1998 - Marek - Indoleamine and the Phenethylamine Hallucinogens.pdf - Multiple Substances - Eroza800

Drug and Alcohol Dependence 51 1998 189 ] 198

Indoleamine and the phenethylamine hallucinogens:

mechanisms of psychotomimetic action

Gerard J. Marek U , George K. Aghajanian

Departments of Psychiatry and Pharmacology, Yale Uni ¨ ersity School of Medicine, Ribicoff Research Facilities of the Connecticut

Mental Health Center, 34 Park Street, New Ha ¨ en, CT 06508, USA

1. Introduction

and this was advanced as the mechanism underlying

the hallucinogenic effects of LSD Gaddum, 1953;

The psychedelic hallucinogens are comprised of

three different groups of compounds according to

. .

Woolley and Shaw, 1954 . Later, LSD was found to

have a 5-HT agonist action in other systems and this

was then advanced as an alternate mechanism to

their chemical structure Fig. 1 : 1 the ergolines

which contain an indole moiety e.g. lysergic acid

account for the hallucinogenic effects of 5-HT Shaw

diethylamide, LSD ; 2 simple indoleamine hallucino-

and Woolley, 1956 . Since their psychotomimetic ef-

fects are similar, these three classes of hallucinogenic

drugs may share a similar mechanism of action at the

receptor level. A prediction derived from this assump-

tion is that ergoline, simple indoleamine, and

phenethylamine hallucinogens should act similarly at

a candidate site for hallucinogenic activity. Early elec-

trophysiological studies had shown that LSD potently

suppressed the ﬁring rate of 5-HT-containing neurons

gens e.g. N , N -dimethyltryptamine, DMT and psilocy-

bin which share an indoleamine structure with the

endogenous neurotransmitter 5-hydroxytryptamine 5-

. .

HT, serotonin ; and 3 the ring-substituted pheneth-

ylamine hallucinogens e.g. mescaline . One of the

outstanding features of ergoline, indoleamine, and

phenethylamine hallucinogens is that they alter all

cortical functions including cognition, perception, and

mood. This implies that the sites mediating the psy-

chotomimetic effects of these hallucinogens are lo-

cated in the neocortex or in subcortical areas with

efferent projections throughout the neocortex. This

review will consider evidence suggesting that both the

indoleamine and phenethylamine hallucinogens bind

to a common neurotransmitter receptor in the brain,

in the midbrain dorsal raphe nucleus Aghajanian et

al., 1968 . However, this effect was later shown to be

dependent upon activation of somatodendritic 5-HT 1A

autoreceptors Sprouse and Aghajanian, 1987 . Later

studies showed that mescaline, a phenethylamine hal-

lucinogen, did not inhibit the ﬁring rate of 5-HT-con-

the 5-hydroxytryptamine

5-HT

receptor, and

taining neurons through 5-HT receptors Haigler

2A 2A

that subsequent activation of this serotonin receptor

mediates the psychotomimetic effects of these halluci-

and Aghajanian, 1973 . These results indicated that

agonist activity at the 5-HT autoreceptor on 5-HT-

containing neurons could not provide a shared mech-

anism of action for all classes of psychedelic halluci-

nogens.

Currently, there are upwards of 14 5-HT receptor

subtypes based on pharmacological, physiological and

nogens. We will also discuss potential site s in the

brain at which the hallucinogens exert their psy-

chotomimetic effects.

2. Hallucinogens and 5-HT receptors

molecular cloning data Hoyer et al., 1994 . The

promiscuity of LSD for most of the 5-HT receptor

subtypes is a not surprising given the historical link-

age of LSD to the serotonergic system. LSD potently

binds to 5-HT

LSD has have been known to interact with the

serotonergic system since the 1950s. Early studies in

receptors, although its

afﬁnity for the 5-HT receptor is comparatively low

Hoyer, 1988; Lovenberg et al., 1993 . In contrast, the

phenethylamine hallucinogens do not bind potently to

U Corresponding author. Tel.:

1 203 7897447; fax:

1 203

the 5-HT family of receptors Titeler et al., 1988;

5627079; e-mail: gerard.marek@yale.edu

0376-8716

$19.00

PII S0376-8716 98 00076-3

simple preparations e.g. carotid arteries and uteri

had found that LSD antagonized the effects of 5-HT

190

G.J. Marek, G.K. Aghajanian

Drug and Alcohol Dependence 51 1998 189

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198

diethylamide LSD and phenethylamine hallucino-

gens in humans have suggested that 5-HT receptors

mediate the hallucinogenic effects of indoleamine and

phenethylamine hallucinogens Glennon et al., 1984 .

LSD has a similar afﬁnity for the 5-HT receptor

K : 0.5

]

2.5 nM and for the 5-HT receptor K :

12 nM; Titeler et al., 1988; Hoyer, 1988 . The K d

of LSD for 5-HT receptors is near the peak plasma

]

levels 10

]

20 nM measured following both i.v. and

oral LSD administration Aghajanian and Bing, 1964;

Hawks and Chiang, 1986 . However, agreement does

not exist regarding whether LSD and other hallucino-

gens act as full or partial agonists Sanders-Bush et

al., 1988; Glennon, 1990; Sheldon and Aghajanian,

1990 or antagonists Pierce and Peroutka, 1988, 1990

at cortical 5-HT receptors.

This issue has been examined recently in the piri-

form cortex Marek and Aghajanian, 1996 using

amino butyric acid GABA -ergic neurons excited by

Fig. 1. Chemical structure of the endogenous neurotransmitter

5-HT via 5-HT receptors Sheldon and Aghajanian,

5-hydroxytryptamine 5-HT, serotonin ; the ergoline hallucinogen

1990; Marek and Aghajanian, 1994 as a model system

to study the effects of both ergoline and pheneth-

ylamine hallucinogens. Both LSD and the pheneth-

lysergic acid diethylamide LSD ; the simple indoleamine hallucino-

gen N , N -dimethyltryptamine DMT ; and the phenethylamine hal-

lucinogen mescaline. The letters A

D in the outline font corre-

spond to shared chemical similarities between the four different

compounds.

]

ylamine hallucinogen 1- 2,5-dimethoxy-4-iodophenyl -

2-aminoproprane DOI excited a subpopulation of

interneurons; both drugs were blocked by the selec-

tive 5-HT antagonist MDL 100,907. The maximal

excitation induced by LSD and DOI was 39% and

55% of the effect of a near-maximal 5-HT concentra-

Pierce and Peroutka, 1989; Zgombick et al., 1992;

either the 5-HT or the 5-HT receptor Peroutka and

tion Fig. 2 . Furthermore, high concentrations of

Hamik, 1988; Gerald et al., 1995 . While LSD has

relatively high afﬁnity for the 5-HT

which excited the interneurons decreased the excita-

tory effect of a near-maximal 5-HT concentration.

Thus, both the indoleamine LSD and the pheneth-

ylamine DOI act as potent partial agonists at least for

Matthes et al., 1993; Monsma et al., 1993; Ruat et al.,

receptors

1993 , phenethylamine hallucinogens do not bind po-

tently or act as an agonist at the 5-HT or the 5-HT

receptors Erlander et al., 1993; Lovenberg et al.,

one subset of cortical 5-HT receptors Figs. 5 and

1993 . However, thus far, no binding data for

phenethylamine hallucinogens has been reported at

the 5-HT receptor. The one class of 5-HT receptors

to which ergoline, simple indoleamine, and pheneth-

ylamine hallucinogens all potently bind to is the 5-HT 2

class which includes the 5-HT , 5-HT , and 5-HT

2A 2B 2C

receptors. The 5-HT receptor has a restricted CNS

3. Hallucinogens and potential CNS site s of action

()

The highest density of 5-HT receptors exists in

the neocortex layer Va and the piriform cortex.

High concentrations of the 5-HT receptor are also

present in the olfactory bulb and subcortical areas

such as the claustrum, nucleus accumbens, the cranial

motor nuclei and the nucleus tractus solitarius. The

psychotomimetic effects of the hallucinogens may be

mediated by a single site or multiple sites. The man-

ner in which the hallucinogens exert profound effects

on cognition, perception and mood suggests that ei-

ther the neocortex or an area with widespread projec-

tions throughout the neocortex mediates the psy-

chotomimetic effects of the hallucinogens via 5-HT 2A

receptor activation.

expression Duxon et al., 1997 . Thus, the 5-HT and

5-HT receptors remain as the most likely shared

targets of action for the ergoline, simple indoleamine,

and phenethylamine hallucinogens. Given the pre-

dominance of 5-HT receptors over 5-HT recep-

tors in most areas of the neocortex Pompeiano et al.,

1994; Wright et al., 1995 , the 5-HT receptor ap-

pears to be the most likely candidate to mediate the

major hallucinogenic effects of indoleamine and

phenethylamine hallucinogens.

Correlations between 5-HT receptor binding af-

ﬁnity and the hallucinogenic potency of lysergic acid

3.8

Adham et al., 1993 . LSD does not bind potently to

LSD 100 nM; Figs. 3 and 4 and DOI 3 and 10

G.J. Marek, G.K. Aghajanian

Drug and Alcohol Dependence 51 1998 189

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198

191

substance P Aghajanian, 1980 . Thus, the hallucino-

gens act indirectly, apparently through afferents to

the LC. The relevance for this discussion, however, is

that the LC has long been noted to enhance the

‘signal to noise’ ratio in modulating post-synaptic ac-

tivity in the forebrain Woodward et al., 1979 . The

action of the hallucinogens on the LC, i.e. suppres-

sion of basal activity together with increased respon-

ses to sensory afferents, can be viewed as enhancing

the ‘signal to noise’ ratio of sensory inputs to the LC

itself. Thus, the hallucinogens could alter sensory

processing throughout the brain via the LC.

3.2. Facial nucleus

Fig. 2. Efﬁcacy of LSD and DOI with respect to 5-HT for excita-

]

100 nM and DOI

LSD and other hallucinogens also have effects on

motor function in addition to their widely recognized

effects on perception, cognition and mood. Hallucino-

gens are known to enhance motor reﬂexes in humans.

Animal studies have also demonstrated that halluci-

M were applied for 10 min to a rat piriform cortical slice

preparation and the resulting excitation of piriform cortical in-

terneurons was compared to the near maximal excitation induced

by 100-

]

nogens enhance reﬂexes via 5-HT receptors Maj et

al., 1976, 1977; Skarsfeldt et al., 1990 . These effects

might be mediated by direct effects of hallucinogens

on motor nuclei themselves. Facial motoneurons, like

other cranial motor nuclei, possess an especially high

M 5-HT. Signiﬁcantly different from the base line, UUU P

0.001 from Marek and Aghajanian, 1996 .

3.1. Locus coeruleus

level of 5-HT binding sites Pazos and Palacios,

1985 and also express a high level of 5-HT receptor

One subcortical area upon which hallucinogens ex-

ert an effect and which projects throughout the entire

neocortex and virtually all regions of the brain is the

mRNA Pompeiano et al., 1994; Wright et al., 1995 .

Thus, the facial motor nucleus has been used as a

model system to study the electrophysiological effects

of hallucinogens since this motor nucleus does not

contain any interneurons.

5-HT, by itself, does not excite facial motoneurons

to the point of ﬁring, but does depolarize facial mo-

toneurons and enhance the excitation observed after

microiontophoretic application of glutamate or stimu-

locus coeruleus LC . The LC is the major cluster of

noradrenergic-containing cells that is present bilater-

ally in the upper pons at the lateral border of the

fourth ventricle. The actions of hallucinogens on the

LC could play a profound role in perceptual changes

since the LC receives a convergence of somatic, vis-

ceral and other sensory inputs from all regions of the

body and has been described as a novelty detector.

The systemic administration of the indoleamine

LSD and the phenethylamines mescaline and DOB in

anesthetized rats decreases spontaneous activity of

the LC but facilitates the activation of LC neurons by

lation of the motor cortex McCall and Aghajanian,

1979 . The increased excitability of facial motoneu-

rons induced by glutamate was associated with a

decreased resting potassium conductance Vander-

Maelen and Aghajanian, 1982 . The ergoline halluci-

nogen LSD, the simple indoleamine hallucinogen

psilocybin, and the phenethylamine hallucinogen

mescaline were all found to enhance the facilitating

effect of iontophoretically applied 5-HT or nore-

sensory inputs Aghajanian, 1980; Rasmussen and

Aghajanian, 1986 . These effects of the hallucinogens

are mediated via the 5-HT receptor because they

are blocked by a number of 5-HT antagonists, in-

pinephrine NE on glutamate-induced excitation

cluding several which possess 30

]

1000-fold selectivity

McCall and Aghajanian, 1980 . This facilitating ef-

fect of 5-HT and the phenethylamine hallucinogen

DOM were found to be mediated by a 5-HT recep-

at the 5-HT vs. the 5-HT receptor Rasmussen

and Aghajanian, 1988 . The hallucinogens are not

acting directly upon the LC neurons because mi-

croiontophoresis of the hallucinogens onto LC cells

does not mimic the effects of systemic administration.

Furthermore, systemic administration of the halluci-

nogens does not enhance the effects of microion-

tophoresis of neurotransmitters with widespread exci-

tatory effects such as glutamate, acetylcholine and

tor Rasmussen and Aghajanian, 1990 . The 5-HT 2A

receptor was found to mediate, at least in part, in-

creases in motoneuron excitability induced by both

5-HT and LSD Garratt et al., 1993 . Furthermore,

5-HT, LSD and DOI were also found to increase the

excitability of facial motoneurons through a second

ionic mechanism; the opening of a non-speciﬁc

tion of piriform cortical interneurons. LSD 3

0.3

192

G.J. Marek, G.K. Aghajanian

Drug and Alcohol Dependence 51 1998 189

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Fig. 3. Firing rate histogram of a piriform cortical interneuron showing that LSD is a partial agonist with respect to 5-HT-induced excitation.

m M and NE 100

m M . The second

panel B shows that the quiescent interneuron begins to ﬁre shortly before the end of the 10-min application with LSD 100 nM and the cell

maintains a steady ﬁring rate. Now, the maximal amplitude of the ﬁring rate for this cell compared to the quiescent baseline is reduced in

response to 100- m M 5-HT, but is unchanged in response to 100- m M NE. A 30-min application of the selective 5-HT antagonist MDL

100,907 suppresses the LSD-induced response C . The last panel D shows that following the MDL 100,907 application, 5-HT 30 and 100

m M does not induce the cell to ﬁre while the response to NE is unchanged modiﬁed from Marek and Aghajanian, 1996 .

cationic current I Garratt et al., 1993 . Taken

together, these studies suggest that the effects of

hallucinogens on motor function in humans, could be

mediated in part, through increasing the excitability

of lower motoneurons.

5-HT receptors Pazos and Palacios, 1985; Hoyer et

al., 1986; Pompeiano et al., 1994; Wright et al., 1995;

Lopez-Gimenez et al., 1997; Willins et al., 1997 . The

distribution of 5-HT receptor binding has a precise

laminar pattern in the rat where it is heavy in layer I

and especially in layer Va Blue et al., 1988 . Recent

3.3. Neocortex

immunohistochemical studies Willins et al., 1997;

Jakab and Goldman-Rakic, 1998 agree that 5-HT 2A

receptors are found both in GABAergic interneurons

and prominently in the apical dendrites of pyramidal

cells.

Since 5-HT receptors have been linked to de-

polarization and the closing of potassium conduc-

tances in a number of brain areas including piriform

As discussed above, the profound effects of halluci-

nogens on cognition, perception and mood suggest

involvement of the neocortex. Certain features of the

sounds are ‘seen’, etc. seem difﬁcult to explain unless

the neocortex is involved in the effects of the halluci-

nogens. As discussed above, the hallucinogenic effects

of all the ergolines, simple indoleamines and the

phenethylamine hallucinogens have been linked to

the 5-HT receptor. Localization of 5-HT recep-

2A 2A

tors by autoradiographic, immunohistochemical, and

in situ mRNA hybridization studies all point to the

neocortex as having the most prominent expression of

cortex Sheldon and Aghajanian, 1990 and the neo-

cortex Araneda and Andrade, 1991; Tanaka and

North, 1993 , the presence of 5-HT receptors on

both interneurons and pyramidal cells might appear

incongruent. However, excitation of several subtypes

of GABAergic interneurons might have interesting

excitatory or modulatory action on pyramidal cells

The top panel A shows the ﬁring rate in response to 2-min bath application of 5-HT 10, 30 and 100

effects of hallucinogens such as synesthesias when

G.J. Marek, G.K. Aghajanian

Drug and Alcohol Dependence 51 1998 189

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Fig. 5. Microiontophoretically applied 5-HT induces EPSCs in the

apical dendritic ﬁeld of a frontoparietal layer V pyramidal cell. At

Va, 5-HT 20 mM ejected at

100 nA from a patch pipette for 30 s induced a brisk response

Fig. 4. LSD 3 ] 100 nM exerts partial agonist properties. The

which began within 6 s see onset a . At site b, near the border of

layer I

maximal response to 5-HT 100

m M , NE 100

m M and the

II, there was a clear but less pronounced response to 5-HT

microiontophoresis. In contrast, at sites lateral ) 100 ] 200 m mto

a radial corridor extending perpendicularly from the recording site

excitatory amino acid agonists AMPA 5 m M both before and after

a 10-min perfusion with 3 nM top panel , 10 nM middle panel

and 100 nM bottom panel LSD. The open bars show the effect of

5-HT, NE or AMPA before LSD application. The hatched bars

demonstrate the effects of LSD on the ﬁring rate for the minute

immediately preceding application of 5-HT, NE or AMPA. The

shaded bars present the maximal response to 5-HT, NE or AMPA

when tested after the LSD application and thus demonstrate the

combined effects of LSD and either 5-HT, NE or AMPA. U P

to the pial surface sites e and d , there were virtually no EPSCs

induced by 5-HT. Microiontophoresis of 5-HT into the basilar

dendritic ﬁeld site c also was not effective. The response of this

cell to bath applied 5-HT is shown at the lower left. At the lower

right is a schematic diagram indicating the relative positions of the

recording rec and microiontophoretic 5-HT micropipettes rela-

tive to cortical layers I-VI; the shaded zones indicate bands of

0.05,

high-density 5-HT receptor binding Blue et al., 1988 . Intracellu-

lar recording was performed with sharp micropipettes containing a

1-M K q -acetate solution.

UU P

0.01,

UUU

0.001 from Marek and Aghajanian, 1996 .

depending upon the nature of the relationship

between the interneuron and the pyramidal cells. For

example, excitation of an interneuron which inhibits

another actively ﬁring GABAergic interneuron that in

turn inhibits a pyramidal cell would result in an

increase in the excitability or ﬁring rate of that

pyramidal cell, i.e. disinhibition. Another unique type

of anatomical relationship to pyramidal cells is seen

with a subpopulation of parvabumin-containing

GABAergic interneurons that are known as Chande-

lier cells based on an impressive array of synaptic

terminals that surround the initial axon segment of

nearby pyramidal cells. The initial axon segment is

the portion of the cell from which action potentials

are generated generally. Hyperpolarization of the cell

together with activation of synaptic inputs that open

tors; Garratt et al., 1993 can lead to a dramatic

sculpturing of cell ﬁring such that cells tend to ﬁre in

bursts McCormick and Pape, 1990 .

A second effect of 5-HT receptor activation in

the neocortex is an increase in the excitability that

occurs with a depolarization, the appearance of de-

polarizing afterpotentials following cell ﬁring, and a

decrease in spike frequency accommodation Araneda

and Andrade, 1991 . Such effects are observed in

roughly one-third of layer V pyramidal cells while

another one-third of the cells are observed to have a

biphasic response to 5-HT, involving a transient hy-

perpolarization mediated via activation of 5-HT 1A

receptors followed by a depolarization Araneda and

site a, near the border of layer IV

cation non-selective I currents e.g. 5-HT recep-

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