ORIGINAL RESEARCH

published: 31 July 2020

doi: 10.3389/fpsyt.2020.00750

Reciprocal Substitution Between

Methamphetamine and Heroin in
Terms of Reinforcement Effects
in Rats
Di-sen Mei 1,2, Yu-jia Cai 2, Fang-min Wang 2, Bao-miao Ma 2, Hui-fen Liu 2,3,
Wen-hua Zhou 2,3* and Jiang-ping Xu 1*
Edited by: 1 Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University,
Yanhui Liao, Guangzhou, China, 2 Zhejiang Provincial Key Lab of Addiction, Ningbo University School of Medicine, Ningbo, China,
Sir Run Run Shaw Hospital, China 3 Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Ningbo University School of

Reviewed by: Medicine, Ningbo, China

Yonghui Li,
University of Chinese Academy of
Sciences, China
Heroin and methamphetamine are both popular illicit drugs in China. Previous clinical data
Jian-Hui Liang, showed that habitual users of either heroin or methamphetamine abuse the other drug for
Peking University, China
substitution in case of unavailability of their preferred drug. The present study aimed to
Ning Wu,
Beijing Institute of Pharmacology & observe whether heroin can substitute the methamphetamine reinforcement effect in rats,
Toxicology, China and vice versa. Rats were trained to self-administer heroin or methamphetamine (both 50
*Correspondence: mg/kg/infusion) under an FR1 reinforcing schedule for 10 days. After having extracted the
Wen-hua Zhou
whzhou@vip.163.com
dose–effect curve of the two drugs, we administered methamphetamine at different doses
Jiang-ping Xu (12.5–200 mg/kg/infusion) to replace heroin during the period of self-administration, and
jpx@smu.edu.cn
vice versa. The heroin dose–effect curve showed an inverted U-shaped trend, and the
Specialty section:
total intake dose of heroin significantly increased when the training dose increased from
This article was submitted to 50 to 100 or 200 mg/kg/infusion. Following replacement with methamphetamine, the total
Addictive Disorders, dose–effect curve shifted leftwards and upwards. By contrast, although the dose–effect
a section of the journal
Frontiers in Psychiatry curve of methamphetamine also showed an inverted U-shaped trend, the total dose of
Received: 05 May 2020 methamphetamine significantly decreased when the training dose decreased from 50 to
Accepted: 16 July 2020 25 mg/kg/infusion; conversely, when the methamphetamine training dose increased, the
Published: 31 July 2020
total dose did not change significantly. The total dose–effect curve shifted rightwards after
Citation:
Mei D-s, Cai Y-j, Wang F-m, Ma B-m,
heroin was substituted with methamphetamine. Although heroin and methamphetamine
Liu H-f, Zhou W-h and Xu J-p (2020) had their own independent reward effects, low doses of methamphetamine can replace
Reciprocal Substitution the heroin reward effect, while high doses of heroin can replace the methamphetamine
Between Methamphetamine
and Heroin in Terms of reward effect. These results demonstrated that heroin and methamphetamine can
Reinforcement Effects in Rats. substitute each other in terms of reinforcement effects in rats.
Front. Psychiatry 11:750.
doi: 10.3389/fpsyt.2020.00750 Keywords: amphetamine, opiate, drug abuse, conditioning reward, addiction

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Mei et al. Rewarding Substitution of Methamphetamine and Heroin

INTRODUCTION MATERIALS AND METHODS

Drug abuse remains a significant public health concern in China Animals and Drugs
and worldwide. The 2016 Annual National Drug Report of China Male Sprague–Dawley rats initially weighing 260 to 300 g
counted about 2.95 million drug abusers registered in China; (Zhejiang Experimental Animal Center, Hangzhou, China)
moreover, real drug users were estimated to be more than 14 were individually housed in a temperature-controlled and
million (1). Before 2014, heroin was the most common illicit ventilated colony room, with food and water available ad
drug in China, followed by methamphetamine (MA), either in libitum. To simulate the rodents’ natural state, all experiments
the form of crystals or pills; henceforth, the number of MA users were conducted during the dark phase of the light–dark cycle
increased significantly coinciding with the reduction of heroin (lights on from 7:30 am to 6:30 pm). We performed the
users (1), suggesting dual drug use epidemics in China. In experiments following the Guide for the Care and Use of
addition, issues related to the combined utilization of MA and Laboratory Animals by the National Institutes of Health
heroin were also identified (2). Further, a 2014 survey conducted (8th edition).
in five major Methadone Maintenance Treatment (MMT) clinics We used heroin (diacetylmorphine HCl) and D-
in the Yunnan province showed that the urine of about 9.2% of methamphetamine — obtained from the National Institute of
participants was positive for both morphine and MA (3). Forensic Science (Beijing, China) — dissolved in sterile 0.9%
Previous clinical data showed that among current heroin users, physiological saline.
half of them used amphetamine during the preceding 6 months
while, in the case of amphetamine users, two-thirds of them used Surgery
heroin in that period; besides, although transitions from The rats were anesthetized with sodium pentobarbital (50 mg/kg,
amphetamines to heroin are more common than those in the i.p.) and implanted with chronically indwelling jugular catheters
other way round, they are relatively common in both directions as previously described (13, 14). The catheter was flushed daily
(4). A 2015 survey from the National HIV Behavioral with 0.3 ml saline containing heparin (5 units) and penicillin B
Surveillance (NHBS) system in Denver, Colorado, showed that (20,000 units) to prevent bacterial infection and maintain
half of the participants injected both MA and heroin during catheter patency. Following the surgery, the rats were allowed
the past 12 months (5). Recently, the last-month use of MA 7 d to recover.
among treatment-seeking opioid users significantly increased
from 18.8% in 2011 to 34.2% in 2017 (6). Since the global Intravenous Self-Administration Training
emergence of combining MA with heroin may have serious The rats were trained to self-administer heroin or MA in operant
public-health implications, understanding the mechanisms chambers following an FR1 schedule for 4 h/d during 10
underlying co-morbidity of MA and heroin use disorders consecutive days. Every session started with a blue light inside
is crucial. the “active” nose-poke hole. The rat received a single infusion
Heroin is a µ-opioid receptor agonist that mimics the effects following a nose-poke inside the “active” hole based on an FR1
of endogenous opioids, resulting in euphoria, analgesia, and schedule. Each infusion was paired with 5 s of illumination at
sedation (7). On the other hand, MA — a psychostimulant — room light, as well as with the noise from the infusion pump, as a
principally affects the monoamine neurotransmitter system, discrete conditioned stimulus (CS). Further, we set a timeout
resulting in alertness feelings, increased energy, and euphoria period of 20 s during which the response produced no
(8). Heroin and MA greatly differ in many aspects, including programmed consequences but was still recorded. Illumination
their pharmacological features, behavioral or neurobiological of the blue light in the “active” nose-poke signaled the end of the
mechanisms, and clinical effects (9, 10); however, heroin and timeout period. Nose-poking in the “inactive” hole produced no
MA share the ability to increase dopamine levels in the programmed consequences.
nucleus accumbens (NAc), one of the terminal regions of the
mesocorticolimbic dopamine projecting system; the activation of Special Experiments
this system and the subsequent dopamine release play a key role Experiment 1: MA Substitution of the Heroin
in the rewarding effects of the drugs (11). Interestingly, heroin is Reinforcement Effects
an attractive option for MA users due to its high purity and Heroin self-administration: All rats (n=19) were trained to self-
relatively low price (12). Similarly, opioids users prefer MA when administer heroin for 10 days (4 h/d; 100 mg/kg/infusion for the
it is easily accessible or cheap (6). Nonetheless, the reasons for first 3 days, 50 mg/kg/infusion for last 7 days) based on an FR1
the combined utilization of MA and heroin are still unclear. reinforcement schedule.
The present study investigates whether heroin and MA Dose–effect response in heroin self-administration: On the
can substitute each other in terms of reinforcement effect in 11th day, the rats were randomly divided into three groups (n =
rats. First, we observed whether MA could replace heroin 6–7/group). Each group self-administered heroin for 4 h with
reinforcement effects in heroin intravenous self-administered doses of either 5, 12.5, or 25 mg/kg/infusion instead of the
rats. Second, we evaluated whether heroin could substitute MA original dose of heroin (50 mg/kg/infusion). On the 12th day,
reinforcement effects in MA self-administered rats. all rats recovered with the original dose of heroin. On the 13th

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Mei et al. Rewarding Substitution of Methamphetamine and Heroin

day, the rats were randomly divided into two groups (n = 9–10/ ANOVA revealed a significant difference in the active pokes
group) and each group was given either 100 or 200 mg/kg of (F5, 41 = 7.6, P<0.01), infusions (F5,41 = 10.4, P<0.01), and total
heroin for 4 h. dose of heroin intake (F5,41 = 18.1, P<0.01). The post hoc
MA substituted for heroin reinforcement: Following another comparisons indicated that at the number active pokes and
recovery day, on the 15th day, the rats were randomly divided infusions at the dose of 25 mg/kg/infusion was significantly
into two groups (n = 9–10/group) with the order mixed and increased compared to other doses. The dose–effect curve of
counterbalanced. Each group self-administered MA doses of heroin showed an inverted U-shaped trend, whose peak likely
either 12.5 or 50 µg/kg/infusion for 4 h. Then, MA doses of 25 being 25 mg/kg/infusion. Nevertheless, the active pokes and the
or 100 mg/kg/infusion were given for 4 h on alternate days, using infusions of high dose of heroin changed not so significantly
the original heroin dose for recovery on interval days. Then in (Figures 1B, C). Besides, the total dose of heroin intake showed a
one groups (n=9) MA dose of 200 mg/kg/infusion were given for linear trend, being higher at high doses (i.e., 100 or 200 mg/kg/
4 h on alternate days. infusion) (Figure 1D).
Experiment 2: Heroin Substitution of the MA
Reinforcement Effects The Dose–Effect Curve of MA Substitution
MA self-administration: All rats (n=16) were trained to self- for Heroin Reinforcement
administer MA for 10 days (4 h/d; 50 mg/kg/infusion) as When the rats were allowed to self-administer several MA doses
described above. instead of heroin, they exhibited significant changes in terms of
Dose–effect response in MA self-administration: On the 11th active pokes (F5, 47 = 2.7, P<0.05) and infusions (F5, 47 = 7.1,
day, the rats were randomly divided into two groups (n=8/ P<0.01). However, post hoc comparisons indicated that MA
group). Each group self-administered MA doses of either 25 or significantly increased the active pokes and the infusions only
100 mg/kg/infusion instead of the original dose of MA (50 mg/ at low doses (Figures 2A, B).
kg/infusion) for 4 h. On the 12th day, all rats recovered with Moreover, multiple comparisons revealed that, when replaced
the original dose of MA (50 mg/kg/infusion). On the 13th day, with MA, the total intake infusions only significantly increased
the rats were randomly divided into two groups (n = 7–8/ above the training MA dose of 50 mg/kg/infusion, and 25 mg/kg/
group) and each group was given either 50 or 200 mg/kg of infusion could equally instead of 50 mg/kg/infusion heroin self-
heroin for 4 h. One rat was abandoned due to an unexpected administration at total dose (Figure 2C). The total dose curve of
physical condition. MA substitution shifted leftwards and upwards compared to the
Heroin substituted for MA reinforcement: After 1 day for total dose–effect curve of heroin (Figure 2D).
recovery, the rats were randomly divided into two groups (n = 5–
6/group) with the order mixed and counterbalanced. Each group The Dose–Effect Curve of MA Self-
used a dose of either 12.5, 25 mg/kg/infusion heroin to replace the Administration
original dose of MA (50 mg/kg/infusion) for 4 h; then, the heroin Rats were successfully trained to self-administer MA under an
doses changed to either 50 or 200 mg/kg/infusion on alternate FR1 reinforcing schedule as well (Figure 3A). When in dose–
days, using the original heroin dose (50 mg/kg/infusion) on effect response in MA self-administration session, the statistical
recovery interval days. analyses indicated significant differences in terms of active pokes
(F3, 27 = 17.5, P<0.01), infusions (F3,27 = 16.4, P<0.01), and total
Data Statistics intake dose of MA (F3,27 = 8.5, P<0.01) at different training doses.
Data are expressed as mean ± SEM. All statistic tests were Post hoc comparisons showed that active pokes and infusions
performed using SPSS (IBM, Armonk, New York, United decreased significantly at high MA doses (100 or 200 mg/kg/
States). The mean amount of “active” and “inactive” pokes, infusion) compared to 50 mg/kg/infusion doses (P<0.01). The
infusions, and total dose during self-administration were dose–effect curve of MA also showed an inverted U-shaped trend
analyzed via One-way ANOVAs with Bonferroni post hoc distribution (Figures 3B, C). However, only the total intake dose
testing when appropriate. And the t test was used to compare of MA decreased at low MA doses (i.e., 25 mg/kg/infusion)
between the two groups. A P-value< 0.05 was considered (P<0.01) (Figure 3D).
statistically significant.
The Dose–Effect Curve of Heroin
Substitution for MA Reinforcement
RESULTS When the rats were allowed to self-administer different doses of
heroin instead of 50 mg/kg/infusion of MA, the statistical
The Dose–Effect Curve of Heroin analyses showed a significant change in the number of active
Self-Administration pokes (F4, 28 = 5.8, P<0.01) and infusions (F4, 28 = 6.8, P<0.01).
Rats were successfully trained to self-administer heroin under an However, post hoc comparisons showed a significant decrease in
FR1 reinforcing schedule (Figure 1A). When in dose–effect the active pokes and infusions following heroin substitution at
response in heroin self-administration session, One-way doses of 50 or 200 mg/kg/infusion (Figures 4A, B).

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Mei et al. Rewarding Substitution of Methamphetamine and Heroin

A B

C D

FIGURE 1 | Dose–effect response in heroin self-administration. Rats (n = 19) were successfully trained to self-administer heroin 4 h/d under an FR1 reinforcing
schedule within 10 days (A). When the heroin trained rats were tested in different dose (5 mg/kg/infusion–200 mg/kg/infusion) of heroin to self-administer 4 h in the
following days (n=6-10/group). The active pokes and the infusions were changed and showed an inverted U trend, whose peak likely being 25 mg/kg/infusion (B, C).
Rats took more heroin when doses increased to wither 100 or 200 mg/kg/infusion and less heroin intake when doses highly decreased to either 5 or 12.5 mg/kg/
infusion, but maintained the total dose unchanged following the dose decreased to lower at 25 mg/kg/infusion (D). **P < 0.01, compared to 25 mg/kg/infusion; #P <
0.05, ##P < 0.01, compared to 50 mg/kg/infusion. Error bars = SEM.

Moreover, the total dose of heroin showed a progressive The dose–effect curve of heroin showed a negative linear trend, and
increase in MA trained rats. Post hoc comparisons indicated the the active response decreased following the dose increase,
total intake dose of heroin significantly decreased at 50 mg/kg/ consistently with the reinforcement theory (19).The limbic
infusion or below when replaced with heroin. Only heroin dopaminergic system was proposed as the neurobiological
doses of 200 mg/kg/infusion could equally substitute MA doses substrate for the rewarding effects of both opiates and
of 50 mg/kg/infusion (Figure 4C). Finally, compared to the psychostimulants. More specifically, heroin indirectly activates
total dose–effect curve of MA, the substituted curve shifted dopaminergic neurons in the ventral tegmental area (VTA),
rightwards (Figure 4D). through inhibition of GABAergic interneurons (20), whereas MA
directly redistributes dopamine from synaptic vesicles to the
synaptic cleft, blocks dopamine reuptake, and inverts the
DISCUSSION direction of dopamine transport (8). According to the existing
literature, both MA and heroin injection produce the release of
According to these results, heroin and methamphetamine could dopamine in the NAc, as analyzed by microdialysis (21, 22).
replace each other during the self-administration training, Further, more selective studies of drug-induced neuronal
suggesting that both opiates and psychostimulants may have a plasticity recently highlighted that these two drugs promote an
common rewarding mechanism. Besides, higher heroin doses overall reward circuitry signaling overlap, particularly through the
seem to be necessary to replace the MA rewarding effects, modification of excitatory synapses in the NAc (23). Therefore, the
whereas lower MA doses seem to be sufficient to replace the common dopamine mechanism could explain the reciprocal
heroin rewarding effects. substitutability between heroin and MA.
With 4 h/d drug access, heroin or MA self-administration were When heroin was replaced with MA, the total dose–effect
stable both over time and across doses after 10-d training (15–18). curve shifted leftwards and upwards, possibly meaning that

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Mei et al. Rewarding Substitution of Methamphetamine and Heroin

A B

C D

FIGURE 2 | MA substituted for heroin reinforcement. As substitution with different dose of MA to self-administer 4 h in heroin trained rats (n=9-10/group), only dose
of 50 mg/kg/infusion of MA significantly increased the active pokes and the lower doses of 12.5, 25, 50 mg/kg/infusion of MA increased the infusions (A, B). The total
dose significantly increased above the training MA dose of 50 mg/kg/infusion, and 25 mg/kg/infusion could equally instead of 50 mg/kg/infusion heroin self-
administration at total dose (C).The total dose–effect curve of MA replacement showed shifted leftward and upward compared to the total dose–effect curve of
heroin (D). *P < 0.05, **P < 0.01, compared to 50 mg/kg/infusion heroin. Error bars = SEM.

MA served as a heroin substitute; in addition, lower MA doses trained by single drug (heroin or cocaine) directly (25). The
seem to be required to produce an identical or even more term “substitution” is typically used in drug discrimination
sensitive rewarding effect of heroin. Likewise, heroin could be procedures to determine if drugs share discriminative stimulus
replaced by a relatively lower dose of MA to reach are warding effects. For example, cocaine can partially substitute the
effect. On the other hand, when MA was replaced with heroin, discriminative stimulus effects of heroin in rats, and when
the dose–effect curve shifted to the rightward, indicating heroin–cocaine combinations are administered to the heroin-
that MA rewarding effect required a higher dose of heroin to trained rats, cocaine did not significantly alter the mean
be replaced. heroin dose–effect curve (26). Nonetheless, in another study
Combining the substitution curves, the original heroin with rhesus monkeys, opioids substituted the cocaine
dose–effect curve was very similar to the dose–effect curve of discriminative stimulus in some, but not in all of them (27).
MA substitution; likewise, the original MA and the curve of Some evidence showed that only small subsets of rats preferred
heroin substitution was also identical. The same trend in two either cocaine or heroin instead of the food alternative in the
separate experiments suggested that heroin and MA choice procedure, indicating the substance-specific pattern of
substitution was symmetrical, and their rewarding effect was drug preference (28). In several experiments, it was repeatedly
independent. The phenomenon was supported by self- shown that when the heroin trained rats resumed heroin
administration heroin and cocaine on alternate days, the training after being given MA instead of heroin, their heroin
escalated levels of cocaine self-administration fail to use was the same as before replacement with MA, indicating
generalize heroin when change the heroin self-administrate that the MA fully met the heroin demand during replacement
back later (24). Similarly, the total dose of heroin or cocaine days. Overall, these results suggest that MA could at least partly
was not different from the total dose the rats intake which substitute heroin, and vice versa. Taken together, although

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Mei et al. Rewarding Substitution of Methamphetamine and Heroin

A B

C D

FIGURE 3 | Dose–effect response in MA self-administration. Rats (n=16) were successfully trained to self-administer MA 4 h/day under an FR1 reinforcing
schedule within 10 days (A). When the MA trained rats were tested in different dose (25 mg/kg/infusion–200 mg/kg/infusion) of MA to self-administer 4 h in the
following days (n=7-8/group). The active pokes and the infusions were changed and showed an inverted U trend. The number of active pokes and infusions
decreased significantly at high MA doses (100 or 200 mg/kg/infusion) compared to 50 mg/kg/infusion doses (B, C). Rat took less MA when dose decreased to
25 mg/kg/infusion, but maintain the total dose unchanged as dose increased (100, 200 mg/kg/infusion) (D). **P < 0.01, compared to 50 mg/kg/infusion MA.
Error bars = SEM.

psychostimulants and opioids seem to have their own its actions (22). Concerning cocaine, serotonin acts on the 5-HT1b
independent way to substitute, MA and heroin did not affect and 5-HT2c receptors with bidirectional feedback to regulate the
the self-administration of the other. levels of dopamine in the NAc (32, 33). This indicates that the
Heroin and MA greatly differ in terms of pharmacological downstream reinforcement mechanisms of the two drugs are not
features as well as in clinical manifestations following their the same. Therefore, MA and other psychostimulants may
utilization (9, 10). The preclinical data indicated that the increase increase the levels of dopamine in NAc more significantly than
in the amount of dopamine induced by MA in the NAc is more heroin. That explained in part why low-dose MA could effectively
than that induced by heroin. For example, when MA doses of 1 mg/ replace heroin.
kg were injected subcutaneously in rats, the levels of dopamine in Previous clinical data showed a rather high frequency of
their NAc increased up to 698% (29); however, when heroin doses combined utilization of MA and heroin in both habitual
of 0.2 mg/kg were injected intravenously in rats, the levels of heroin and MA users (2, 5). Further, preclinical studies
dopamine in their NAc only increased up to 300% (30). Besides, demonstrated that MA–heroin combinations (“speedballs”)
gamma-vinyl GABA — an inhibitor of irreversible GABA- produce greater rewarding effects (34); for example, urine
transaminase — only partially blocks the dopamine increase in of MMT patients in Yunnan tested positive for both
the NAc caused by MA, yet completely inhibits the dopamine morphine and MA (3), and half had used amphetamine
increase in the NAc caused by heroin (31). By contrast, heroin among current primary heroin users while two-thirds of
could enhance its rewarding effect through the CB1 receptor and primary amphetamine users had used heroin (4). The main
other mechanisms independents of the dopamine levels in the NAc reasons for transition in drug use reside in either obtaining
(21); further, MA also released large amounts of serotonin through synergistic high or balancing out the effects of each other and

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Mei et al. Rewarding Substitution of Methamphetamine and Heroin

A B

C D

FIGURE 4 | Heroin substituted for MA reinforcement. As substitution with different dose of heroin to self-administer 4 h in MA trained rats (n = 5–6/group), the
higher doses (50, 200 mg/kg/infusion) of heroin significantly decreased the active pokes and the infusions (A, B). The total intake dose of heroin significantly
decreased at 50 mg/kg/infusion or below when replaced with heroin, and 200 mg/kg/infusion heroin could equally instead of 50 mg/kg/infusion MA self-administration
at total dose (C). The total dose–effect curve of heroin replacement showed shifted rightward and downward compared to the total dose–effect curve of MA (D) *P <
0.05, **P < 0.01, compared to 50 mg/kg/infusion MA. Error bars = SEM.

keeping body functions as normal as possible (6). Another ETHICS STATEMENT

reason for drug transition is related to the price and
availability of drugs: when MA prices increase, co-users The animal study was reviewed and approved by Animal Ethics
choose to consume more heroin, and vice versa (35). The Committee of Ningbo University.
drug-market period in which injecting initiation occurred
sensitively influenced the kind of first injected drug, thereby
influencing some aspects of subsequent drug use in Australia AUTHOR CONTRIBUTIONS
(36).The present results provided the first direct evidence for
the transition between MA and heroin use due to the D-SM designed and performed research, analysis the data, and
reciprocal substitutability of their rewarding effects. The the writing of the paper. Y-JC, F-MW, and B-MM performed
crisis of the global emergence of combining MA with heroin research and data collection. H-FL were responsible for
use is merging, and attention should be paid to their negative guarantee of animal and experimental conditions. W-HZ and
effects on public health (37). In conclusion, the present study J-PX were responsible for the study concept and design, revising
demonstrated that heroin and MA can partly substitute each the paper, and study supervision.
other; further, heroin and MA may follow their independent
dose–effect mechanism during the substitution process.
FUNDING
DATA AVAILABILITY STATEMENT This work was supported by National Nature Science Foundation
(81671321), National Key Research and Development Program of
The raw data supporting the conclusions of this article will be China Grant (2017YFC1310403), and Ningbo Natural Science
made available by the authors, without undue reservation. Foundation (2019A610294) of China.

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Mei et al. Rewarding Substitution of Methamphetamine and Heroin

REFERENCES 21. Caille S, Parsons LH. SR141716A reduces the reinforcing properties of heroin
but not heroin-induced increases in nucleus accumbens dopamine in rats. Eur
1. NMPA of China (National Medical Products Administration of China). National J Neurosci (2003) 18:3145–9. doi: 10.1111/j.1460-9568.2003.02961.x
Drug Abuse Monitoring report of china 2016. In: The National Medical Products 22. Cruickshank CC, Dyer KR. A review of the clinical pharmacology of
Administration of China Publication (2017). methamphetamine. Addiction (2009) 104:1085–99. doi: 10.1111/j.1360-0443.
2. Dong H, Yang M, Liu L, Zhang C, Liu M, Shen Y, et al. Comparison of 2009.02564.x
demographic characteristics and psychiatric comorbidity among 23. Hearing M, Graziane N, Dong Y, Thomas MJ. Opioid and Psychostimulant
methamphetamine-, heroin- and methamphetamine-heroin co- dependent Plasticity: Targeting Overlap in Nucleus Accumbens Glutamate Signaling.
males in Hunan, China. BMC Psychiatry (2017) 17:183. doi: 10.1186/s12888- Trends Pharmacol Sci (2018) 39:276–94. doi: 10.1016/j.tips.2017.12.004
017-1346-7 24. Lenoir M, Guillem K, Koob GF, Ahmed SH. Drug specificity in extended
3. Wang R, Ding Y, Bai H, Duan S, Ye R, Yang Y, et al. Illicit Heroin and access cocaine and heroin self-administration. Addict Biol (2012) 17:964–76.
Methamphetamine Use among Methadone Maintenance Treatment Patients doi: 10.1111/j.1369-1600.2011.00385.x
in Dehong Prefecture of Yunnan Province, China. PloS One (2015) 10: 25. Leri F, Stewart J. Drug-induced reinstatement to heroin and cocaine seeking: a
e0133431. doi: 10.1371/journal.pone.0133431 rodent model of relapse in polydrug use. Exp Clin Psychopharmacol (2001)
4. Darke S, Kaye S, Ross J. Transitions between the injection of heroin and 9:297–306. doi: 10.1037/1064-1297.9.3.297
amphetamines. Addiction (1999) 94:1795–803. doi: 10.1046/j.1360-0443. 26. Lamas X, Negus SS, Gatch MB, Mello NK. Effects of heroin/cocaine combinations
1999.941217955.x in rats trained to discriminate heroin or cocaine from saline. Pharmacol Biochem
5. Al-Tayyib A, Koester S, Langegger S, Raville L. Heroin and Behav (1998) 60:357–64. doi: 10.1016/s0091-3057(98)00021-5
Methamphetamine Injection: An Emerging Drug Use Pattern. Subst Use 27. Negus SS, Gatch MB, Mello NK. Effects of mu opioid agonists alone and in
Misuse (2017) 52:1051–8. doi: 10.1080/10826084.2016.1271432 combination with cocaine and D-amphetamine in rhesus monkeys trained to
6. Ellis MS, Kasper ZA, Cicero TJ. Twin epidemics: The surging rise of discriminate cocaine. Neuropsychopharmacology (1998) 18:325–38.
methamphetamine use in chronic opioid users. Drug Alcohol Depend doi: 10.1016/s0893-133x(97)00163-2
(2018) 193:14–20. doi: 10.1016/j.drugalcdep.2018.08.029 28. Tunstall BJ, Riley AL, Kearns DN. Drug specificity in drug versus food choice
7. Schuckit MA. Treatment of Opioid-Use Disorders. New Engl J Medicine in male rats. Exp Clin Psychopharmacol (2014) 22:364–72. doi: 10.1037/
(2016) 375:357–68. doi: 10.1056/NEJMra1604339 a0037019
8. Panenka WJ, Procyshyn RM, Lecomte T, MacEwan GW, Flynn SW, Honer 29. Shimosato K, Nagao N, Watanabe S, Kitayama S. Suppressive effects of
WG, et al. Methamphetamine use: A comprehensive review of molecular, trihexyphenidyl on methamphetamine-induced dopamine release as measured
preclinical and clinical findings. Drug Alcohol Dependence (2013) 129:167–79. by in vivo microdialysis. Synapse (2003) 49:47–54. doi: 10.1002/syn.10191
doi: 10.1016/j.drugalcdep.2012.11.016 30. Wise RA, Leone P, Rivest R, Leeb K. Elevations of nucleus accumbens
9. Karila L, Weinstein A, Aubin HJ, Benyamina A, Reynaud M, Batki SL. dopamine and DOPAC levels during intravenous heroin self-
Pharmacological approaches to methamphetamine dependence: a focused review. administration. Synapse (1995) 21:140–8. doi: 10.1002/syn.890210207
Br J Clin Pharmacol (2010) 69:578–92. doi: 10.1111/j.1365-2125.2010.03639.x 31. Gerasimov MR, Ashby CR, Gardner EL, Mills MJ, Brodie JD, Dewey SL.
10. Badiani A, Belin D, Epstein D, Calu D, Shaham Y. Opiate versus Gamma-vinyl GABA inhibits methamphetamine, heroin, or ethanol-induced
psychostimulant addiction: the differences do matter. Nat Rev Neurosci increases in nucleus accumbens dopamine. Synapse (1999) 34:11–9.
(2011) 12:685–700. doi: 10.1038/nrn3104 doi: 10.1002/(sici)1098-2396(199910)34:1<11::aid-syn2>3.0.co;2-5
11. Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci (2004) 32. Neumaier JF, Vincow ES, Arvanitogiannis A, Wise RA, Carlezon WA.
5:483–94. doi: 10.1038/nrn1406 Elevated expression of 5-HT1B receptors in nucleus accumbens efferents
12. Darke S, Kaye S, Duflou J. Rates, characteristics and circumstances of sensitizes animals to cocaine. J Neurosci (2002) 22:10856–63. doi: 10.1523/
methamphetamine-related death in Australia: a national 7-year study. JNEUROSCI.22-24-10856.2002
Addiction (2017) 112:2191–201. doi: 10.1111/add.13897 33. Rocha BA, Goulding EH, O’Dell LE, Mead AN, Coufal NG, Parsons LH, et al.
13. Zhou W, Liu H, Zhang F, Tang S, Zhu H, Lai M, et al. Role of acetylcholine Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in
transmission in nucleus accumbens and ventral tegmental area in heroin- serotonin 5-hydroxytryptamine 2C receptor mutant mice. J Neurosci (2002)
seeking induced by conditioned cues. Neuroscience (2007) 144:1209–18. 22:10039–45. doi: 10.1523/JNEUROSCI.22-22-10039.2002
doi: 10.1016/j.neuroscience.2006.11.013 34. Ranaldi R, Wise RA. Intravenous self-administration of methamphetamine-
14. Lai M, Chen W, Zhu H, Zhou X, Liu H, Zhang F, et al. Low dose risperidone heroin (speedball) combinations under a progressive-ratio schedule of
attenuates cue-induced but not heroin-induced reinstatement of heroin reinforcement in rats. Neuroreport (2000) 11:2621–3. doi: 10.1097/00001756-
seeking in an animal model of relapse. Int J Neuropsychopharmacol (2013) 200008210-00003
16:1569–75. doi: 10.1017/s1461145712001563 35. Chalmers J, Bradford D, Jones C. The effect of methamphetamine and heroin
15. Zhu H, Lai M, Chen W, Mei D, Zhang F, Liu H, et al. N- price on polydrug use: A behavioural economics analysis in Sydney, Australia.
acetylaspartylglutamate Inhibits Heroin Self-Administration and Heroin- Int J Drug Policy (2010) 21:381–9. doi: 10.1016/j.drugpo.2010.06.002
Seeking Behaviors Induced by Cue or Priming in Rats. Neurosci Bulletin 36. Horyniak D, Stoove M, Degenhardt L, Aitken C, Kerr T, Dietze P. How do
(2017) 33:396–404. doi: 10.1007/s12264-017-0140-3 drug market changes affect characteristics of injecting initiation and
16. Lai M, Zhu H, Sun A, Zhuang D, Fu D, Chen W, et al. The phosphodiesterase- subsequent patterns of drug use? Findings from a cohort of regular heroin
4 inhibitor rolipram attenuates heroin-seeking behavior induced by cues or and methamphetamine injectors in Melbourne, Australia. Int J Drug Policy
heroin priming in rats. Int J Neuropsychopharmacol (2014) 17:1397–407. (2015) 26:43–50. doi: 10.1016/j.drugpo.2014.09.002
doi: 10.1017/s1461145714000595 37. Lancet. Opioids and methamphetamine: a tale of two crises. Lancet (2018)
17. Hart EE, Gerson JO, Izquierdo A. Persistent effect of withdrawal from 391:713. doi: 10.1016/s0140-6736(18)30319-2
intravenous methamphetamine self-administration on brain activation and
behavioral economic indices involving an effort cost. Neuropharmacology Conflict of Interest: The authors declare that the research was conducted in the
(2018) 140:130–8. doi: 10.1016/j.neuropharm.2018.07.023 absence of any commercial or financial relationships that could be construed as a
18. Xu X, Pan J, Li X, Cui Y, Mao Z, Wu B, et al. Inhibition of Methamphetamine Self- potential conflict of interest.
Administration and Reinstatement by Central Blockade of Angiotensin II Receptor
in Rats. J Pharmacol Exp Ther (2019) 369:244–58. doi: 10.1124/jpet.118.255729 Copyright © 2020 Mei, Cai, Wang, Ma, Liu, Zhou and Xu. This is an open-access
19. Wise RA, Koob GF. The development and maintenance of drug addiction. article distributed under the terms of the Creative Commons Attribution License
Neuropsychopharmacology (2014) 39:254–62. doi: 10.1038/npp.2013.261 (CC BY). The use, distribution or reproduction in other forums is permitted, provided
20. Pierce RC, Kumaresan V. The mesolimbic dopamine system: The final the original author(s) and the copyright owner(s) are credited and that the original
common pathway for the reinforcing effect of drugs of abuse? Neurosci publication in this journal is cited, in accordance with accepted academic practice. No
Biobehav Rev (2006) 30:215–38. doi: 10.1016/j.neubiorev.2005.04.016 use, distribution or reproduction is permitted which does not comply with these terms.

Frontiers in Psychiatry | www.frontiersin.org 8 July 2020 | Volume 11 | Article 750