Assessment of cocaine-like discriminative stimulus effects of dopamine D3 receptor ligands

doi:10.1016/0014-2999(95)00411-D

European Journal of Pharmacology

Volume 281, Issue 2, 4 August 1995, Pages R7-R9

https://doi.org/10.1016/0014-2999(95)00411-D Get rights and content

Abstract

The highly selective dopamine D₃ receptor ligand, (+)-PD 128907 4aR10bR-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl-2H5H[4,3-b]-1,4-oxazin-9-ol), and other dopamine D₃ receptor ligands, (±)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin and (+)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin, substituted for the discriminative stimulus effects of cocaine in rats, an animal model of subjective effects in humans. Substitution only occurred at doses that markedly decreased responding. These results suggest that dopamine D₃ receptors may be involved in the subjective effects of cocaine, and therefore may be a target for the discovery of treatments for cocaine dependence.

References (8)

G. Damsma et al.
Pharmacological aspects of R-(+)-7-OH-DPAT, a putative dopamine D₃ receptor ligand
Eur. J. Pharmacol.
(1993)
M.J. Kuhar et al.
The dopamine hypothesis of the reinforcing properties of cocaine
Trends Neurosci.
(1991)
J.M. Witkin
Pharmacotherapy of cocaine abuse: preclinical development
Neurosci. Biobehav. Rev.
(1994)
S.B. Caine et al.
Modulation of cocaine self-administration in the rat through D-3 dopamine receptors
Science
(1993)

There are more references available in the full text version of this article.

Cited by (73)

Predicting abuse potential of stimulants and other dopaminergic drugs: Overview and recommendations
2014, Neuropharmacology
Citation Excerpt :
In some instances, the discrepancies were related to the training dose of cocaine. With 7-OH-DPAT in rodents, full substitution occurred with larger cocaine-training doses (Acri et al., 1995; Garner and Baker, 1999; Ukai and Mitsunaga, 2005) and partial substitution occurred with smaller cocaine-training doses (Baker et al., 1998). The opposite occurred with 7-OH-DPAT in NHPs where larger cocaine-training doses yielded partial substitution (Lamas et al., 1996; Spealman, 1996) and smaller cocaine-training doses yielded full substitution (Sinnott et al., 1999).
Examination of a drug's abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion.
This article is part of the Special Issue entitled ‘CNS Stimulants’.
You are what you eat: Influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists
2012, Neuropharmacology
Citation Excerpt :
A number of chemically diverse DA reuptake inhibitors, DA releasers, and direct-acting DA receptor agonists can mimic the behavioral (e.g. discriminative stimulus) effects of drugs like cocaine and some DA receptor antagonists attenuate the effects of cocaine (Acri et al., 1995; Caine and Koob, 1993; Spealman, 1996; Witkin et al., 1991). Although the relative contribution of each receptor subtype to the effects of cocaine is not fully known, D2 and D3 receptors are thought to mediate many of the behavioral effects of cocaine (Acri et al., 1995; Caine and Koob, 1993; Sinnott et al., 1999; Spealman, 1996). A number of studies indicate an important role for DA in the effects of cocaine; however, and in contrast to direct-acting DA receptor agonists, other neurotransmitter systems are thought to play a role in mediating the effects of cocaine, including norepinephrine (Johanson and Barrett, 1993) and serotonin (Cunningham and Callahan, 1991) systems.
The important role of dopamine (DA) in mediating feeding behavior and the positive reinforcing effects of some drugs is well recognized. Less widely studied is how feeding conditions might impact the sensitivity of drugs acting on DA systems. Food restriction, for example, has often been the focus of aging and longevity studies; however, other studies have demonstrated that mild food restriction markedly increases sensitivity to direct- and indirect-acting DA receptor agonists. Moreover, it is becoming clear that not only the amount of food, but the type of food, is an important factor in modifying the effects of drugs. Given the increased consumption of high fat and sugary foods, studies are exploring how consumption of highly palatable food impacts DA neurochemistry and the effects of drugs acting on these systems. For example, eating high fat chow increases sensitivity to some behavioral effects of direct- as well as indirect-acting DA receptor agonists. A compelling mechanistic possibility is that central DA pathways that mediate the effects of some drugs are regulated by one or more of the endocrine hormones (e.g. insulin) that undergo marked changes during food restriction or after consuming high fat or sugary foods. Although traditionally recognized as an important signaling molecule in regulating energy homeostasis, insulin can also regulate DA neurochemistry. Because direct- and indirect-acting DA receptor drugs are used therapeutically and some are abused, a better understanding of how food intake impacts response to these drugs would likely facilitate improved treatment of clinical disorders and provide information that would be relevant to the causes of vulnerability to abuse drugs.
This article is part of a Special Issue entitled ‘Central Control of Food Intake’.
Levo-tetrahydropalmatine attenuates cocaine self-administration under a progressive-ratio schedule and cocaine discrimination in rats
2010, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Roles for DA in cocaine's discriminative stimulus (Callahan et al., 1997) and reinforcing (Anderson and Pierce, 2005) effects have been well established. Drugs that interfere with DA actions at D1 (Kleven et al., 1988; Barrett and Appel, 1989; Kleven et al., 1990; Vanover et al., 1991; Witkin et al., 1991; Sinnott and Nader, 2001), D2 (Barrett and Appel, 1989; Kleven et al., 1990; Costanza et al., 2001), or D3 (Beardsley et al., 2001; Martelle et al., 2007) DA receptors through antagonism or partial agonism have been reported to attenuate cocaine's discriminative stimulus properties, while agonists at D1 (Callahan et al., 1991; Spealman et al., 1991; Witkin et al., 1991; Sinnott and Nader, 2001; Chausmer and Katz, 2002), D2 (Callahan et al., 1991; Spealman et al., 1991; Witkin et al., 1991; Callahan and Cunningham, 1993; Katz and Witkin, 1993), or D3 (Acri et al., 1995; Lamas et al., 1996; Spealman, 1996; Sinnott et al., 1999) receptors have been reported to promote cocaine generalization in drug discrimination protocols. Likewise D1 (Hubner and Moreton, 1991; Depoortere et al., 1993), D2 (Roberts et al., 1989; Hubner and Moreton, 1991) and D3 (Xi et al., 2005; 2006) DA receptor antagonists have been reported to reduce breaking points for cocaine SA under a PR schedule, while D1 (Rowlett et al., 2007), D2 (Rowlett et al., 2007), and D3 (Caine and Koob, 1995) receptor agonists have been reported to have the opposite effect.
Levo-tetrahydropalmatine (l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine self-administration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine. In adult male Sprague–Dawley rats self-administering cocaine (0.5 or 1.0 mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5 mg/kg doses. l-THP also reduced the breaking point and response rate for PR SA of sucrose-sweetened food pellets, although the decrease was significant only at the 7.5 mg/kg l-THP dose. In rats trained to discriminate cocaine (10 mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5 mg/kg) produced a rightward shift in the dose–response curve for cocaine generalization. During generalization testing, l-THP reduced response rate, but only at the 7.5 mg/kg dose. l-THP also prevented substitution of the dopamine D2/D3 receptor agonist, (±) 7-OH-DPAT, for cocaine suggesting a potential role for antagonism of D2 and/or D3 receptors in the effects of l-THP. These data further demonstrate that l-THP attenuates the reinforcing and subjective effects of cocaine at doses that do not produce marked motor effects and provide additional evidence that l-THP may have utility for the management of cocaine addiction.
Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine
2006, Behavioural Brain Research
Stress and drug-associated cues can trigger drug desire and relapse in abstinent cocaine users. Although the role of these two factors in relapse is well documented, it remains unclear as to whether an interaction between stress and drug-associated cues can lead to an enhancement in cocaine-seeking behavior. Here, we assessed the effects of the anxiogenic α₂-noradrenergic receptor antagonist, yohimbine, on reinstatement of cocaine-seeking in rats either in the presence or absence of cocaine-associated cues. Yohimbine pretreatment in the absence of cocaine-associated cues or cues by themselves reliably reinstated responding on the previously cocaine-paired lever (3–4 times higher than extinction levels). However, animals showed greatly potentiated responding if yohimbine preceded cue-induced reinstatement (10–13 times higher than extinction levels, or 3–5 times over cues or yohimbine alone). While cocaine self-administration produced a significant increase in plasma corticosterone, plasma corticosterone levels did not show a clear relationship to cocaine-paired lever responding during cue and/or yohimbine-induced reinstatement. These results demonstrate that exposure to drug-paired cues during a stressful state can greatly potentiate cocaine-seeking and suggest that future treatment interventions should target multiple modalities.
The role of central dopamine D<inf>3</inf> receptors in drug addiction: A review of pharmacological evidence
2005, Brain Research Reviews
The cDNA for the dopamine D₃ receptor was isolated and characterized in 1990. Subsequent studies have indicated that D₃ receptors, as well as D₃ receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D₃ receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D₃ receptors. The interpretation of results from studies using mixed D₂/D₃ agonists and/or antagonists is problematic because these agents have low selectivity for D₃ over D₂ receptors and it is likely that their actions are primarily related to D₂ receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D₃ receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D₃ receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D₃ receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D₃ receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stress-induced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D₃ receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction.
Synthesis and biological characterization of novel hybrid 7-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro- naphthalen-2-ol and their heterocyclic bioisosteric analogues for dopamine D2 and D3 receptors
2004, Bioorganic and Medicinal Chemistry
In a recent preliminary communication we described the development of a series of hybrid molecules for the dopamine D2 and D3 receptor subtypes. The design of these compounds was based on combining pharmacophoric elements of aminotetralin and piperazine molecular fragments derived from known dopamine receptor agonist and antagonist molecules. Molecules developed from this approach exhibited high affinity and selectivity for the D3 receptor as judged from preliminary [³H]spiperone binding data. In this report, we have expanded our previous finding by developing additional novel molecules and additionally evaluated functional activities of these novel molecules in the [³H]thymidine incorporation mitogenesis assay. The binding results indicated highest selectivity in the bioisosteric benzothiazole derivative N6-[2-(4-phenyl-piperazin-1-yl)-ethyl]-N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine (14) for the D3 receptor whereas the racemic compound 7-({2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ol (10c) showed the strongest potency. Mitogenesis studies to evaluate functional activity demonstrated potent agonist properties in these novel derivatives for both D2 and D3 receptors. In this regard, compound 7-{[4-(4-phenyl-piperazin-1-yl)-butyl]-prop-2-ynyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol (7b) exhibited the most potent agonist activity at the D3 receptor, 10 times more potent than quinpirole and was also the most selective compound for the D3 receptor in this series. Racemic compound 10a was resolved; however, little separation of activity was found between the two enantiomers of 10a. The marginally more active enantiomer (−)-10a was examined in vivo using the 6-OH-DA induced unilaterally lesioned rat model to evaluate its activity in producing contralateral rotations. The results demonstrated that in comparison to the reference compound apomorphine, (−)-10a was quite potent in inducing contralateral rotations and exhibited longer duration of action.

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Rapid communicationAssessment of cocaine-like discriminative stimulus effects of dopamine D3 receptor ligands

Abstract

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