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Alcoholism & Drug Dependence

Hiranita and Collins, J Alcohol Drug Depend 2015, 3:4

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Differential Roles for Dopamine D1-Like and D2-Like Receptors in Mediating

the Reinforcing Effects of Cocaine: Convergent Evidence from Pharmacological
and Genetic Studies
Takato Hiranita1* and Gregory T Collins2,3
Division of Neurotoxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road Jefferson, AR 720799501, USA
2
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., Mail Code 7764, San Antonio, TX 78229, USA
3
South Texas Veterans Health Care System, 7400 Merton Minter Dr, San Antonio, TX 78229, USA
1

Non-standard Abbreviations
DA: Dopamine; DAT: Dopamine Transporter; D1R: D1 Receptor;
D2R: D2 Receptor; D3R: D3 Receptor; D4R: D4 Receptor; D5R: D5
Receptor; D1-likeR: D1-Like Receptor; D2-likeR: D2-Like Receptor; DEC:
Dose-effect Curve; FR: Fixed Ratio; KI: Knockin; KO: Knockout; MOR:
-Opioid Receptor; PR: Progressive Ratio; SA: Self-Administration;
WT: Wild-Type
A series of studies by Drs. Barak Caine, James Woods, Gregory
Collins, Jonathan Katz and Takato Hiranita demonstrated a novel
and unique reinforcing effect using dopamine (DA) D2-like receptor
[D2-like R: D2, D3, and D4 receptor subtypes (respectively, D2R, D3R,
and D4R)] agonists in rats and genetically modified mice. In order to
understand how important their findings are, a comparison was made
regarding the reinforcing effects of DA D2-like R full agonists with
those of DA uptake inhibitors and of a DA D1-like receptor [D1-like
R, D1 and D5 receptor subtypes (D1R and D5R)] full agonist ()-SKF
82958.

DA transporter (DAT) as a binding site of cocaine

A drug self-administration (SA) procedure has been used to directly
assess reinforcing effects of various drugs across pharmacological
classes including cocaine under various schedules of reinforcement
in various species because of its relative high face and predictive
validities [1-3]. Using a drug SA procedure, a number of preclinical
and clinical studies have demonstrated substantial implication of DA
in reinforcing effects of cocaine [2,4]. Among a large number of other
presynaptic and postsynaptic sites that cocaine can bind, an inhibition
of DA uptake through the DAT is known to be a primary mechanism
underlying reinforcing effects of cocaine [5-8]. In fact, a standard DA
uptake inhibitor methylphenidate (see Table 1 for details) maintain SA
responding above vehicle levels under a fixed ratio (FR) schedule of
reinforcement in nave rats [9] and when evaluated in rats trained to
self-administer cocaine [6,10,11]. Further, pretreatment with standard
DA uptake inhibitors also produces a leftward shift of the dose-effect
curve (DEC) for cocaine SA, suggesting that they potentiate the
reinforcing effects of cocaine [6,10]. [12-14] In addition, cocaine was
not reinforcing in mice that underwent a genetic inactivation of the
DAT [knockout (KO) and knockin (KI)] [7,8].

SA of direct DA receptor ligands

A DA D1-like receptor [D1-like R: D1 and D5 receptor subtypes
(respectively, D1R and D5R)] direct full agonist: As with the DA
uptake inhibitor methylphenidate [15], the DA D1-like R full agonist
()-SKF 82958 was reliably reinforcing under an FR schedule of
reinforcement in drug nave rats [16] and rhesus monkeys [17]. When
substituted for cocaine, there are mixed results. For example, ()-SKF
82958 maintained SA responding above vehicle levels in mice [18,7] and
rhesus monkeys [19] when substituted for cocaine. However, a range
J Alcohol Drug Depend
ISSN: 2329-6488 JALDD, an open access journal

of the reliably reinforcing doses of ()-SKF 82958 in nave animals and

when assessed in animals trained to self-administer cocaine [7, 16-19]
failed to maintain SA responding above vehicle levels in rats previously
trained to self-administer cocaine [20]. Nonetheless, these results
suggest a substantial role of DA D1-like Rs in cocaine reinforcement.
DA D2-like R direct full agonists: In contrast to the DA D1-like
R full agonist ()-SKF 82958, reinforcing effects of the DA D2-like R
full agonists are not appreciable in nave subjects. For example, none
of doses of the DA D2-like R full agonist quinpirole maintained SA
responding above vehicle levels in experimentally nave rats [21] and in
rats with a responding-reinforced history using food or ()-ketamine
[21]. Further, quinpirole was not reinforcing in rats trained to selfadminister cocaine when the cocaine-paired stimulus was omitted from
the contingency (i.e., SA responding resulted in quinpirole infusions
without presentations of the previously cocaine-paired stimulus) [22].
In marked contrast, quinpirole [21-23] as well as other DA D2-like
R full agonists [()-quinelorane [20,24], ()-7-OH-DPAT [20,25],
and pramipexole [25] all maintained high levels of responding when
substituted for cocaine and delivered in conjunction with the cocainepaired stimulus. The results from Drs. Woods and Collins are discussed
more below (see Section E). In addition, a more recent study using the
DA D3R full agonist PF-592,379 demonstrated a lack of reinforcing
effects of the DA D3R full agonist when substituted for cocaine with
response-dependent presentations of a cocaine-paired stimulus [9].
Thus, these results suggest the relatively limited role of DA D2-like Rs
in mediating the reinforcing effects of cocaine, especially nave subjects,
which is quite distinct from the DA uptake inhibitors, such as cocaine
[21,26] and methylphenidate [25], and the DA D1-like R full agonist
()-SKF 82958 [16,17].

Effects of genetic manipulation of DA receptors

Studies using a genetic disruption of the DA receptor subtypes in
mice also have revealed the distinct role of each DA receptor subtype
in cocaine SA under an FR schedule of reinforcement. Genetic

*Corresponding author: Takato Hiranita, Division of Neurotoxicology, National

Center for Toxicological Research (NCTR), U.S. Food and Drug Administration
(FDA), 3900 NCTR Road Jefferson, AR 72079-9501, USA, Tel: 870-543-6823; Fax:
870-543-7745; E-mail: [Link]@[Link]
Received: July 16, 2015; Accepted: July 20, 2015; Published: July 25, 2015
Citation: Hiranita T, Collins GT (2015) Differential Roles for Dopamine D1-Like and
D2-Like Receptors in Mediating the Reinforcing Effects of Cocaine: Convergent
Evidence from Pharmacological and Genetic Studies. J Alcohol Drug Depend 3:
e124. doi:10.4172/23296488.1000e124
Copyright 2015 Hiranita T, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.

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Citation: Comann JC, Bonnet U (2015) Screening for Misuse of Approved Antidementives in the Elderly Non-Demented Hospital Population. J
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Page 2 of 5
Pharmacological Class

Self-administered
Drug
d-Methamphetamine

DA releaser
d-Amphetamine

Reinforcement history Primary finding (reference)

None

Dose-dependently maintained SA responding above vehicle levels in rats [26]

(-)-Heroin

Dose-dependently maintained SA responding above vehicle levels in rats [11]

()-Ketamine

Dose-dependently maintained SA responding above vehicle levels in rats [11]

Cocaine

d-Methamphetamine

Dose-dependently maintained SA responding above vehicle levels in rats [11,26]

(-)-Heroin

Dose-dependently maintained SA responding above vehicle levels in rats [11]

()-Ketamine

Dose-dependently maintained SA responding above vehicle levels in rats [11]

None

Cocaine

Food

Maintained SA responding above vehicle levels in rats [21]

None of the doses maintained SA responding above vehicle levels in DAT KO
mice [7]
None of the doses maintained SA responding above vehicle levels in DAT KI
mice [8]
None of the doses maintained SA responding above vehicle levels in DA D1R KO
mice [18]
None of the doses maintained SA responding above vehicle levels in DA D4R KO
mice [28]

Dose-dependently maintained SA responding above vehicle levels in rats [11]

(-)-Heroin

Dose-dependently maintained SA responding above vehicle levels in rats [11]

()-Ketamine

Dose-dependently maintained SA responding above vehicle levels in rats [11]

None

Dose-dependently maintained SA responding above vehicle levels in rats [25]

Cocaine

Dose-dependently maintained SA responding above vehicle levels in rats [6,10]

Nomifensine

Cocaine

Dose-dependently maintained SA responding above vehicle levels in rats [10]

RTI-366

Cocaine

Dose-dependently maintained SA responding above vehicle levels in rats [10]

Cocaine

Dose-dependently maintained SA responding above vehicle levels in rats [10]

d-Methamphetamine

Dose-dependently maintained SA responding above vehicle levels in rats [11]

(-)-Heroin

Dose-dependently maintained SA responding above vehicle levels in rats [11]

()-Ketamine

Dose-dependently maintained SA responding above vehicle levels in rats [11]

Food

Dose-dependently maintained SA responding above vehicle levels in rats [16]

Dose-dependently maintained SA responding above vehicle levels in DAT KO mice [7]
None of the doses maintained SA responding above vehicle levels in DA D1R KO
mice [18]

None of doses tested maintained SA responding above vehicle levels in rats [20]
Dose-dependently maintained SA responding above vehicle levels in mice[18]
Maintained SA responding above vehicle levels in DAT KI mice [8]

Methylphenidate

WIN 35,428

()-SKF 82958
Cocaine
()-7-OH-DPAT

Cocaine

Dose-dependently maintained SA responding above vehicle levels in rats [12,20]

Pramipexole

Cocaine

Dose-dependently maintained SA responding above vehicle levels in rats [15]

Cocaine

Dose-dependently maintained SA responding above vehicle levels in rats and mice

[18,20,24]

None

Failed to maintained SA responding above vehicle levels even in rats when responsepaired stimulus was presented response-dependently [21]

Food

Failed to maintained SA responding above vehicle levels in rats even when foodpaired stimulus was presented response-dependently [21]

Cocaine

Remifentanil

Dose-dependently maintained SA responding above vehicle levels in rats [21]

()-Ketamine

Failed to maintained SA responding above vehicle levels in rats even when

()-ketamine -paired stimulus was presented response-dependently [21]

Cocaine

None of doses tested maintained SA responding above vehicle levels in rats [9]

()-Quinelorane

DA D2-like R full agonist

Quinpirole

DA D3R full agonist

Dose-dependently maintained SA responding above vehicle levels in rats [11,21]

Failed to maintained SA responding above vehicle levels in DA D1R KO mice [18]

d-Methamphetamine

DA uptake inhibitor

DA D1-like R full agonist

Dose-dependently maintained SA responding above vehicle levels in mice [8]

Dose-dependently maintained SA responding above vehicle levels and virtually without
any shift in a cocaine SA DEC in DAT KI mice [8]

PF-592,379

Maintained SA responding above vehicle levels in rats [22,23]

Failed to maintained SA responding above vehicle levels in rats when cocainepaired stimuli were omitted [22]

Table 1: Self-administration (SA) of DA receptor agonists in rats and mice. SA was defined as operant responding maintained above levels of vehicle injections. Unless
described, drug injections were response-dependently accompanied with a stimulus change DEC, dose-effect curve.

disruptions of each DA receptor subtype could cause a developmental

impairment and/or a functionally compensatory mechanism other
than their physiological functions. However, consistent with results of
assessment of a capacity of direct DA receptor full agonists to induce
or maintain SA responding mentioned above (see Section B), it appears
that DA D1-like Rs are undoubtedly more critical than DA D2-like Rs
in the reinforcing effects of cocaine and perhaps another DA uptake
inhibitors.

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DA D1R KO mice: For example, at doses that reliably maintained

SA responding in drug-nave wild-type (WT) mice, cocaine was virtually
ineffective at maintaining SA responding in DA D1R KO mice that had
been trained to nose-poke for food [18]. However, as a positive control, the
-opioid receptor (MOR) full agonist remifentanil was reinforcing in DA
D1R KO mice [18]. On the other hand, there is no report assessing cocaine
SA using DA D5R KO mice at this point. Thus the results suggest D1Rs play
an essential role in mediating the reinforcing effects of cocaine.

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Citation: Comann JC, Bonnet U (2015) Screening for Misuse of Approved Antidementives in the Elderly Non-Demented Hospital Population. J
Alcohol Drug Depend 3: e124. doi:10.4172/23296488.1000e124

Page 3 of 5
DA D2-like R KO mice: In marked contrast to DA D1Rs [18], it
appears that DA D2-like Rs are not necessary for cocaine to function
as a reinforcer. For example, cocaine maintained comparable levels
of SA responding in both DA D2R WT and KO mice, with only a
modest rightward/upward shift of the descending limb of the DEC
for cocaine SA observed in the DA D2R KO mice [24]. Similar to mice
lacking DA D2Rs [24], genetic deletion of the DA D3R did not alter
the reinforcing effects of cocaine as assess by either FR or progressive
ratio (PR) schedules of reinforcement [27]. In addition, there was no
appreciable difference in acquisition rates of SA responding with a
fixed dose of cocaine (1.0 mg/kg/inj) between DA D4R KO mice and
their WT controls [28]. Nonetheless, those findings from studies using
DA D2-like R KO mice suggest that none of the DA D2-like R subtypes
are strictly necessary to induce cocaine reinforcement. The conclusion
from studies using DA D2-like R KO mice is in stark contrast to those
using DA D1R KO mice, and suggest that in that DAs effects at DA
D1Rs, but not DA D2Rs, are required for cocaine reinforcement.

Effects of pretreatment with DA receptor direct ligands on

cocaine SA
The reinforcing effects of cocaine under an FR schedule of
reinforcement in rats have been demonstrated to be substantially
affected by transient pharmacological manipulations using direct DA
receptor ligands given as a pre-session treatment. The results further
indicate quite distinct role of DA D1-like and D2-like receptors
in cocaine reinforcement (see Table 2 for details). Regarding DA
direct agonists, only studies using full agonists are discussed since
partial agonists generally can function as an antagonist against
pharmacological effects of full agonists.
DA D1-like R direct full agonists: In marked contrast to the
standard DA uptake inhibitors [6,10-14], pretreatment with DA D1-like
R full agonists produce a dose-dependent downward shift of the DECs
for cocaine SA [12,20], suggesting an insurmountable antagonism
of cocaine reinforcement. Importantly, the apparent antagonism of
cocaine SA was relatively selective because the doses of DA D1-like
R agonists that decreased cocaine SA did not alter food-maintained
behavior under an identical schedule of reinforcement [12,20].
However, the insurmountable antagonism of cocaine SA with the D1like R full agonists is not so surprising since the MOR full agonists
(-)-morphine and ()-methadone both also produce downward shifts
of the DEC for SA of the MOR full agonist (-)-heroin [11]. Further,
pre-feeding time-dependently shifted down rather than to the left a
curve of responding maintained by presentations of different numbers
of food pellets [11]. Thus these downward shifts in responding
maintained by cocaine, (-)-heroin, and food may indicate satiation-like
effects of the DA D1-like R full agonists. On the other hand, previous
studies demonstrated an appreciable mechanism resulting in flattened
curves theoretically [29] and practically [30], if only the ascending limb
of DECs is sensitive to a pretreatment. It would be very important to
assess whether the DA D1-like R agonism-induced decreases in cocaine
SA are truly mediated through the DA D1-like Rs.
DA D2-like R direct full agonists: As with standard indirect DA
receptor agonists [6,10-14] but in marked contrast to the DA D1-like
R full agonists [12,20], pretreatment with DA D2-like R full agonists
dose-dependently shift the DECs of cocaine SA to the left [12,20]. In
fact, the potentiation of cocaine reinforcement by DA D2-like R full
agonists is indistinguishable from that produced by standard DA
uptake inhibitors [6,10-14]. These findings may suggest a fundamental
role of D2-like Rs in the maintenance of the reinforcing effects of

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cocaine. However, as discussed below (See Section E), the effects of DA

D2-like R full agonists may be to enhance the conditioned reinforcing
effects of cocaine-pared stimuli rather than the primary reinforcing
effects of cocaine [21-23].
DA receptor antagonists: The DA D1-like R antagonist SCH39166 and the DA D2-like R antagonist S (-)-eticlopride dosedependently shift the DECs of cocaine SA to the right, suggesting a
competitive and typical antagonism of the reinforcing effects of
cocaine [12,24,26,31]. Further, a combination with intermediate doses
of the DA D1-like R antagonist SCH-39166 and the preferential D2R
antagonist L-741,626 was more effective than either compound alone
to antagonize cocaine SA [26]. In addition, L-741,626 produced a dosedependent rightward shift of the DEC of cocaine SA [26] while the DA
D3/4R antagonist L-745,829 and the DA D4R antagonist L-745,870 were
ineffective against cocaine SA [24]. Thus, these findings suggest that the
reinforcing effects of cocaine are mediated by a combined effect of DA
at DA D1-like as well as D2 receptors.

Effects of pretreatment with direct DA D2-like R ligands on

responding maintained by presentations of a stimulus paired
with cocaine injections
As mentioned above in a section D2, the potentiation of cocaine SA
with the DA D2-likeR full agonists [12,20] was indistinguishable from the
effects of pretreatments with typical DA uptake inhibitors [6,10-14].
These findings may suggest thatD2-like Rs are capable of modulating
(i.e., enhancing) the primary reinforcing effects of cocaine; however,
the results of a series of studies by Drs. Woods and Collins suggest
an alternative mechanism. First, as noted above (section B.2) the
apparent reinforcing effects of the DA D2-like R full agonist quinpirole
were highly dependent upon experimental history, with quinpirole
maintaining high rates of responding in rats that were trained to selfadminister cocaine, and rates of responding that were no different
than vehicle in rats that were either experimentally nave, or trained
to respond for food or ()-ketamine [21]. Although the importance
of reinforcement history in determining the reinforcing effects of DA
D2-like R agonists has not been systematically evaluated, a history of
cocaine SA is sufficient to establish the reinforcing effects of a number
of structurally diverse DA D2-like R agonists [e.g., quinpirole [21-23],
()-quinelorane [20,24], ()-7-OH-DPAT [20,25], and pramipexole
(Collins et al., 2012b)]. In addition to an appropriate reinforcement
history, the apparent reinforcing effects of DA D2-like R agonists
(quinpirole and pramipexole) also appear to depend on the responsecontingent presentation of the stimuli that were previously paired
with the training drug (e.g., cocaine-paired stimuli) [15,21-23]. Not
only do DA D2-like R agonists fail to maintain SA responding if
they are delivered without the cocaine-paired stimuli [21,22], but
removing the cocaine-paired stimuli from the contingency after SA
responding for a DA D2-like R agonist has been established results in
a rapid extinction of responding [15]. Similarly, pretreatment of rats
with DA D2-like R agonists dose-dependently increases responding
maintained by presentations of a cocaine-paired stimulus, an effect
that is not observed when food-paired or neutral stimuli are used as
the maintaining event [15,21-23]. Together, these findings suggest the
capacity of the D2-like R full agonists to maintain SA responding when
substituted for cocaine SA [15,21-23] and of pretreatments of DA D2like R agonists to shift the cocaine SA DECs to the left [12,20] results
from a DA D2-like R agonist-induced enhancement of the conditioned
reinforcing effects of the cocaine-paired stimulus rather than a primary
reinforcing effect of the DA D2-like R agonist or from a DA D2-like
R agonist-induced enhancement of the primary reinforcing effects of

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Citation: Comann JC, Bonnet U (2015) Screening for Misuse of Approved Antidementives in the Elderly Non-Demented Hospital Population. J
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Page 4 of 5
Pharmacological Class
DA releaser

DA uptake inhibitor

Pretreated drug
d-Amphetamine

Primary finding (reference)

Dose-dependent leftward shifts in a cocaine SA DEC in rats [12]
Dose-dependent leftward shifts in a d-methamphetamine SA DEC in rats [14]

Cocaine

Leftward shifts in a cocaine SA DEC [12]

GBR 12909

Dose-dependent leftward shifts in a cocaine SA DEC in rats [12]

Methylphenidate

Dose-dependent leftward shifts in a cocaine SA DEC in rats [6,10,13]

Nomifensine

Dose-dependent leftward shifts in a cocaine SA DEC in rats [10]

RTI-366

Dose-dependent leftward shifts in a cocaine SA DEC in rats [14]

WIN 35,428

Dose-dependent leftward shifts in a cocaine SA DEC in rats [10]

Dose-dependent leftward shifts in a d-methamphetamine SA DEC in rats [11]

DA D1-like R full agonist

DA D1-like R antagonist

()-SKF 82958

Dose-dependent downward shifts in a cocaine SA DEC in rats [12,20]

R(+)-6-Br-APB

Dose-dependent downward shifts in a cocaine SA DEC in rats [12]

SCH 23390

Right-shifted a cocaine SA DEC in mice [18]

SCH 39166

Dose-dependent rightward shifts in a cocaine SA DEC in rats [12,26]

()-7-OH-DPAT
DA D2-like R full agonist

Dose-dependent leftward shifts in a cocaine SA DEC in rats [12,20]

()-Quinelorane

Dose-dependent leftward shifts in a cocaine SA DEC in rats [12,20]

quinpirole

Increased SA responding maintained by cocaine with response-dependent presentations of cocaine-paired

stimulus in rats [22]
Without effects on SA responding maintained by cocaine without presentations of cocaine-paired
stimuli in rats [22]
Dose-dependent rightward shifts in a cocaine SA DEC in rats [12,24,31]

DA D2-like R antagonist

S(-)-Eticlopride

Preferential D2R antagonist

L-741,626

Dose-dependent rightward shifts in a cocaine SA DEC in rats [26]

DA D3/4R antagonist

L-745,829

Decreased only an ascending limb of a cocaine SA DEC in rats [24]

DA D4R antagonist

L-745,870

Virtually without a shift in a cocaine SA DEC in rats [24]

Table 2: Effects of pretreatment with DA receptor agonists in rats and mice. Unless described, drug injections were response-dependently accompanied with a stimulus
change.

cocaine [32]. In addition to providing a mechanism for the apparent

reinforcing effects of the DA D2-like R full agonist, such as relationship
(i.e., DA D2-like Rs enhancing conditioned reinforcing effects) also
provides an appreciable explanation for why cocaine is fully capable of
functioning as a reinforcer in DA D2-like R KO mice [33].

Summary
The reinforcing effects of cocaine are initiated by its inhibition of
DA uptake, resulting in an enhancement of dopaminergic transmission
in the central nervous system [34,35]. The reinforcing effects of cocaine
are mediated though both DA D1-like and D2-like receptors; however,
each of these two families of receptors has substantially distinct
roles in mediating cocaine reinforcement. The literature cited above
indicates an essential role of DA D1-like Rs in the primary reinforcing
effects of cocaine. In marked contrast, the primary reinforcing effects
of cocaine can be produced without DA D2-like Rs. However, Drs.
Woods and Collins demonstrated the appreciable capacity of the DA
D2-like R full agonists to dose-dependently enhance the conditioned
reinforcing effects of cocaine-paired stimulus, but not cocaine per
se. These findings are useful in understanding how DA D2-like R
antagonists can antagonize several effects of various compounds across
pharmacological classes including methamphetamine, opioids, ethanol,
nicotine, and non-competitive NMDA glutamate receptor antagonist.
Given a lack of effects of DA receptor antagonists on SA of (-)-heroin
and ()-ketamine (Hiranita et al., 2013b), DA D2-like Rs might likely
contribute to maintenance of D2-like R-mediated conditioning effects
of (-)-heroin and ()-ketamine, but not to their primary reinforcing
effects since (-)-heroin and ()-ketamine can increase DA levels
J Alcohol Drug Depend
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in brains. Further these findings could have a substantial impact on

a psychiatric research field since DA is involved in a wide range of
various psychiatric diseases and symptoms.

Declaration of Interests
None declared.
Acknowledgments
The present work was supported by the Division of Neurotoxicology/NCTR/
U.S. FDA. The information in the present article is not a formal dissemination of
information by the FDA and does not represent agency position or policy.

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J Alcohol Drug Depend

ISSN: 2329-6488 JALDD, an open access journal

Volume 3 Issue 4 1000e124