Objective: This study was designed to examine whether enriched environments (EE) would attenuate object recognition and spatial learning and memory deficits and locomotor sensitization induced by methadone maintenance treatment (MMT) in morphine-withdrawn rats. Methods: Male Wistar rats (170 ± 10 g) were injected with bi-daily doses (10 mg/kg, 12-h intervals) of morphine for 14 days. Rats receiving MMT were reared in the standard environment (SE) or EE during 30 days of morphine withdrawal. Then, the rats were tested for object recognition (the object recognition memory test, ORMT) and spatial learning and memory (the water maze) and then challenged with morphine (1 mg/kg, i.p.) and evaluated for locomotor activity (open-field box). Results: The results revealed that the dependent/saline/EE (D/Sal/EE) and D/methadone/EE (D/Meth/EE) rats exhibited significant preference for the new object (p = 0.006 and p = 0.049), spent more time in the target zone (p = 0.045 and p = 0.005) on the water maze, and displayed a lower level of distance traveled (p = 0.002 and p = 0.0001) compared to their control groups reared in SE. Conclusions: We conclude that exposure to EE could ameliorate the object recognition and spatial memory deficits and also decrease locomotor sensitivity in morphine-withdrawn rats receiving MMT. Thus, EE may be beneficial in the treatment of addiction during MMT.

1.
Wang
JS
,
Ruan
Y
,
Taylor
RM
,
Donovan
JL
,
Markowitz
JS
,
DeVane
CL
.
Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice
.
Psychopharmacology (Berl)
.
2004
Apr
;
173
(
1-2
):
132
8
.
[PubMed]
0033-3158
2.
Berkowitz
BA
.
The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone
.
Clin Pharmacokinet
.
1976
;
1
(
3
):
219
30
.
[PubMed]
0312-5963
3.
He
L
,
Kim
J
,
Ou
C
,
McFadden
W
,
van Rijn
RM
,
Whistler
JL
.
Methadone antinociception is dependent on peripheral opioid receptors
.
J Pain
.
2009
Apr
;
10
(
4
):
369
79
.
[PubMed]
1526-5900
4.
Kristensen
K
,
Christensen
CB
,
Christrup
LL
.
The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine
.
Life Sci
.
1995
;
56
(
2
):
PL45
50
.
[PubMed]
0024-3205
5.
Chiang
YC
,
Hung
TW
,
Lee
CW
,
Yan
JY
,
Ho
IK
.
Enhancement of tolerance development to morphine in rats prenatally exposed to morphine, methadone, and buprenorphine
.
J Biomed Sci
.
2010
Jun
;
17
(
1
):
46
.
[PubMed]
1021-7770
6.
Marsch
LA
.
The efficacy of methadone maintenance interventions in reducing illicit opiate use, HIV risk behavior and criminality: a meta-analysis
.
Addiction
.
1998
Apr
;
93
(
4
):
515
32
.
[PubMed]
0965-2140
7.
Darke
S
,
McDonald
S
,
Kaye
S
,
Torok
M
.
Comparative patterns of cognitive performance amongst opioid maintenance patients, abstinent opioid users and non-opioid users
.
Drug Alcohol Depend
.
2012
Dec
;
126
(
3
):
309
15
.
[PubMed]
0376-8716
8.
Soyka
M
,
Limmer
C
,
Lehnert
R
,
Koller
G
,
Martin
G
,
Küfner
H
, et al.
A comparison of cognitive function in patients under maintenance treatment with heroin, methadone, or buprenorphine and healthy controls: an open pilot study
.
Am J Drug Alcohol Abuse
.
2011
Nov
;
37
(
6
):
497
508
.
[PubMed]
0095-2990
9.
Soyka
M
,
Zingg
C
,
Koller
G
,
Hennig-Fast
K
.
Cognitive function in short- and long-term substitution treatment: are there differences?
World J Biol Psychiatry
.
2010
Mar
;
11
(
2 Pt 2
):
400
8
.
[PubMed]
1562-2975
10.
Wang
GY
,
Wouldes
TA
,
Russell
BR
.
Methadone maintenance treatment and cognitive function: a systematic review
.
Curr Drug Abuse Rev
.
2013
Sep
;
6
(
3
):
220
30
.
[PubMed]
1874-4737
11.
Lin
WC
,
Chou
KH
,
Chen
CC
,
Huang
CC
,
Chen
HL
,
Lu
CH
, et al.
White matter abnormalities correlating with memory and depression in heroin users under methadone maintenance treatment
.
PLoS One
.
2012
;
7
(
4
):
e33809
.
[PubMed]
1932-6203
12.
Chen
HH
,
Chiang
YC
,
Yuan
ZF
,
Kuo
CC
,
Lai
MD
,
Hung
TW
, et al.
Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats
.
Neuropsychiatr Dis Treat
.
2015
Mar
;
11
:
609
18
.
[PubMed]
1176-6328
13.
Li
W
,
Li
Q
,
Wang
Y
,
Zhu
J
,
Ye
J
,
Yan
X
, et al.
Methadone-induced damage to white matter integrity in methadone maintenance patients: A longitudinal self-control dti study
.
Sci Rep
.
2016
Jan
;
6
(
1
):
19662
.
[PubMed]
2045-2322
14.
Langleben
DD
,
Ruparel
K
,
Elman
I
,
Busch-Winokur
S
,
Pratiwadi
R
,
Loughead
J
, et al.
Acute effect of methadone maintenance dose on brain FMRI response to heroin-related cues
.
Am J Psychiatry
.
2008
Mar
;
165
(
3
):
390
4
.
[PubMed]
0002-953X
15.
Kalivas
PW
,
O’Brien
C
.
Drug addiction as a pathology of staged neuroplasticity
.
Neuropsychopharmacology
.
2008
Jan
;
33
(
1
):
166
80
.
[PubMed]
0893-133X
16.
Levran
O
,
Peles
E
,
Randesi
M
,
Correa da Rosa
J
,
Ott
J
,
Rotrosen
J
, et al.
Synaptic plasticity and signal transduction gene polymorphisms and vulnerability to drug addictions in populations of european or african ancestry
.
CNS Neurosci Ther
.
2015
Nov
;
21
(
11
):
898
904
.
[PubMed]
1755-5930
17.
Mangold
DL
,
Peyrot
M
,
Giggey
P
,
Wand
GS
.
Endogenous opioid activity is associated with obsessive-compulsive symptomology in individuals with a family history of alcoholism
.
Neuropsychopharmacology
.
2000
Jun
;
22
(
6
):
595
607
.
[PubMed]
0893-133X
18.
Garland
EL
,
Froeliger
B
,
Zeidan
F
,
Partin
K
,
Howard
MO
.
The downward spiral of chronic pain, prescription opioid misuse, and addiction: cognitive, affective, and neuropsychopharmacologic pathways
.
Neurosci Biobehav Rev
.
2013
Dec
;
37
(
10 Pt 2
):
2597
607
.
[PubMed]
0149-7634
19.
Cheetham
A
,
Allen
NB
,
Yücel
M
,
Lubman
DI
.
The role of affective dysregulation in drug addiction
.
Clin Psychol Rev
.
2010
Aug
;
30
(
6
):
621
34
.
[PubMed]
0272-7358
20.
Garland
EL
,
Froeliger
B
,
Howard
MO
.
Mindfulness training targets neurocognitive mechanisms of addiction at the attention-appraisal-emotion interface
.
Front Psychiatry
.
2014
Jan
;
4
:
173
.
[PubMed]
1664-0640
21.
Curran
HV
,
Bolton
J
,
Wanigaratne
S
,
Smyth
C
.
Additional methadone increases craving for heroin: a double-blind, placebo-controlled study of chronic opiate users receiving methadone substitution treatment
.
Addiction
.
1999
May
;
94
(
5
):
665
74
.
[PubMed]
0965-2140
22.
Allouche
S
,
Le Marec
T
,
Noble
F
,
Marie
N
.
Different patterns of administration modulate propensity of methadone and buprenorphine to promote locomotor sensitization in mice
.
Prog Neuropsychopharmacol Biol Psychiatry
.
2013
Jan
;
40
:
286
91
.
[PubMed]
0278-5846
23.
Taracha
E
,
Chrapusta
SJ
,
Lehner
M
,
Skórzewska
A
,
Maciejak
P
,
Szyndler
J
, et al.
Morphine and methadone pre-exposures differently modify brain regional Fos protein expression and locomotor activity responses to morphine challenge in the rat
.
Drug Alcohol Depend
.
2008
Sep
;
97
(
1-2
):
21
32
.
[PubMed]
0376-8716
24.
Alizadeh
M
,
Zahedi-Khorasani
M
,
Bandegi
AR
,
Yousefi
B
,
Rashidy-Pour
A
,
Sameni
HR
, et al.
Effects of treadmill exercise on methadone withdrawal-induced locomotor sensitization and the ventral pallidum and ventral tegmental area BDNF levels in morphine withdrawn rats receiving methadone maintenance treatment
.
Neurosci Lett
.
2018
Sep
;
683
:
33
7
.
[PubMed]
0304-3940
25.
Mohammed
AH
,
Zhu
SW
,
Darmopil
S
,
Hjerling-Leffler
J
,
Ernfors
P
,
Winblad
B
, et al.
Environmental enrichment and the brain
.
Prog Brain Res
.
2002
;
138
:
109
33
.
[PubMed]
0079-6123
26.
van Praag
H
,
Kempermann
G
,
Gage
FH
.
Neural consequences of environmental enrichment
.
Nat Rev Neurosci
.
2000
Dec
;
1
(
3
):
191
8
.
[PubMed]
1471-003X
27.
Galeano
P
,
Blanco
E
,
Logica Tornatore
TM
,
Romero
JI
,
Holubiec
MI
,
Rodríguez de Fonseca
F
, et al.
Life-long environmental enrichment counteracts spatial learning, reference and working memory deficits in middle-aged rats subjected to perinatal asphyxia
.
Front Behav Neurosci
.
2015
Jan
;
8
:
406
.
[PubMed]
1662-5153
28.
Will
B
,
Galani
R
,
Kelche
C
,
Rosenzweig
MR
.
Recovery from brain injury in animals: relative efficacy of environmental enrichment, physical exercise or formal training (1990-2002)
.
Prog Neurobiol
.
2004
Feb
;
72
(
3
):
167
82
.
[PubMed]
0301-0082
29.
Hammami-Abrand Abadi
A
,
Miladi-Gorji
H
.
Effects of environmental enrichment on behavioral and spatial cognitive deficits in morphine-dependent and -withdrawn rats
.
Can J Physiol Pharmacol
.
2017
Feb
;
95
(
2
):
163
9
.
[PubMed]
0008-4212
30.
Khalaji
S
,
Bigdeli
I
,
Ghorbani
R
,
Miladi-Gorji
H
:
Environmental enrichment attenuates morphine-induced conditioned place preference and locomotor sensitization in maternally-separated rat pups.
Basic Clin Neurosci.
2018
:0-0.
31.
Morisot
N
,
Contarino
A
.
The CRF1 and the CRF2 receptor mediate recognition memory deficits and vulnerability induced by opiate withdrawal
.
Neuropharmacology
.
2016
Jun
;
105
:
500
7
.
[PubMed]
0028-3908
32.
Mesa-Gresa
P
,
Pérez-Martinez
A
,
Redolat
R
.
Environmental enrichment improves novel object recognition and enhances agonistic behavior in male mice
.
Aggress Behav
.
2013
Jul-Aug
;
39
(
4
):
269
79
.
[PubMed]
0096-140X
33.
Mokhtari-Zaer
A
,
Ghodrati-Jaldbakhan
S
,
Vafaei
AA
,
Miladi-Gorji
H
,
Akhavan
MM
,
Bandegi
AR
, et al.
Effects of voluntary and treadmill exercise on spontaneous withdrawal signs, cognitive deficits and alterations in apoptosis-associated proteins in morphine-dependent rats
.
Behav Brain Res
.
2014
Sep
;
271
:
160
70
.
[PubMed]
0166-4328
34.
Nilsson
M
,
Perfilieva
E
,
Johansson
U
,
Orwar
O
,
Eriksson
PS
.
Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory
.
J Neurobiol
.
1999
Jun
;
39
(
4
):
569
78
.
[PubMed]
0022-3034
35.
Zhang
S
,
Xie
H
,
Wang
Y
,
Li
D
,
Du
L
,
Wu
Y
, et al.
Enriched environment improves behavioral performance and attenuates inflammatory response induced by tnf-α in healthy adult mice
.
Eur J Inflamm
.
2017
;
15
(
3
):
200
9
. 1721-727X
36.
Segovia
G
,
Yagüe
AG
,
García-Verdugo
JM
,
Mora
F
.
Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats
.
Brain Res Bull
.
2006
Jun
;
70
(
1
):
8
14
.
[PubMed]
0361-9230
37.
Filiano
AJ
,
Xu
Y
,
Tustison
NJ
,
Marsh
RL
,
Baker
W
,
Smirnov
I
, et al.
Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour
.
Nature
.
2016
Jul
;
535
(
7612
):
425
9
.
[PubMed]
0028-0836
38.
Steketee
JD
,
Kalivas
PW
.
Drug wanting: behavioral sensitization and relapse to drug-seeking behavior
.
Pharmacol Rev
.
2011
Jun
;
63
(
2
):
348
65
.
[PubMed]
0031-6997
39.
Xu
Z
,
Hou
B
,
Gao
Y
,
He
F
,
Zhang
C
.
Effects of enriched environment on morphine-induced reward in mice
.
Exp Neurol
.
2007
Apr
;
204
(
2
):
714
9
.
[PubMed]
0014-4886
40.
Antunes
M
,
Biala
G
.
The novel object recognition memory: neurobiology, test procedure, and its modifications
.
Cogn Process
.
2012
May
;
13
(
2
):
93
110
.
[PubMed]
1612-4782
41.
Solinas
M
,
Thiriet
N
,
Chauvet
C
,
Jaber
M
.
Prevention and treatment of drug addiction by environmental enrichment
.
Prog Neurobiol
.
2010
Dec
;
92
(
4
):
572
92
.
[PubMed]
0301-0082
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.