = sham-operated rats, bulb = bulbectomised rats.
95x60mm (300 x 300 DPI)
Page 24 of 26
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
Effect of bulbectomy and repeated LSD application on [
35
S]-GTP-gamma-S binding to hippocampal
membranes stimulated by various agonists (per cent of basal binding). Note that from the bulbectomy
associated anomalies, LSD selectively normalised 5-HT
2
signalling (as induced by alpha-
MS). Mean + SEM (n
= 4-6); comparison of groups of interest, * p < .05, (NS) = trend (p < .10). Sham = sham-operated rats,
bulb = bulbectomised rats; alpha-MS = alpha-methylserotonin.
115x75mm (300 x 300 DPI)
Page 25 of 26
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
Effect of bulbectomy and repeated LSD application on [
35
S]-GTP-gamma-S binding to frontocortical
membranes stimulated by various agonists (per cent of basal binding). Note that from the bulbectomy
associated anomalies, none was normalised by LSD. Mean + SEM (n = 4-6); comparison of groups of
interest, * p < .05, (NS) = trend (p < .10). Sham = sham-operated rats, bulb = bulbectomised rats; alpha-
MS = alpha-methylserotonin.
113x72mm (300 x 300 DPI)
Page 26 of 26
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
Repeated LSD in an animal model of depression
Original Paper
Repeated lysergic acid diethylamide (LSD) in an animal model of depression:
Normalisation of learning behaviour and hippocampal 5-HT
2
signalling
Tobias Buchborn
1,*
, Helmut Schröder
1
, Volker Höllt
1
, Gisela Grecksch
1
1
Institute of Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, 39120
Magdeburg, Germany
*Corresponding author: Dipl. Psych. Tobias Buchborn, Institute of Pharmacology and Toxicology,
Faculty of medicine, Otto-von-Guericke University Magdeburg, Leipziger Straße 44, 39120 Magdeburg,
Germany; phone: +49(0)391-67-21983, fax: +49(0)391-67-15869; e-mail: tobias.buchborn@med.ovgu.de
Disclaimer:
This research received no specific grant from any funding agency in the public,
commercial, or not-for-profit sectors.
The authors declare that there is no conflict of interest.
Page 27 of 26
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
... By contrast, LSD and psilocybin produced a sustained FST antidepressant-like effect in the Wistar-Kyoto model of depression at 5 weeks after a single dose, whereas the effects of ketamine were only transient [53]. Repeated LSD treatment also reversed the deficits in active avoidance learning in the olfactory bulbectomy model of depression, without affecting control rats [91]. In two separate studies, a single psilocybin injection reversed the hedonic and active avoidance deficits in mice subjected to chronic stress, accompanied by a strengthening of excitatory neurotransmission in the HPC or mPFC [31,48]. ...
... In these studies, partial (~30%) 5-HT2AR antagonism using low-dose ketanserin was only sufficient to block the psilocybin-induced psychotomimetic (i.e., head-twitch) but not synaptic or antidepressant-like responses, possibly implicating 5-HT2AR-independent mechanisms [31,48]. Although limited, preclinical studies also suggest that psychedelics can enhance the acquisition of associative learning with both aversive or appetitive unconditioned stimuli [17,91,92], while also facilitating the extinction of fear memory [51,52,87]. Finally, psilocybin enhances measures of motivation and attention in poor-performing rats, as does ketamine [88]. ...
Article
The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has inspired tremendous interest in the underlying neurobiological mechanisms. We review preclinical and clinical evidence supporting neuroplasticity as a convergent downstream mechanism of action for these novel fast-acting antidepressants. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex. These include increased glutamate release, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins, and synaptogenesis. Such influences may facilitate adaptive rewiring of pathological neurocircuitry, thus providing a neuroplasticity-focused framework to explain the robust and sustained therapeutic effects of these compounds.
... Preclinical evidence shows that 5-HT 2A receptor agonists have antidepressant effects. Antidepressant-like actions were reported in rodents after administration of the 5-HT 2A agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (Masuda and Sugiyama, 2000), LSD (Buchborn et al., 2014;Hibicke et al., 2020), psilocybin (Hibicke et al., 2020), and DMT (Cameron et al., , 2019. However, a rodent study with psilocin and psilocybin showed no antidepressant effects (Jefsen et al., 2019). ...
... Repeated administration of psychedelics induces 5-HT 2A receptor desensitization (Romano et al., 2010;Roth et al., 1995), decreased signaling (Gresch et al., 2005), and downregulation (Aloyo et al., 2001;Smith et al., 1999). Desensitization of hippocampal 5-HT 2A receptors produced by repeated LSD administration was reported to be associated with enhanced learning (Romano et al., 2010; see for review Harvey, 2003;Zhang and Stackman, 2015) and with reduced hippocampal 5-HT 2A receptor signaling and normalization of learning in an animal model of depression (Buchborn et al., 2014). In line with and even more relevant to the human model of single/few doses of these drugs required in clinical trials, a cell-line study showed that desensitization can occur rapidly (24 h) and without downregulation (Roth et al., 1995). ...
Article
Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.
... In a recent study LSD did not elicit anxiolytic-like effects in the elevated plus maze test in rats, but it induced a sustained antidepressant-like effect in the forced swim test 5 weeks after a single LSD administration (0.15 mg/kg) [42]. A previous study found that repeated LSD (0.13 mg/kg daily for 11 days) reversed the stress-induced deficits in active avoidance learning and normalized 5-HT 2A receptor-mediated hippocampal 5-HT signaling in a model of depression [43]. Another recent study reported that a high dose of LSD (0.3 mg/kg) induces an antidepressant-like trend in the tail suspension test (TST), but this trend did not reach statistical significance [44]. ...
Article
Lysergic acid diethylamide (LSD) is a serotonergic psychedelic compound receiving increasing interest due to putative anxiolytic and antidepressant properties. However, the potential neurobiological mechanisms mediating these effects remain elusive. Employing in vivo electrophysiology, microionthophoresis, behavioral paradigms and morphology assays, we assessed the impact of acute and chronic LSD administration on anxiety-like behavior, on the cortical dendritic spines and on the activity of serotonin (5-HT) neurons originating in the dorsal raphe nucleus (DRN) in male mice exposed to chronic restraint stress. We found that while the acute intraperitoneal (i.p.) administration of LSD (5, 15 and 30 and 60 μg/kg) did not produce any anxiolytic or antidepressant effects in non-stressed mice, the dose of 30 µg/kg (daily for 7 days) prevented the stress-induced anxiety-like behavior and the stress-induced decrease of cortical spine densitiy. Interestingly, while LSD acutely decreased the firing activity of 5-HT neurons, repeated LSD increased their basal firing rate and restored the low 5-HT firing induced by stress. This effect was accompanied by a decreased inhibitory response of 5-HT neurons to microiontophoretic applications of the 5-HT1A agonist 8-OH-DPAT (8-hydroxy-N,N-dipropyl-2-aminotetralin). In conclusion, repeated LSD prevents the exacerbation of anxiety-like behavior following chronic stress exposure, but has no behavioral effects in non-stressed mice. These effects are paralleled by increased cortical spinogenesis and an enhancement of 5-HT neurotransmission which might be due to 5-HT1A receptors desensitization. Increased cortical spine density and enhancement of serotonergic neurotransmission may thus represent a candidate mechanism which mediate the therapeutic effects of serotonergic psychedelics on stress-induced anxiety.
... This might explain the rapid antidepressant effect observed in the clinical studies that have been conducted on psilocybin [129]. Therefore, 5-HT 2A and 5-HT 1A signaling normalization might help to explain the possible antidepressant and anti-suicidal effects of psilocybin [130]. ...
Article
Full-text available
The available interventions for people who are at risk of suicide have limited efficacy. Recently, research on new mental health treatments has started to consider psychedelic compounds, particularly psilocybin, a molecule with a few thousand years of history of use in human societies. The possible effects of psilocybin on suicidal ideation and behaviors have not been specifically studied yet; however, the current knowledge on the suicidal process and the available data on es/ketamine suggest that psylocibin could be used to modulate the thoughts and behavioral patterns in individu- als who are at risk of suicidal behaviors. Here, we summarize the available evidence on the possible mechanisms underlying psilocybin positive effects on suicide risk. Major pathways related to suicidal behaviors that might be modulated by psylocibin include serotonin receptors. Specifically, psylocibin directly stimulates the serotonin 2A receptor (5HT2A), targeting the inflammatory and oxidative stress pathways and leading to a rapid increase in brain plasticity and inflammation suppression and increases in cognitive flexibility, spirituality, and empathy. We also present preliminary epidemio- logical data and provide a rationale for studying psilocybin in individuals with suicidal ideation or who are at risk of suicidal behaviors. This review presents a framework to understand the basis for psilocybin use in individuals who are at risk of suicidal behaviors and calls for clinical studies.
... Indeed, Hibicke and Nichols (2020) showed that psilocybin, administered one month before testing, restored the deficits in pattern separation induced by developmental stress in rats and this effect correlated with antidepressant effects in a forced swimming test. Other studies in rodents reported an association between the neuroplastic effects of psychedelics and increased performance in fear extinction and learning and memory tasks (Buchborn, Schröder, Höllt, & Grecksch, 2014;Cameron, Benson, Dunlap, & Olson, 2018;Catlow et al., 2013;Morales-Garcia et al., 2020). Together, these findings are supportive of our hypothesis but clearly more studies are needed to validate our model, as some of the connections between the proposed levels remain insufficiently substantiated (see further). ...
Book
Full-text available
This textbook provides a comprehensive overview of the currently used concepts, approaches and technologies in the discovery and development of new treatments for the full spectrum of disorders of the central nervous system. It guides the reader through all essential steps, from finding an innovative idea, to the registration of a new drug. Divided into four sections, the book starts by presenting a broad perspective on current approaches in central nervous system (CNS) drug discovery. The second section addresses the generation of ideas for the identification of targets and novel treatment strategies; covers core functions in early discovery, and provides an example of a novel treatment paradigm: brain stimulation. The third section highlights strategies and technologies in translational CNS drug discovery. In an effort to bridge the gap between discovery and clinical development, it also covers brain imaging, EEG and cognitive testing approaches. The fourth section extensively discusses the clinical phase of drug development, covering the basics of early clinical testing for psychopharmacological drugs. The book’s final chapter addresses the registration for newly developed drugs. Written by experts from academia and industry, the book covers important basics and best practices, as well as recent developments in drug discovery. Offering in-depth insights into the world of drug development, it represents essential reading for early researchers who want to prepare for a career in drug discovery in academia or industry.
... Indeed, Hibicke and Nichols (2020) showed that psilocybin, administered one month before testing, restored the deficits in pattern separation induced by developmental stress in rats and this effect correlated with antidepressant effects in a forced swimming test. Other studies in rodents reported an association between the neuroplastic effects of psychedelics and increased performance in fear extinction and learning and memory tasks (Buchborn, Schröder, Höllt, & Grecksch, 2014;Cameron, Benson, Dunlap, & Olson, 2018;Catlow et al., 2013;Morales-Garcia et al., 2020). Together, these findings are supportive of our hypothesis but clearly more studies are needed to validate our model, as some of the connections between the proposed levels remain insufficiently substantiated (see further). ...
Article
Full-text available
The high symptomatic and biological heterogeneity of major depressive disorder (MDD) makes it very difficult to find broadly efficacious treatments that work against all symptoms. Concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. The Research Domain Criteria (RDoC) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. Evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems RDoC domain. Cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. Psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. We propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. At the psychobiological level, we hypothesize that the negativity bias in MDD is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. Pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. Impairment in this process may underlie the negative cognitive bias in MDD by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. On the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. Together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. Based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in MDD.
Article
The resurgence of interest in using psychedelic drugs, including lysergic acid diethylamide (LSD), in psychiatry has drawn attention to the medically unsupervised practice of 'microdosing'. Thousands of users claim that very low doses of LSD, taken at 3-4-day intervals, improve mood and cognitive function., However, few controlled studies have described the effects of the drug when taken in this way. Here, in a double-blind controlled study, we studied the effects of four repeated doses of LSD tartrate (13 or 26 μg) or placebo, administered to healthy adults at 3-4 day intervals, on mood, cognitive performance and responses to emotional tasks. Participants were randomly assigned to one of three drug conditions: placebo (N = 18), 13 μg LSD (N = 19), or 26 μg LSD (N = 19). They attended four 5-hour drug-administration sessions separated by 3-4 days, followed by a drug-free follow-up session 3-4 days after the last session. LSD (26 μg) produced modest subjective effects including increased ratings of 'feeling a drug effect' and both stimulant-like and LSD-like effects, but the drug did not improve mood or affect performance on psychomotor or most emotional tasks. No residual effects were detected on mood or task performance on the drug-free follow-up session. We conclude that within the context of a controlled setting and a limited number of administrations, repeated low doses of LSD are safe, but produce negligible changes in mood or cognition in healthy volunteers.
Chapter
The serotonergic system has long been implicated in widespread functions in the peripheral and central nervous system (CNS). Serotonin or 5-hydroxytryptamine (5-HT) in the CNS is a key neurotransmitter known to modulate numerous physiological and behavioral functions including mood, emotion, cognition, and sleep. Abnormal functioning of the serotonergic system may be involved in pathological conditions of the brain involved in psychiatric and neurodegenerative disorders such as mood disorders, Parkinson’s disease, Alzheimer’s disease, and epilepsy. In the past several decades, neuroimaging of the CNS serotonergic system has led to great advancements in understanding the pathophysiology of these various disorders and disease progression as well as the development of drug treatments. This review provides a summary on the radioligands used for positron emission tomography (PET) imaging of serotonergic receptors and transporter.
Article
Psychedelics are increasingly being recognized for their potential to treat a wide range of brain disorders including depression, post-traumatic stress disorder (PTSD), and substance use disorder. Their broad therapeutic potential might result from an ability to rescue cortical atrophy common to many neuropsychiatric and neurodegenerative diseases by impacting neurotrophic factor gene expression, activating neuronal growth and survival mechanisms, and modulating the immune system. While the therapeutic potential of psychedelics has not yet been extended to neurodegenerative disorders, we provide evidence suggesting that approaches based on psychedelic science might prove useful for treating these diseases. The primary target of psychedelics, the 5-HT2A receptor, plays key roles in cortical neuron health and is dysregulated in Alzheimer’s disease. Moreover, evidence suggests that psychedelics and related compounds could prove useful for treating the behavioral and psychological symptoms of dementia (BPSD). While more research is needed to probe the effects of psychedelics in models of neurodegenerative diseases, the robust effects of these compounds on structural and functional neuroplasticity and inflammation clearly warrant further investigation.
Article
What is the effect of activating a single modulatory neuronal receptor type on entire brain network dynamics? Can such effect be isolated at all? These are important questions because characterizing elementary neuronal processes that influence network activity across the given anatomical backbone is fundamental to guide theories of brain function. Here, we introduce the concept of the cortical ‘receptome’ taking into account the distribution and densities of expression of different modulatory receptor types across the brain’s anatomical connectivity matrix. By modeling whole‐brain dynamics in silico, we suggest a bidirectional coupling between modulatory neurotransmission and neuronal connectivity hardware exemplified by the impact of single serotonergic (5‐HT) receptor types on cortical dynamics. As experimental support of this concept, we show how optogenetic tools enable specific activation of a single 5‐HT receptor type across the cortex as well as in vivo measurement of its distinct effects on cortical processing. Altogether, we demonstrate how the structural neuronal connectivity backbone and its modulation by a single neurotransmitter system allows access to a rich repertoire of different brain states that are fundamental for flexible behavior. We further propose that irregular receptor expression patterns —genetically predisposed or acquired during lifetime— may predispose for neuropsychiatric disorders like addiction, depression, and anxiety along with distinct changes in brain state. Our long‐term vision is that such diseases could be treated through rationally targeted therapeutic interventions of high specificity to eventually recover natural transitions of brain states.
Article
The behavioral effects of bulbectomy and subsequent antidepressant treatment in two mice strains were compared on measures of open field behavior and passive and active avoidance 2 and 4 weeks after surgery. After bulbectomy, both strains displayed elevated locomotion in open field, corrected by antidepressants. Enhanced rearing was decreased by antidepressants in C57B1/6J, but not in DBA/2J mice. Passive avoidance, being intact 2 weeks after surgery in both strains, was strongly impaired 4 weeks after bulbectomy in C57B1/6J mice, with antidepressants restoring the performance. Active avoidance acquisition and retention were also dramatically disturbed in C57B1/6J mice 2 and 4 weeks after surgery, and antidepressants had recuperative effect. In contrast, bulbectomized DBA/2J mice didn't show any significant passive or active avoidance deficits, and antidepressant treatment seemed to have no effect on their learning ability. The observed strain differences suggest that bulbectomy may produce quite diverse neurophysiological and neurochemical alterations in two strains.
Article
Thirty min prior to training rats in an active-avoidance task they were injected intracisternally (IC) with 3 mg diethyldithiocarbamate (DDC), a norepinephrine (NE) synthesis inhibitor. They showed complete retention of memory for about 10 min after training. Subsequently, memory decayed to the naive level over the next 80 min but reappeared later. The brain NE level fell to 50% of its normal level 30 min after the injection. 90 min later it recovered to 85% of its normal level. The dopamine level did not change. We have shown previously that brief-hypoxia causes a delayed transient amnesia. The time-course of the DDC-induced amnesia was identical. Both treatments are interpreted to interfere with Medium-Term-Memory (MTM) formation. The DDC-induced transient amnesia could be prevented by injecting 10 μg NE IC 30 min prior to training. It was concluded that NE is needed shortly after training for MTM formation. Rats were injected IC with 4 μg ethacrinic acid 30 min prior to training. They showed complete retention of memory 2 min after training, amnesia 10 min after training, complete retention 15–90 min after training and partial amnesia 3.5 hr later. Thus, ethacrinic acid appears to interfere with short-term-memory formation. These and earlier results obtained with other treatments are incorporated into a four-phase model of memory formation with parallel processing.
Article
Describes the use of psychedelic drug therapy to alleviate the emotional and physical suffering of 50 23-81 yr old terminal cancer patients. In 43 patients, 200-500 mcg of LSD was orally administered as an adjunct to brief intensive psychotherapy. In 7 patients, 60-105 mg of dipropyltryptamine was administered. Results were assessed using a clinical rating scale reflecting (a) the degree of depression and psychological isolation; (b) difficulty in management; and (c) acceptance or fear of death and pain. Pre- and posttreatment ratings indicate significant improvement on most of the clinical assessments and a trend toward a reduction in narcotic medication. Brief case histories are presented. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
1. Alterations of 5-hydroxytryptaminergic mechanisms are thought to play a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes. 2. We have used one of the most reliable models of depression, the olfactory bulbectomized rat to study the long term consequences of this manipulation and of subchronic imipramine treatment on two parameters of 5-hydroxytryptaminergic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tryptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy. 3. The Bmax value of [3H]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both significantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated controls. 4. Imipramine treatment, either by daily injections or by subcutaneous implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal cortex of bulbectomized, but not of sham-operated control rats and restored the deficient learning performance of bulbectomized rats. 5. Both effects were more pronounced after continuous drug administration by imipramine-releasing polymers compared to daily i.p. injections. 6. These findings indicate that bulbectomy leads to a compensatory 5-hydroxytryptaminergic hyperinnervation of the frontal cortex. Chronic antidepressant treatment seems to attenuate the increased output of the 5-hydroxytryptaminergic projections in the frontal cortex through the destabilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydroxytryptaminergic nerve endings in this brain region.
Article
The receptor involvement in the p-chloroamphetamine (PCA, 2.5 mg kg-1) induced impairment of active avoidance acquisition was examined in the male rat. The avoidance deficit was blocked at low doses by serotonergic (5-HT)-receptor blocking agents but not by α-adrenergic-, β-adrenergic-, opiate-, muscarinic- or dopamine D2-receptor antagonists. The potency of the 5-HT antagonists to block the PCA- induced deficit correlated with their affinity in displacing [3H]ketanserin but not [3H]5-HT binding in the frontal cortex. The potencies of the 5-HT antagonists to block the action of PCA could not be related to their action on muscarinic-, histaminergic H1- or dopaminergic D2-receptor binding in vitro. It is concluded that the avoidance learning deficit caused by PCA-induced 5-HT release is related to activation of 5-HT receptors in the frontal cortex having the characteristics of a 5-HT2 receptor.
Article
Bilateral removal of the olfactory bulbs in rats produces a behavioural abnormality that is defined by hyperactivity in the open-field test. This abnormality may be related to depression since these behavioural effects can be attenuated by antidepressant drugs. Moreover, changes in the cholinergic and serotonergic system may be involved in the pathogenesis of depression. Thus, muscarinic cholinergic and serotonin2 receptors were measured by quantitative autoradiography after the bilateral removal of the olfactory bulbs from the rat. In OB rats, muscarinic receptor density was decreased in several brain regions including the amygdaloid cortex, the basal ganglia, hippocampus, hypothalamus, cortex and olfactory regions. Serotonin2 receptors were increased in all cortical regions, in the hippocampus and the thalamus. When OB rats were treated chronically for 35 days with mianserin (5 mg/kg i. p.) or desipramine (7·5 mg/kg i. p.) the behavioural hyperactivity was reversed and muscarinic receptor density was increased in the hippocampus and cortical regions while serotonin2 receptors were normalized. The results are consistent with a cholinergic and serotonin involvement in depressive illness and suggest that the cholinergic and serotonergic modulatory properties of antidepressant drugs may contribute to their therapeutic effectiveness.
Article
1 Alterations of 5-hydroxytryptaminergic mechanisms are thought to play a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes. 2 We have used one of the most reliable models of depression, the olfactory bulbectomized rat to study the long term consequences of this manipulation and of subchronic imipramine treatment on two parameters of 5-hydroxytryptaminergic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tryptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy. 3 The B max value of [ 3 H]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both signi®cantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated controls. 4 Imipramine treatment, either by daily injections or by subcutaneous implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal cortex of bulbectomized, but not of sham-operated control rats and restored the de®cient learning performance of bulbectomized rats. 5 Both e€ects were more pronounced after continuous drug administration by imipramine-releasing polymers compared to daily i.p. injections. 6 These ®ndings indicate that bulbectomy leads to a compensatory 5-hydroxytryptaminergic hyperinnervation of the frontal cortex. Chronic antidepressant treatment seems to attenuate the increased output of the 5-hydroxytryptaminergic projections in the frontal cortex through the destabilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydroxytryptaminergic nerve endings in this brain region.