Cocaine self-administration is increased by both D1 and D2 dopamine antagonists

doi:10.1016/0091-3057(91)90168-2

Pharmacology Biochemistry and Behavior

Volume 39, Issue 3, July 1991, Pages 799-802

https://doi.org/10.1016/0091-3057(91)90168-2 Get rights and content

Abstract

Rats were trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement with a 1-min time-out period following each infusion. Cocaine was available at doses of either 0.1, 0.3 or 1.0 mg/kg/infusion. A low dose (3 μg/kg) of the D1 antagonist SCH23390 caused an increase in cocaine self-administration which was more prominent at higher, as compared to lower, doses of cocaine. Higher doses of SCH23390 generally caused decreases in self-administration which may in part be due to the response-decreasing properties of this agent. The D2 antagonist spiperone generally caused an increase in self-administration of cocaine. These data suggest that cocaine reinforcement depends upon both D1 and D2 receptor subtypes.

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Dopamine D1 and D3 receptor polypharmacology as a potential treatment approach for substance use disorder
2018, Neuroscience and Biobehavioral Reviews
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The D1-like receptor antagonist, SCH 23390, and partial agonist, SKF 38393, have been shown to reduce BSR (Nakajima and O’Regan, 1991) while the D1-like receptor agonists, SKF 82958 and A77636, to facilitate BSR (Carr et al., 2001; Gilliss et al., 2002; Lazenka et al., 2016; Ranaldi and Beninger, 1994). In drug self-administration studies, D1-like receptor antagonists SCH 23390, A69024 and SCH 39166 increase cocaine intake, but high doses of the antagonists decrease responding in rats and monkeys (Barrett et al., 2004; Britton et al., 1991; Caine and Koob, 1994; Caine et al., 1999; Corrigall and Coen, 1991a; Hubner and Moreton, 1991; Koob et al., 1987). A higher rate of cocaine intake under the treatment of SCH 23390 has been associated with a greater increase in DA oxidation current (i.e., a measure of extracellular DA concentration) in the NAcc.
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.
The Clockδ19 mutation in mice fails to alter the primary and secondary reinforcing properties of nicotine
2013, Drug and Alcohol Dependence
Citation Excerpt :
For example, DA D1 receptors (D1R) play a critical role in Pavlovian learning and Pavlovian-incentive learning (Di Chiara, 2002; Hyman, 2005), but the infusion of DA D1R antagonists into the NAcc core has no effect on the acquisition of nicotine CPP (Spina et al., 2006), but blocks the acquisition of cocaine CPP in rats (Baker et al., 1998). Furthermore, both peripheral and central administration of the D1R antagonist SCH-23390 has been demonstrated to decrease nicotine self-administration in rodents (Corrigall and Coen, 1991b; David et al., 2006; Stairs et al., 2010), but in general increases cocaine self-administration (Caine and Koob, 1994; Corrigall and Coen, 1991a; Koob et al., 1987; Stairs et al., 2010). Thus, contrasting effects of nicotine and cocaine associated with DA-mediated reinforcement and motivation may underlie the differences seen here and those reported for cocaine CPP and SA.
Clock genes have been demonstrated to play a role in behavioral responses to a variety of drugs of abuse, including cocaine, amphetamine, morphine, and ethanol. However, no studies to date have examined the role of Clock genes on nicotine-mediated behaviors. We examined the involvement of Clock, one of several Clock genes, on the effects of nicotine by examining mice with the ClockΔ19 mutation in behaviors commonly used to assess drug effects in rodents.
We first measured the locomotor effects of nicotine in mutants and wild type mice in response to repeated nicotine injections (0.175 mg/kg, IP). To assess the secondary properties of nicotine, we measured the ability of nicotine (0.175 mg/kg, IP) to induce a conditioned place preference. Finally, we measured the primary reinforcing properties of nicotine at two doses (0.01 and 0.03 mg/kg/infusion, IV) using the self-administration paradigm.
Mutant mice demonstrated no difference in magnitude of the sensitized response to nicotine as compared to wild-type controls. In the conditioned place preference paradigm, mutant and wild-type mice demonstrated a similar preference for a nicotine-paired environment. And finally, mutant and wild-type mice demonstrated a similar acquisition of nicotine self-administration, as indicated by the number of responses on a nicotine-paired lever and the number of nicotine reinforcers achieved during sessions.
The ClockΔ19 mutation appears to have no effect on the reinforcing properties of nicotine, in contrast to its demonstrated role in cocaine reinforcement. Further studies are needed to determine the effect of other Clock genes on nicotine reinforcement.
Obesity-resistant S5B rats showed greater cocaine conditioned place preference than the obesity-prone OM rats
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Citation Excerpt :
Conceivably BC efficacy is affected by specific genetic differences inherent between the two strains which remain to be defined. This disruption of CPP is supportive of prior studies that have shown that selective DA agonists can disrupt cocaine self-administration [34–36] and CPP [37–39]. Thus, BC as shown in the present study to reduce cocaine preference should warrant further investigation with respect to clinical application, perhaps limited to only a relatively high dose.
Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne–Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains.
OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions.
OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine.
Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.
Gestational treatment with methylazoxymethanol (MAM) that disrupts hippocampal-dependent memory does not alter behavioural response to cocaine
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Schizophrenia is associated with increased rates of substance abuse that are thought to be the result of changes in cortical and mesolimbic dopamine activity. Previous work has shown that gestational methylazoxymethanol acetate (MAM) treatment induces increased mesolimbic dopamine activity when given around the time of embryonic day 17 (ED17), suggesting that MAM treatment may model some aspects of schizophrenia. Given that increased dopaminergic activity facilitates aspects of drug self-administration and reinstatement of drug seeking, the current experiments sought to assess cocaine self-administration in MAM treated animals. Experiment 1 examined the acquisition of cocaine self-administration in ED17 MAM and saline treated rats using a sub-threshold dose of cocaine. In experiment 2 ED17 MAM and saline treated animals were trained to self-administer cocaine and were then assessed under varying doses of cocaine (dose–response), followed by extinction and drug-induced reinstatement of responding. A subset of these animals was trained on a win-shift radial maze task, designed to detect impairments in hippocampal-dependent memory. In experiment 3, MAM and saline treated animals were assessed on a progressive ratio schedule of cocaine delivery. Finally, in experiment 4 MAM and saline treated animals were assessed on cocaine-induced locomotor activity across a range of doses of cocaine. MAM treatment disrupted performance of the win-shift task but did not alter cocaine self-administration or cocaine-induced locomotion. Implications of these results for the MAM model of schizophrenia are discussed.
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Brief communicationCocaine self-administration is increased by both D1 and D2 dopamine antagonists

Abstract

Neurosci. Lett.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

A rodent model for nicotine self-administration

Brief communication
Cocaine self-administration is increased by both D1 and D2 dopamine antagonists