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Article ; Online: Neurobiology of reward-related learning.

Galaj, Ewa / Ranaldi, Robert

2021 Volume 124, Page(s) 224–234

Abstract: A major goal in psychology is to understand how environmental stimuli associated with primary rewards come to function as conditioned stimuli, acquiring the capacity to elicit similar responses to those elicited by primary rewards. Our neurobiological ... ...

Abstract	A major goal in psychology is to understand how environmental stimuli associated with primary rewards come to function as conditioned stimuli, acquiring the capacity to elicit similar responses to those elicited by primary rewards. Our neurobiological model is predicated on the Hebbian idea that concurrent synaptic activity on the primary reward neural substrate-proposed to be ventral tegmental area (VTA) dopamine (DA) neurons-strengthens the synapses involved. We propose that VTA DA neurons receive both a strong unconditioned stimulus signal (acetylcholine stimulation of DA cells) from the primary reward capable of unconditionally activating DA cells and a weak stimulus signal (glutamate stimulation of DA cells) from the neutral stimulus. Through joint stimulation the weak signal is potentiated and capable of activating the VTA DA cells, eliciting a conditioned response. The learning occurs when this joint stimulation initiates intracellular second-messenger cascades resulting in enhanced glutamate-DA synapses. In this review we present evidence that led us to propose this model and the most recent evidence supporting it.
MeSH term(s)	Conditioning, Classical ; Dopaminergic Neurons ; Learning ; Reward ; Ventral Tegmental Area
Language	English
Publishing date	2021-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	282464-4
ISSN	1873-7528 ; 0149-7634
ISSN (online)	1873-7528
ISSN	0149-7634
DOI	10.1016/j.neubiorev.2021.02.007
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Article: Dopamine and reward seeking: the role of ventral tegmental area.

Ranaldi, Robert

Reviews in the neurosciences

2014 Volume 25, Issue 5, Page(s) 621–630

Abstract: Reward seeking is controlled by conditioned stimuli (CSs). There is a positive relation between mesocorticolimbic dopamine (DA) and the performance of learned reward-directed behavior. The mechanisms by which reward-, including drug-, associated stimuli ... ...

Abstract	Reward seeking is controlled by conditioned stimuli (CSs). There is a positive relation between mesocorticolimbic dopamine (DA) and the performance of learned reward-directed behavior. The mechanisms by which reward-, including drug-, associated stimuli come to acquire the capacity to activate the DA systems are not fully understood. In this review, we discuss the possible neurochemical mechanisms within the ventral tegmental area that may be involved in how CSs acquire the capacity to activate ventral tegmental area (VTA) DA neurons based on principles of long-term potentiation in the VTA and the role of mesocorticolimbic DA in reward-related learning. We propose that CSs function as such because they acquire the capacity to activate VTA DA neurons. Furthermore, CSs come to acquire this control of VTA DA cells when there is coincident N-methyl-d-aspartate receptor stimulation on VTA DA cells and strong depolarization of VTA DA cells, possibly by muscarinic acetylcholine receptor stimulation on these cells. This coincident activity leads to the strengthening of CS-associated glutamatergic synapses and the control by CSs of mesocorticolimbic DA systems and reward-directed behavior.
MeSH term(s)	Animals ; Dopamine/metabolism ; Humans ; Neuronal Plasticity ; Reward ; Synapses/metabolism ; Synapses/physiology ; Ventral Tegmental Area/metabolism ; Ventral Tegmental Area/physiology
Chemical Substances	Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2014
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	639035-3
ISSN	2191-0200 ; 0334-1763
ISSN (online)	2191-0200
ISSN	0334-1763
DOI	10.1515/revneuro-2014-0019
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Article ; Online: Environmental enrichment facilitates cocaine abstinence in an animal conflict model.

Ewing, Scott / Ranaldi, Robert

Pharmacology, biochemistry, and behavior

2018 Volume 166, Page(s) 35–41

Abstract: In this study, we sought to discover if housing in an enriched environment (EE) is an efficacious intervention for encouraging abstinence from cocaine seeking in an animal "conflict" model of abstinence. Sixteen Long-Evans rats were trained in 3-h daily ... ...

Abstract	In this study, we sought to discover if housing in an enriched environment (EE) is an efficacious intervention for encouraging abstinence from cocaine seeking in an animal "conflict" model of abstinence. Sixteen Long-Evans rats were trained in 3-h daily sessions to self-administer a cocaine solution (1 mg/kg/infusion) until each demonstrated a stable pattern of drug-seeking. Afterward, half were placed in EE cages equipped with toys, obstacles, and a running wheel, while the other half were given clean, standard laboratory housing. All rats then completed daily 30-min sessions during which the 2/3 of flooring closest to the self-administration levers was electrified, causing discomfort should they approach the levers; current strength (mA) was increased after every day of drug seeking until the rat ceased activity on the active lever for 3 consecutive sessions (abstinence). Rats housed in EE abstained after fewer days and at lower current strengths than rats in standard housing. These results support the idea that EE administered after the development of a cocaine-taking habit may be an effective strategy to facilitate abstinence.
MeSH term(s)	Animals ; Behavior, Addictive/prevention & control ; Behavior, Addictive/psychology ; Cocaine/administration & dosage ; Cocaine-Related Disorders/prevention & control ; Cocaine-Related Disorders/psychology ; Drug-Seeking Behavior/drug effects ; Environment ; Male ; Random Allocation ; Rats ; Rats, Long-Evans ; Self Administration
Chemical Substances	Cocaine (I5Y540LHVR)
Language	English
Publishing date	2018-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2018.01.006
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Article ; Online: CaMKII antagonism in the ventral tegmental area impairs acquisition of conditioned approach learning in rats.

Nisanov, Rudolf / Schelbaum, Eva / Morris, Debra / Ranaldi, Robert

Neurobiology of learning and memory

2020 Volume 175, Page(s) 107299

Abstract: This study investigated the role of ... ...

Abstract	This study investigated the role of calcium
MeSH term(s)	Animals ; Behavior, Animal/drug effects ; Benzylamines/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/physiology ; Choice Behavior/physiology ; Conditioning, Classical/drug effects ; Conditioning, Classical/physiology ; Learning/drug effects ; Learning/physiology ; Male ; Microinjections ; Protein Kinase Inhibitors/pharmacology ; Rats ; Sulfonamides/pharmacology ; Ventral Tegmental Area/drug effects ; Ventral Tegmental Area/physiology
Chemical Substances	Benzylamines ; Protein Kinase Inhibitors ; Sulfonamides ; KN 93 (139298-40-1) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17)
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1223366-3
ISSN	1095-9564 ; 1074-7427
ISSN (online)	1095-9564
ISSN	1074-7427
DOI	10.1016/j.nlm.2020.107299
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Article ; Online: Environmental enrichment facilitates electric barrier induced heroin abstinence after incubation of craving in male and female rats.

Barrera, Eddy D / Timken, Patrick D / Lee, Elaine / Persaud, Kirk R S / Goldstein, Hindy / Parasram, Daleya N / Vashisht, Apoorva / Ranaldi, Robert

Drug and alcohol dependence

2023 Volume 244, Page(s) 109799

Abstract: Background: Treatment strategies that aim to promote abstinence to heroin use and reduce vulnerability to drug-use resumption are limited in sustainability and long-term efficacy. We have previously shown that environmental enrichment (EE), when ... ...

Abstract	Background: Treatment strategies that aim to promote abstinence to heroin use and reduce vulnerability to drug-use resumption are limited in sustainability and long-term efficacy. We have previously shown that environmental enrichment (EE), when implemented after drug self-administration, reduces drug-seeking and promotes abstinence to cocaine and heroin in male rats. Here, we tested the effects of EE on abstinence in an animal conflict model in males and females, and after periods where incubation of craving may occur. Methods: Male and female rats were trained to self-administer heroin followed by 3 or 21 days of a no-event-interval (NEI). Following NEI, rats were permanently moved to environmental enrichment (EE) or new standard (nEE) housing 3 days prior to resuming self-administration in the presence of an electric barrier adjacent to the drug access lever. Electric barrier current was increased daily until rats ceased self-administration. Results: We found that 21 days of NEI led to significantly greater heroin self-administration and a trend toward shorter latencies to emit the first active lever press in the first abstinence session compared to 3 days of NEI. EE, when compared to nEE, led to longer latencies in the first abstinence session. Also, EE groups of both sexes and in both NEIs achieved abstinence criteria in significantly fewer numbers of sessions. Conclusions: EE facilitates abstinence in males and females and after periods where incubation of craving may occur. This suggests that EE may benefit individuals attempting to abstain from heroin use and may aid in the development of long term treatment strategies.
MeSH term(s)	Rats ; Male ; Female ; Animals ; Heroin/pharmacology ; Craving ; Rats, Sprague-Dawley ; Cocaine/pharmacology ; Heroin Dependence ; Self Administration ; Cues
Chemical Substances	Heroin (70D95007SX) ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2023-02-07
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	519918-9
ISSN	1879-0046 ; 0376-8716
ISSN (online)	1879-0046
ISSN	0376-8716
DOI	10.1016/j.drugalcdep.2023.109799
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Article ; Online: The D3 receptor antagonist SR 21502 reduces cue-induced reinstatement of methamphetamine-seeking in rats.

Ranaldi, Robert / Timken, Patrick / Parasram, Daleya / Ali, Tasmia / Zhang, Sixue / Moukha-Chafiq, Omar / Augelli-Szafran, Corinne / Streicher, John M

Neuroscience letters

2023 Volume 806, Page(s) 137237

Abstract: There is as of yet no FDA-approved medication for methamphetamine use disorder. Although dopamine D3 receptor antagonists have been shown to be useful in reducing methamphetamine seeking in animal models their translation to the clinic has been hindered ... ...

Abstract	There is as of yet no FDA-approved medication for methamphetamine use disorder. Although dopamine D3 receptor antagonists have been shown to be useful in reducing methamphetamine seeking in animal models their translation to the clinic has been hindered because currently tested compounds can produce dangerously high blood pressure. Thus, it is important to continue to explore other classes of D3 antagonists. We report here the effects of SR 21502, a selective D3 receptor antagonist, on cue-induced reinstatement (i.e., relapse) of methamphetamine-seeking in rats. In Experiment 1, rats were trained to self-administer methamphetamine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with one of several doses of SR 21502 on cue-induced reinstatement of responding. SR 21502 significantly reduced cue-induced reinstatement of methamphetamine-seeking. In Experiment 2, animals were trained to lever press for food under a PR schedule and tested with the lowest dose of SR 21502 that caused a significant reduction in Experiment 1. These animals responded on average 8 times more than the vehicle-treated rats in Experiment 1, eliminating the possibility that SR 21502-treated rats in Experiment 1 responded less because they were incapacitated. In summary, these data suggest that SR 21502 may selectively inhibit methamphetamine-seeking and may constitute a promising pharmacotherapeutic agent for methamphetamine or other drug use disorders.
MeSH term(s)	Rats ; Animals ; Methamphetamine/pharmacology ; Cues ; Extinction, Psychological ; Reinforcement, Psychology ; Dopamine Antagonists/pharmacology ; Self Administration ; Dose-Response Relationship, Drug
Chemical Substances	Methamphetamine (44RAL3456C) ; SR 21502 ; Dopamine Antagonists
Language	English
Publishing date	2023-04-12
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2023.137237
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Article ; Online: Therapeutic efficacy of environmental enrichment for substance use disorders.

Galaj, Ewa / Barrera, Eddy D / Ranaldi, Robert

Pharmacology, biochemistry, and behavior

2019 Volume 188, Page(s) 172829

Abstract: Addiction to drug and alcohol is regarded as a major health problem worldwide for which available treatments show limited effectiveness. The biggest challenge remains to enhance the capacities of interventions to reduce craving, prevent relapse and ... ...

Abstract	Addiction to drug and alcohol is regarded as a major health problem worldwide for which available treatments show limited effectiveness. The biggest challenge remains to enhance the capacities of interventions to reduce craving, prevent relapse and promote long-term recovery. New strategies to meet these challenges are being explored. Findings from preclinical work suggest that environmental enrichment (EE) holds therapeutic potential for the treatment of substance use disorders, as demonstrated in a number of animal models of drug abuse. The EE intervention introduced after drug exposure leads to attenuation of compulsive drug taking, attenuation of the rewarding (and reinforcing) effects of drugs, reductions in control of behavior by drug cues, and, very importantly, relapse prevention. Clinical work also suggests that multidimensional EE interventions (involving physical activity, social interaction, vocational training, recreational and community involvement) might produce similar therapeutic effects, if implemented continuously and rigorously. In this review we survey preclinical and clinical studies assessing the efficacy of EE as a behavioral intervention for substance use disorders and address related challenges. We also review work providing empirical evidence for EE-induced neuroplasticity within the mesocorticolimbic system that is believed to contribute to the seemingly therapeutic effects of EE on drug and alcohol-related behaviors.
MeSH term(s)	Animals ; Brain/physiology ; Conditioning, Psychological/physiology ; Environment ; Exercise/physiology ; Exercise/psychology ; Humans ; Recurrence ; Substance-Related Disorders/physiopathology ; Substance-Related Disorders/psychology ; Substance-Related Disorders/therapy ; Treatment Outcome
Language	English
Publishing date	2019-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2019.172829
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Article ; Online: Low-dose polypharmacology targeting dopamine D1 and D3 receptors reduces cue-induced relapse to heroin seeking in rats.

Ewing, Scott T / Dorcely, Chris / Maidi, Rivka / Paker, Gulsah / Schelbaum, Eva / Ranaldi, Robert

Addiction biology

2021 Volume 26, Issue 4, Page(s) e12988

Abstract: Chemical compounds that target dopamine (DA) D1 or D3 receptors have shown promise as potential interventions in animal models of cue-induced relapse. However, undesirable side effects or pharmacodynamic profiles have limited the advancement of new ... ...

Abstract	Chemical compounds that target dopamine (DA) D1 or D3 receptors have shown promise as potential interventions in animal models of cue-induced relapse. However, undesirable side effects or pharmacodynamic profiles have limited the advancement of new compounds in preclinical studies when administered as independent treatments. In this series of experiments, we explored the effects of coadministration of a D1-receptor partial agonist (SKF 77434) and a D3-receptor antagonist (NGB 2904) in heroin-seeking rats within a "conflict" model of abstinence and cue-induced relapse. Rats were first trained to press a lever to self-administer heroin, and drug delivery was paired contingently with cues (e.g., light and pump noise). Self-initiated abstinence was facilitated by applying electrical current to the flooring in front of the levers. Lastly, a relapse response was provoked by noncontingent presentation of conditioned cues. Prior to provocation, rats received a systemic injection of SKF 77434, NGB 2904, or a combination of both compounds to assess treatment effects on lever pressing. Results indicated that the coadministration of low (i.e., independently ineffective) doses of both compounds was more effective in reducing cue-induced relapse to heroin seeking than either compound alone, with some evidence of drug synergism. Follow-up studies indicated that this reduction was not due to motoric impairment nor enhanced sensitivity to the electrified flooring and that this treatment did not significantly affect motivation for food. Implications for the treatment of opiate use disorder and recommendations for further research are discussed.
MeSH term(s)	Animals ; Conditioning, Operant ; Cues ; Dopamine Antagonists/pharmacology ; Drug-Seeking Behavior/drug effects ; Extinction, Psychological/drug effects ; Heroin/administration & dosage ; Male ; Polypharmacology ; Rats ; Receptors, Dopamine D1/antagonists & inhibitors ; Recurrence ; Self Administration
Chemical Substances	Dopamine Antagonists ; Receptors, Dopamine D1 ; Heroin (70D95007SX)
Language	English
Publishing date	2021-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1324314-7
ISSN	1369-1600 ; 1355-6215
ISSN (online)	1369-1600
ISSN	1355-6215
DOI	10.1111/adb.12988
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Article ; Online: Environmental enrichment reduces heroin seeking following incubation of craving in both male and female rats.

Barrera, Eddy D / Loughlin, Lacey / Greenberger, Stephen / Ewing, Scott / Hachimine, Priscila / Ranaldi, Robert

Drug and alcohol dependence

2021 Volume 226, Page(s) 108852

Abstract: Background: Contemporary treatments for heroin use disorder demonstrate only limited efficacy when the goals are long term abstinence and prevention of relapse. We have demonstrated that environmental enrichment (EE) reduces cue-induced heroin ... ...

Abstract	Background: Contemporary treatments for heroin use disorder demonstrate only limited efficacy when the goals are long term abstinence and prevention of relapse. We have demonstrated that environmental enrichment (EE) reduces cue-induced heroin reinstatement in male rats. The present study is an attempt to extend the "anti-relapse" effects of EE to female rats and to periods where incubation of craving is hypothesized to occur. Methods: This experiment implemented a 3-phase procedure. In Phase 1, male and female rats were trained to self-administer heroin for 15 days. Phase 2 consisted of a 3- or 15-day forced abstinence (FA) period. In Phase 3 half of the rats were placed into EE and the other half in non-EE housing and subsequently tested for responding in extinction (no heroin or cues) for 15 days followed by a cue-induced reinstatement test. Results: We found that rats in the 15 days FA condition showed significantly enhanced drug seeking during extinction, irrespective of sex. We also found that EE significantly reduced this effect. During reinstatement, EE significantly reduced drug seeking in male and female rats and in both 3- and 15-day FA groups. Conclusions: EE, with or without prolonged FA, effectively reduced heroin seeking in male and female rats. These findings indicate that EE can reduce drug-seeking in males and females and when putative incubation of craving (i.e., prolonged abstinence period) has occurred and suggest that it may aid in the development of future long-term behavioral treatments for individuals at risk for heroin relapse.
MeSH term(s)	Animals ; Conditioning, Operant ; Craving ; Cues ; Drug-Seeking Behavior ; Extinction, Psychological ; Female ; Heroin ; Male ; Rats ; Rats, Sprague-Dawley ; Self Administration
Chemical Substances	Heroin (70D95007SX)
Language	English
Publishing date	2021-06-24
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	519918-9
ISSN	1879-0046 ; 0376-8716
ISSN (online)	1879-0046
ISSN	0376-8716
DOI	10.1016/j.drugalcdep.2021.108852
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Article ; Online: Dopamine D1 and D3 receptor polypharmacology as a potential treatment approach for substance use disorder.

Galaj, Ewa / Ewing, Scott / Ranaldi, Robert

Neuroscience and biobehavioral reviews

2018 Volume 89, Page(s) 13–28

Abstract: In the search for efficacious pharmacotherapies to treat cocaine addiction much attention has been given to agents targeting dopamine D1 or D3 receptors because of the involvement of these receptors in drug-related behaviors. D1-like and D3 receptor ... ...

Abstract	In the search for efficacious pharmacotherapies to treat cocaine addiction much attention has been given to agents targeting dopamine D1 or D3 receptors because of the involvement of these receptors in drug-related behaviors. D1-like and D3 receptor partial agonists and antagonists have been shown to reduce drug reward, reinstatement of drug seeking and conditioned place preference in rodents and non-human primates. However, translation of these encouraging results to clinical settings has been limited due to a number of factors including toxicity, poor pharmacokinetic properties and extrapyramidal and sedative side effects. This review highlights the role of D1 and D3 receptors in drug reward and seeking, the discovery of D1-D3 heteromers and their potential as targets in the treatment of addiction.
MeSH term(s)	Animals ; Cocaine-Related Disorders/drug therapy ; Cocaine-Related Disorders/psychology ; Dopamine/pharmacology ; Dopamine Antagonists/therapeutic use ; Drug-Seeking Behavior ; Humans ; Receptors, Dopamine D1/drug effects ; Receptors, Dopamine D2/drug effects
Chemical Substances	Dopamine Antagonists ; Receptors, Dopamine D1 ; Receptors, Dopamine D2 ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2018-03-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	282464-4
ISSN	1873-7528 ; 0149-7634
ISSN (online)	1873-7528
ISSN	0149-7634
DOI	10.1016/j.neubiorev.2018.03.020
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