5-meo-dmt.5ht1a.paradox, biotransformation
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Pharmacology Biochemistry and Behavior, Vol. 65, No. 1, pp. 75–82, 2000
© 1999 Elsevier Science Inc.
Printed in the USA. All rights reserved
0091-3057/00/$–see front matter
PII S0091-3057(99)00178-1
-Dimethyltryptamine:
An Indoleamine Hallucinogen That Induces
Stimulus Control Via 5-HT
The Paradox of
5-Methoxy-
N,N
1A
Receptors
J. C. WINTER, R. A. FILIPINK, D. TIMINERI, S. E. HELSLEY AND R. A. RABIN
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences,
State University of New York at Buffalo, 102 Farber Hall, SUNY at Buffalo, Buffalo, NY 14214-3000
Received 26 June 1998; Revised 21 May 1999; Accepted 4 June 1999
WINTER, J. C., R. A. FILIPINK, D. TIMINERI, S. E. HELSLEY AND R. A. RABIN.
The paradox of 5-meth-
oxy-
N,N
-dimethyltryptamine: An indoleamine hallucinogen that induces stimulus control via 5-HT
1
A
receptors
. PHARMA-
COL BIOCHEM BEHAV
65
(1) 75–82, 2000.—Stimulus control was established in rats trained to discriminate either 5-meth-
)-2,5-dimethoxy-4-methylamphetamine (0.56 mg/kg) from saline. Tests of
antagonism of stimulus control were conducted using the 5-HT
N,N
-dimethyltryptamine (3 mg/kg) or (
2
antagonists (
6
)-pindolol and WAY-100635, and the 5-HT
1A
2
receptor antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and WAY-100635 both produced a significant
degree of antagonism of stimulus control, but pirenperone was much less effective. Likewise, the full generalization of
5-MeO-DMT to the selective 5-HT
]-8-hydroxy-dipropylaminotetralin was blocked by WAY-100635, but unaf-
fected by pirenperone. In contrast, the partial generalization of 5-MeO-DMT to the 5-HT
1A
agonist [
6
agonist DOM was completely an-
tagonized by pirenperone, but was unaffected by WAY-100635. Similarly, in rats trained with (
2
)-DOM, pirenperone com-
pletely blocked stimulus control, but WAY-100635 was inactive. The results obtained in rats trained with (
2
)-DOM and
tested with 5-MeO-DMT were more complex. Although the intraperitoneal route had been used for both training drugs, a
significant degree of generalization of (
2
)-DOM to 5-MeO-DMT was seen only when the latter drug was administered sub-
cutaneously. Furthermore, when the previously effective dose of pirenperone was given in combination with 5-MeO-DMT
(SC), complete suppression of responding resulted. However, the combination of pirenperone and WAY-100635 given prior
to 5-MeO-DMT restored responding in (
2
2
)-DOM-trained rats, and provided evidence of antagonism of the partial substitu-
)-DOM. The present data indicate that 5-MeO-DMT–induced stimulus control is mediated pri-
marily by interactions with 5-HT
2
receptors. In addition, however, the present findings suggest that 5-MeO-DMT induces a
compound stimulus that includes an element mediated by interactions with a 5-HT
1A
receptors. The latter component is not es-
sential for 5-MeO-DMT–induced stimulus control, but is revealed in animals tested or trained with a 5-HT
2
-selective agonist
2
)-DOM. Based upon the present data, we conclude that 5-MeO-DMT differs from DOM with respect to the sero-
tonergic element that mediates stimulus control in the rat, but that it shares with DOM a functionally significant interaction
with 5-HT
2
2
receptors. © 1999 Elsevier Science Inc.
5-Methoxy-
N,N
-dimethyltryptamine
Drug-induced stimulus control
5-HT
1A
5-HT
2A
Rat
FOLLOWING the demonstration that hallucinogens can
function as discriminative stimuli in animals (22), drug-
induced stimulus control has often been used in attempts to
establish the mechanism of action of these agents. Thus, for
example, the observation that the stimulus effects of mesca-
line—a phenethylamine hallucinogen—are blocked by sero-
tonergic antagonists (6,43) provided support for the venerable
hypothesis of Gaddum (12) that receptors for 5-hydroxy-
tryptamine (5-HT) are crucial to the action of hallucinogenic
drugs. This observation was later extended to other hallucino-
Requests for reprints should be addressed to Dr. J. C. Winter, SUNY–Buffalo, School of Medicine & Biomedical Sciences, Department of
Pharmacology & Technology, 102 Farber Hall, Buffalo, NY 14214-3000.
75
oxy-
tion of 5-MeO-DMT for (
such as (
76
WINTER ET AL.
-
dimethyltryptamine [DMT; (16)]. Although serotonergic sys-
tems are clearly relevant to the effects of LSD, the question
remains as to which specific 5-HT receptor subtypes are in-
volved. This issue has become more complicated as the origi-
nal division of 5-HT receptors into 5-HT
N,N
provided immediately following training sessions. Caloric in-
take was controlled so as to maintain adult body weights of
approximately 300 g. All animals used were maintained in ac-
cordance with the
Guide for Care and Use of Laboratory Ani-
of the Institute of Laboratory Animal Resources, Na-
tional Research Council. All experimental protocols were
approved by the Laboratory Animal Care Committee of
SUNY at Buffalo.
subtypes
(33) has been expanded and reorganized to include seven dis-
tinct families or classes of 5-HT receptors, with some families
including multiple subtypes (23).
The observed blockade of the stimulus effects of DOM,
LSD, and mescaline by 5-HT antagonists that were consid-
ered relatively selective for the 5-HT
1
and 5-HT
2
Apparatus
receptor subtype led
Glennon and colleagues to hypothesize that classical halluci-
nogens act as 5-HT
2
Six small-animal test chambers (Coulbourne Instruments
model E 10-10) were used for all experiments. These were
housed in larger light-proof, sound-insulated boxes that con-
tained a house light and an exhaust fan. Chambers contained
two levers mounted at opposite ends of one wall. Centered
between the levers was a dipper that delivered 0.1 ml of
sweetened condensed milk diluted 2:1 with tap water. Ses-
sions were managed by a micro-computer using operant con-
trol software (Coulbourne Instruments D91-12, version 4.0).
agonists (14,17,18,30). Subsequently, the
close correlation between affinities of the 5-HT
2
and 5-HT
2A
2C
receptor subtypes for serotonergic ligands suggested that the
5-HT
receptor may play an independent or complementary
role in hallucinogenic activity (34,41). However, using a series
of nonselective serotonergic antagonists, it was concluded on
the basis of antagonist correlation analysis that the 5-HT
2C
re-
ceptor exerts a predominant influence in the stimulus effects
of indoleamine and phenethylamine hallucinogens (9). Using
purportedly selective 5-HT
2A
Procedure
Training.
After learning to drink from the dipper, rats
were trained to press first one and then the other of the two
levers. The number of responses for each reinforcement was
gradually increased from 1 to 10. During this time, the rein-
forced lever was alternated on a random basis. All subsequent
training and testing sessions used a fixed-ratio 10 (FR10)
schedule of reinforcement. Discrimination training was then
begun. Before each 10 min training session, subjects were in-
jected IP with either saline or drug. Following the adminis-
tration of drug, every tenth response on the drug-appropriate
lever was reinforced. Similarly, responses on the saline-appro-
priate lever were reinforced on a FR10 schedule following the
injection of saline. For half of the subjects, the left lever was
designated as the drug-appropriate lever. During discrimina-
tion training, drug, and saline were alternated on a daily basis.
Drug-induced stimulus control was assumed to be present when,
in five consecutive sessions, 83% or more of all responses
prior to the delivery of the first reinforcer were on the appro-
priate lever.
Groups of animals were trained with 5-MeO-DMT (
antagonists,
Schreiber et al. (35) had earlier reached the same conclusion
with respect to the stimulus effects of 2,4-dimethoxy-4-iodo-
amphetamine.
Against this background, stimulus control by the indole-
amine hallucinogen, 5-methoxy-
2A
and 5-HT
2C
-dimethyltryptamine (5-
MeO-DMT), is puzzling. In the most extensive analysis to
date of 5-MeO-DMT–induced stimulus control, Spencer and
colleagues (38) concluded that “the 5-HT
N,N
receptor subtype
is strongly involved. . .” Although it is true that a number of
investigators have suggested that 5-HT
1A
–mediated events
are factors in the behavioral effects of phenethylamine and in-
doleamine hallucinogens (1,5,19,32,41), this receptor appears
to play a modulatory role rather than be directly involved in
the stimulus effects of the hallucinogens. With respect to
5-MeO-DMT, the conclusion reached by Spencer et al. (38)
was based primarily upon (a) the fact that the potencies of
drugs substituting for 5-MeO-DMT were best correlated with
affinities at the 5-HT
1A
receptor; and (b) a significant degree of
blockade by pindolol, a drug which, when beta-adrenergic sys-
tems can be ruled out, functions as a selective antagonist at the
5-HT
1A
n
5
9). Pretreatment times for the IP injec-
tion of 5-MeO-DMT (3 mg/kg) and (
2
)-DOM (
n
5
)-DOM (0.56 mg/kg)
were 15 (15) and 75 (8) min, respectively. After stimulus con-
trol with the training drugs was well established, tests of gen-
eralization and of antagonism were conducted once per week
in each animal as long as performance during the remainder
of the week did not fall below a criterion level of 83% correct
responding. Subjects were assigned to test groups with the in-
tention of including equal numbers of those trained on the
previous day with saline and drug, respectively. During test
sessions, no responses were reinforced, and the session was
terminated after the emission of 10 responses on either lever.
The distribution of responses between the two levers was ex-
pressed as the percentage of total responses emitted on the
drug-appropriate lever. Response rate was calculated for each
session by dividing total number of responses emitted prior to
lever selection, that is, prior to the emission of 10 responses
on either lever, by elapsed time.
For purposes of discussion of these data, complete general-
ization of a training drug to a test drug is said to be present
when (a) a mean of 80% or more of all test responses occurs
on the drug-appropriate lever; (b) there is no significant dif-
ference between the response distributions of the training
2
receptor (42). In addition, binding data show high affin-
ity of 5-MeO-DMT for 5-HT
1A
receptors (20,38), and behavior-
ally significant activity at those receptors is indicated by similar
effects of 8-OH-DPAT and 5-MeO-DMT on forepaw treading
in the rat (42) and by the complete generalization of TVX Q
7821, a highly selective 5-HT
1A
agonist, to 5-MeO-DMT (37).
The present investigation was designed to test the hypoth-
esis that stimulus control by 5-MeO-DMT is mediated by
5-HT
1A
receptors. In addition, the hypothesis that 5-MeO-
DMT produces functionally significant effects at 5-HT
1A
recep-
tors was tested using the antagonists, WAY-100635, and piren-
perone, in rats trained with 5-MeO-DMT and with (
2A
2
)-DOM.
METHOD
Animals
Male Fischer-344 rats were obtained from Charles River
Breeding Laboratories, Inc. (Wilmington, MA) at an age of
approximately 6 weeks. They were housed in pairs, and al-
lowed free access to water in the home cage. All handling and
testing occurred during daytime hours. Standard rat chow was
gens including lysergic acid diethylamide [LSD; (27,44)], 2,5-
dimethoxy-4-methylamphetamine [DOM; (44)], and
mals
12) or (
5-HT
1A
RECEPTORS AND 5-MeO-DMT
77
drug and the test drug; and (c) there is a statistically signifi-
cant difference between the response distributions of the test
drug and saline control sessions. An intermediate degree of
generalization is defined as being present when response dis-
tributions after a test drug are less than 80% drug-appropri-
ate, and are significantly different from both training condi-
tions. Finally, when the response distribution after a test drug
is not different from that in saline control sessions, an absence
of generalization of the training drug to the test drug is as-
sumed. Similar criteria are applied to the definitions of full,
partial, and no antagonism. Thus, full antagonism is assumed
to be present when (a) less than 20% of all test responses are
on the training drug-appropriate lever; (b) there is no signifi-
cant difference between the response distributions in the test
of antagonism and the saline control, and (c) there is a statisti-
cally significant difference between the response distributions
of the test drug alone and in combination with the antagonist.
Drugs
)8-hydroxy-dipropylaminotetralin HCl
(8-OH-DPAT), and 5-methoxy-
6
)-Pindolol, (
6
-dimethyltryptamine ox-
alate were purchased from Research Biochemicals Interna-
tional. The following drugs were generously provided by the
organizations indicated: (
N,N
)-DOM HCl (National Institute on
Drug Abuse, Rockville, MD), WAY-100635 (Wyeth-Ayerst
Research, Princeton, NJ), pirenperone (Janssen Pharmaceu-
tica, Beerse, Belgium). All drugs were dissolved in 0.9% sa-
line solution and injected in a volume of 1 ml/kg body weight.
The IP route was employed for all drugs with the exception of
WAY-100635, which was injected SC.
2
FIG. 1. Dose–response relationships for WAY-100635 (squares)
and (
6
)-pindolol (diamonds) as antagonists of the training dose of
5-MeO-DMT (3 mg/kg). 5-MeO-DMT and (
6
)-pindolol were
injected IP, 15 and 60 min, respectively, before testing. WAY-100635
was injected SC, 30 min before testing. Each point represents the
mean of 1 determination in each of 10 subjects (
6
SEM). A number
next to a data point on the rate panel indicates the number of subjects
completing the session if less than 10. Ordinate: upper panel—mean
percentage of responses on the 5-MeO-DMT–appropriate lever;
lower panel—response rate. Data shown at points V and TD on the
abscissa (open hexagons) are means (
6
SEM) for the vehicle (saline)
and training drug sessions. Abscissa: dose plotted on a log scale. Sta-
tistical comparisons are between saline control, 5-MeO-DMT con-
trol, and the combination of antagonist and 5-MeO-DMT.
*Significantly different (
p
,
0.05) from 5-MeO-DMT. #Significantly
different from saline.
1
Significantly different from both 5-MeO-
DMT and saline.
Statistical Analysis
-test
or analysis of variance with subsequent multiple comparisons
by the method of Student–Newman–Keuls. In those instances
when the transformed data failed either a test of normality or
a test of equal variance, the Mann–Whitney rank-sum test or
analysis of variance on ranks was used. Differences were con-
sidered to be statistically significant if the probability of their
having arisen by chance was
t
0.05. All analyses were con-
ducted using SigmaStat for Windows™ (Jandel Scientific
Software, San Rafael, CA). In those instances when more
than one drug was tested in combination with a training drug,
control data were repeated for each comparison, and statisti-
cal analyses were applied using the appropriate control ses-
sions. However, for purposes of clarity, mean values for con-
trol data are shown in all figures.
,
shown in Fig. 2A. At the two higher doses of 5-MeO-DMT,
against which the antagonists were examined, WAY-100635
was clearly the more effective drug. Nonetheless, by the crite-
ria applied in this study, pirenperone produced an intermedi-
ate degree of antagonism when given in combination with the
training dose of 5-MeO-DMT.
When the prototypical 5-HT
RESULTS
Figure 1 shows the effects of pretreatment with either
WAY-100635 or pindolol on drug-appropriate responding fol-
lowing administration of the training dose of 5-MeO-DMT.
Although neither drug blocked 5-MeO-DMT completely,
both produced a significant intermediate degree of antago-
nism. In this regard, WAY-100635 was somewhat more effec-
tive and, given its greater selectivity for the 5-HT
agonist, 8-OH-DPAT, was
tested in rats trained with 5-MeO-DMT (Fig. 2A), complete
generalization of the training drug was observed. However,
the stimulus effects of 8-OH-DPAT were differentially
blocked by pirenperone and WAY-100635. Although the
former had no effect, WAY-100635 completely antagonized
the substitution of 8-OH-DPAT for 5-MeO-DMT. With re-
spect to the rate of responding, WAY-100635 antagonized the
rate-suppressant effects of 8-OH-DPAT at a dose of 0.4 mg/
kg. In contrast, pirenperone further suppressed responding in
combination with the 0.6 mg/kg dose 8-OH-DPAT.
compared
with pindolol (10,42), subsequent experiments employed
WAY-100635.
The dose–response relationship for 5-MeO-DMT and the
effects of the antagonists WAY-100635 and pirenperone are
1A
(
Behavioral data expressed as “percent drug-appropriate
responding” were transformed by squaring each value. If the
transformed data passed tests of normality and equal vari-
ance, statistical significance was assessed using Student’s
1A
78
WINTER ET AL.
-selective agonist, DOM. An intermediate
degree of generalization was observed at all but the lowest
dose tested. In addition, the results of tests in which DOM
was combined with WAY-100635 and pirenperone, respec-
tively, are shown. In contrast with the data presented in Fig.
2A for 5-MeO-DMT in rats trained with 5-MeO-DMT, the
partial generalization of 5-MeO-DMT to (
2
)-DOM was com-
pletely blocked by pirenperone, while WAY-100635 was
without antagonistic effects.
The dose–response relationship for (
2
)-DOM in rats
trained with that drug (0.56 mg/kg) is shown in Fig. 3A, to-
gether with the interactions of (
2
)-DOM with the antago-
nists, WAY-100635, pindolol, and pirenperone. The results
are as would be predicted from previous studies in that the
5-HT
2
antagonists, WAY-100635 and pindolol, were ineffec-
tive, while pirenperone produced complete antagonism.
When 8-OH-DPAT was tested in (
1A
)-DOM–trained subjects
(data not shown), no generalization was observed, but WAY-
100635 significantly antagonized the rate suppressant effects
of 8-OH-DPAT.
When animals trained with (
2
)-DOM were tested with
5-MeO-DMT (Fig. 3A), no statistically significant generaliza-
tion occurred at any dose. Furthermore, no significant inter-
actions occurred between either pirenperone or WAY-
100635 at doses of 5-MeO-DMT ranging from 0.3 to 3 mg/kg.
However, at the highest dose tested (6 mg/kg), the combina-
tion of 5-MeO-DMT and WAY-100635 resulted in an inter-
mediate degree of substitution for DOM. When the same
(
2
)-DOM-trained rats were tested with 5-MeO-DMT admin-
istered via the subcutaneous route (Fig. 3B), a significant in-
termediate degree of generalization was observed together
with a dose-related suppression of response rate. Although
WAY-100635 did not block the partial substitution of 5-MeO-
DMT for (
)-DOM, the suppression of response rates was
significantly antagonized. When pirenperone was given in
combination with 5-MeO-DMT, responding was completely
suppressed; hence, stimulus control could not be assessed.
However, the administration of both WAY-100635 and piren-
perone in combination with 5-MeO-DMT resulted in a resto-
ration of responding and a significant antagonism of the par-
tial substitution of 5-MeO-DMT for (
2
2
)-DOM.
DISCUSSION
The data of Fig. 1 indicate a substantial degree of antago-
nism of 5-MeO-DMT–induced stimulus control both by
WAY-100635 and by pindolol. The latter observation is in
agreement with the results of Spencer et al. (38), although
those investigators observed a somewhat higher degree of
antagonism. We are unaware of any previous reports of the
antagonism by WAY-100635 of stimulus control by 5-MeO-
DMT but, given the high degree of selectivity of WAY-
FIG. 2. (A) Dose–response relationships for 8-OH-DPAT and
5-MeO-DMT (circles) in rats trained with 5-MeO-DMT (3 mg/kg) as
a discriminative stimulus and the interaction of 8-OH-DPAT and
5-MeO-DMT with pirenperone (0.16 mg/kg; triangles) and with
WAY-100635 (0.3 mg/kg; squares). Pirenperone was injected IP, 60
min before testing. The points at 1.5 and 3.0 mg/kg of 5-MeO-DMT
represent the mean of two determinations in each of the subjects. Sta-
tistical comparisons are between 8-OH-DPAT and 5-MeO-DMT,
respectively, alone and in combination with either pirenperone or
WAY-100635. All other details are as in Fig. 1. (B) Dose–response
relationship for (
2
)-
DOM with pirenperone (0.16 mg/kg; triangles) and with WAY-
100635 (0.3 mg/kg; squares). Each point on the dose–response curve
for 5-MeO-DMT represents the mean of three determinations in
each subject. (
2
)-DOM was administered IP 75 min before testing.
All other details are as in Fig. 1.
2
Figure 2B shows the tests of generalization of 5-MeO-
DMT to the 5-HT
2
)-DOM (circles) in rats trained with 5-MeO-DMT
(3 mg/kg) as a discriminative stimulus and the interaction of (
5-HT
1A
RECEPTORS AND 5-MeO-DMT
79
receptor (10), the data of Fig. 1
strongly support an effect mediated by that receptor.
The contrast seen in Fig. 2A between the respective abili-
ties of WAY-100635 and pirenperone to antagonize the
5-MeO-DMT cue provides further evidence favoring the hy-
pothesis that a 5-HT
1A
-mediated mechanism predominates.
Furthermore, these data argue that 5-MeO-DMT does not in-
duce stimulus control via 5-HT
1A
receptors as do other in-
doleamine and phenethylamine hallucinogens (9,35). Al-
though it is true that pirenperone is nonselective with respect
to dopaminergic, adrenergic, and serotonergic receptors (26),
it is more selective within the family of serotonergic recep-
tors. Thus, in rat cortex, pirenperone exhibits an affinity for
undifferentiated 5-HT
2A
receptors, which is more than a thou-
sand times greater than at the 5-HT
2
receptor (24). Further-
more, previous studies have provided ample evidence that
pirenperone is an effective antagonist of the stimulus effects
of LSD-induced stimulus control and of the generalization of
LSD to (
1A
)-DOM–induced
stimulus control [(9); present investigation, Fig. 3A]. Al-
though it was earlier reported that pizotifen (pizotyline, BC-
105), a drug that is moderately selective for 5-HT
)-DOM (7,47) as well as of (
2
2
receptors
receptors (28,47), completely antagonizes
stimulus control by 5-MeO-DMT (15,49,50) when a training
dose of 1.5 mg/kg is used, only partial blockade was observed
by Spencer et al. (38) using a training dose of 1.25 mg/kg.
In the landmark study by Spencer et al. (38), complete
generalization of 5-MeO-DMT to the 5-HT
1
-selective ago-
nist, 8-OH-DPAT, was observed. That finding is fully repli-
cated in Fig. 2A, together with a demonstration of complete
antagonism of 8-OH-DPAT by the selective 5-HT
1A
antago-
nist, WAY-100635, and an absence of antagonism by piren-
perone. It should be noted that generalization between
5-MeO-DMT and 8-OH-DPAT is not symmetrical in that ani-
mals trained with 8-OH-DPAT yielded a maximum of 38%
8-OH-DPAT–appropriate responding when tested with a
range of doses of 5-MeO-DMT (13). However, Fozard et al.
(11) made the interesting observation that full generalization
occurred if the rats were pretreated with ketanserin prior to
administration of 5-MeO-DMT. The authors interpreted this
to suggest, in consonance with the present hypothesis, that
5-MeO-DMT produces functionally significant agonistic ef-
fects at both 5-HT
1A
receptors, with the latter
masking the former in 8-OH-DPAT–trained animals.
When (
1A
and 5-HT
2
)-DOM was tested in rats trained with 5-MeO-
DMT, a significant intermediate degree of generalization was
seen (Fig. 2B). This finding differs somewhat from the full
generalization of 5-MeO-DMT to racemic DOM reported
earlier by Glennon et al. (15). Of greater significance, how-
ever, is the contrast between the effects of WAY-100635 and
pirenperone on stimulus control directly mediated by 5-MeO-
DMT (Fig. 2A) and the effects of the antagonists upon the
partial generalization of 5-MeO-DMT to (
2
)-DOM (Fig.
FIG. 3. (A) Dose–response relationships for (
2
)-DOM and 5-MeO-
)-DOM (0.56 mg/kg) as a dis-
criminative stimulus and the interaction of (
2
training conditions. Data shown at points V and TD on the abscissa
(closed hexagons) are means (
)-DOM and 5-MeO-
DMT with pirenperone (0.16 mg/kg; triangles), with WAY-100635
(0.3 mg/kg; squares), and with (
2
SEM) for the vehicle and training
drug sessions. (B) Dose–response relationship for 5-MeO-DMT (cir-
cles) administered SC to rats trained with (
6
)-pindolol (5 mg/kg; diamonds).
Each point represents the mean of one determination in each of nine
subjects. A number next to a data point on the rate panel indicates
the number of subjects completing the session if less than 9. *Signifi-
cantly different from DOM alone.
6
)-DOM as a discrimina-
tive stimulus and the interaction of 5-MeO-DMT with pirenperone
(0.16 mg/kg; triangles), WAY-100635 (0.3 mg/kg; squares), and the
combination of pirenperone and WAY-100635 (hexagons). *Signifi-
cantly different from 5-MeO-DMT alone.
2
1
Significantly different from both
100635 for the 5-HT
6
relative to 5-HT
2
DMT (circles) in rats trained with (
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