Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration

doi:10.1016/S0091-3057(02)00731-1

Pharmacology Biochemistry and Behavior

Volume 72, Issue 3, June 2002, Pages 623-632

https://doi.org/10.1016/S0091-3057(02)00731-1 Get rights and content

Abstract

Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), on cocaine-seeking behavior and re-establishment of cocaine self-administration were examined. Rats were trained to lever press for cocaine infusions (0.25 mg/kg iv). Some were then tested for cocaine-seeking behavior (i.e., lever presses in the absence of cocaine re-inforcement) immediately following acute 7-OH-DPAT (0.001, 0.01, 0.1, or 1.0 mg/kg sc) or saline administration. Others were tested immediately or 2–23 h following repeated daily 7-OH-DPAT (1.0 mg/kg sc) or saline administration for extinction of cocaine-seeking behavior, cocaine re-instatement of cocaine-seeking behavior, and re-establishment of cocaine self-administration following extinction. 7-OH-DPAT-induced changes in locomotion were also assessed. Cocaine-experienced animals exhibited cross-tolerance to the transient hypoactivity produced by acute 7-OH-DPAT administration. Acute administration of low doses (0.01–0.1 mg/kg) of 7-OH-DPAT attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then increased, cocaine-seeking behavior. In animals tested immediately following one of the repeated administrations, 7-OH-DPAT did not alter cocaine self-administration, but sensitized locomotion. Repeated 7-OH-DPAT administration also increased cocaine-seeking behavior when administered 0 h, but not 2 or 4 h, before cocaine priming (15 mg/kg ip) and testing. In animals tested 17–23 h following one of the repeated administrations, cocaine-seeking behavior and re-establishment of cocaine self-administration were attenuated, but maintenance of self-administration following re-establishment, cocaine re-instatement of extinguished cocaine-seeking behavior, and spontaneous locomotion were unaltered. The findings suggest that following repeated administration, 7-OH-DPAT produces a transient increase (<2 h) in incentive motivation for cocaine that is followed by a protracted decrease in incentive motivation for cocaine.

Introduction

Cocaine and cocaine-associated stimuli are thought to produce incentive motivational effects that contribute to cocaine craving and relapse Stewart et al., 1984, Robinson and Berridge, 1993. Incentive motivation for cocaine can be measured in animals as cocaine-seeking behavior using the extinction/re-instatement model Stewart, 1983, Markou et al., 1993, Carroll and Comer, 1996. In this model, animals are typically trained to lever press for a cocaine reinforcer and are subsequently tested for extinction and re-instatement of cocaine-seeking behavior (i.e., nonreinforced lever pressing) following exposure to cocaine or cocaine-associated stimuli De Wit and Stewart, 1981, Stewart, 1983.

Studies with D2-like agonists suggest that stimulation of D2-like receptors may modulate incentive motivation for cocaine. Consistent with this idea, acute administration of the D2-like dopamine (DA) agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) at high doses reinstates extinguished cocaine-seeking behavior (3 and 10 mg/kg ip) and increases cocaine re-instatement of extinguished cocaine-seeking behavior (0.3 mg/kg sc) (Self et al., 1996). However, it is unclear whether low doses of 7-OH-DPAT (i.e., ≤0.1 mg/kg sc) alter cocaine-seeking behavior. Low doses of 7-OH-DPAT produce some behavioral effects that are opposite to those produced by the higher doses examined previously. For instance, high doses of 7-OH-DPAT are self-administered, produce conditioned place preference (CPP), reinstate extinguished cocaine-seeking behavior, and increase cocaine re-instatement of extinguished cocaine-seeking behavior Caine and Koob, 1993, Caine et al., 1999, Mallet and Beninger, 1994, Chaperon and Thiébot, 1996, Self et al., 1996. In contrast, low doses of 7-OH-DPAT fail to produce self-administration, CPP, or re-instatement of extinguished cocaine-seeking behavior Nader and Mach, 1996, Khroyan et al., 1995, Self et al., 1996 and attenuate cocaine-CPP and decrease the rate of cocaine self-administration Caine and Koob, 1993, Caine and Koob, 1995, Caine et al., 1999, Khroyan et al., 1999, Parsons et al., 1996. Based on these behavioral effects of low doses, it seems that low doses of 7-OH-DPAT would attenuate cocaine-seeking behavior and that targeted development of drugs that produce the low-dose behavioral profile may be useful for the treatment of cocaine dependence. On the other hand, both low and high doses of 7-OH-DPAT possess cocaine-like discriminative stimulus effects Acri et al., 1995, Lamas et al., 1996, Spealman et al., 1999, Sinnott et al., 1999, Caine et al., 2000 and these effects may facilitate cocaine-seeking behavior (Caine et al., 2000). Thus, one goal of the present study was to examine the effects of low doses of 7-OH-DPAT on extinction of cocaine-seeking behavior.

Another goal of the present study was to examine whether the effects of 7-OH-DPAT on cocaine-seeking behavior change after repeated administration of the drug. This question is particularly important since a chronic regimen would most likely be employed for treatment of cocaine dependence. Furthermore, repeated administration of 7-OH-DPAT may have different effects than acute administration due to possible neural adaptations in systems that mediate incentive motivation for cocaine. For instance, the incentive sensitization theory suggests that enduring sensitization of mesolimbic DA systems elicited by chronic cocaine exposure may underlie compulsive drug seeking and relapse in cocaine addicts (Robinson and Berridge, 1993). Chronic continuous 7-OH-DPAT administration (14 day, 1 mg/kg/day) produces adaptations in DA systems, including a decrease in D2 receptor binding in the nucleus accumbens, ventral pallidum, and substantia nigra and an up-regulation of D3 receptors in the ventral pallidum and substantia nigra in rats (Stanwood et al., 2000). Thus, the present study examined whether repeated 7-OH-DPAT administration (1 mg/kg sc) would alter propensity for cocaine-seeking behavior.

The present study assessed the effects of acute and repeated 7-OH-DPAT administration on extinction of cocaine-seeking behavior. Effects of repeated 7-OH-DPAT administration on cocaine re-instatement of extinguished cocaine-seeking behavior and re-establishment of cocaine self-administration following extinction were also assessed. To thoroughly evaluate the effects of repeated 7-OH-DPAT administration, both its immediate and protracted (i.e., late-emerging, long-lasting) effects were examined. Protracted effects were measured 17–23 h after administration and are thought to reflect changes in incentive motivation that result from neural adaptations to the 7-OH-DPAT regimen in the absence of immediate effects of 7-OH-DPAT. Locomotor activity was also measured as a behavioral control to assess whether effects of 7-OH-DPAT on motor activity may have influenced operant measures.

Section snippets

Animals

Male Sprague–Dawley rats, weighing 250±25 g at the start of the experiment, were housed individually in a climate-controlled colony room with a reversed 12-h light–dark cycle (lights on at 1800 h). Housing conditions were in accordance with the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Sciences, National Research Council, 1996). Animals were acclimated to handling over a 5-day period prior to the start of the experiment.

Autoshaping

To expedite

Cocaine intake

Cocaine intake did not differ among the cocaine-trained groups. The mean number of cocaine infusions (±S.E.M.) self-administered by the cocaine-trained groups was 24.24±2.43 infusions/session (i.e., 1 infusion/4.95 min) and the mean cocaine intake (±S.E.M.) was 2.16±0.39 mg/session.

Cocaine-seeking behavior

Acute administration of 7-OH-DPAT produced a dose-dependent change in cocaine-seeking behavior (see Fig. 1), without altering the latency of the first response (data not shown). The overall ANOVA of cocaine-seeking

Effects of acute 7-OH-DPAT administration

Acute administration of 7-OH-DPAT produced a dose-dependent change in cocaine-seeking behavior (see Fig. 1). Low doses of 7-OH-DPAT (0.01–0.1 mg/kg) attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then enhanced, cocaine-seeking behavior relative to saline treatment. It is unlikely that acute administration of 7-OH-DPAT impaired operant responding, since 7-OH-DPAT did not alter response latency. Furthermore, the highest dose of 7-OH-DPAT

Acknowledgements

The authors thank David A. Baker, Jeremy Daum, and Sheila E. Specio for their expert technical assistance and their helpful comments on earlier versions of this manuscript. This research was supported by USPS Grants DA11064 and DA05816 and by a grant from the Howard Hughes Medical Institute through the Undergraduate Biological Sciences Education Program.

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Methamphetamine (METH) is a potent psychostimulant, repeated use of which can result in a substance abuse disorder. Withdrawn individuals are highly prone to relapse, which may be driven, at least in part, by a hyperresponsivity to METH-associated cues that can prompt METH-seeking. Clinically efficacious pharmacotherapies for METH abuse are critically needed. Mirtazapine (Remeron) is an atypical antidepressant that antagonizes activated norepinephrine_α2, histamine₁ serotonin (5-HT)_2A/C, and 5-HT₃ receptors. This pharmacologic profile prompted our interest in its potential for preventing relapse to METH-taking. This study tested the hypothesis that mirtazapine would attenuate METH-seeking in rats trained to self-administer METH.
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Alterations in dopamine output within the various subnuclei of the amygdala have previously been implicated in cocaine reinforcement, as well as cocaine-seeking behavior. To elucidate the potential for increased stimulation of D1- and D2-like receptors (D1Rs and D2Rs, respectively) specifically in the central nucleus of the amygdala (CeA) to modulate cue- and cocaine-elicited reinstatement of cocaine-seeking behavior, we infused either the D1R agonist, SKF-38393 (0–4.0 μg/side) or the D2R agonist, 7-OH-DPAT (0–4.0 μg/side) into the CeA immediately prior to tests for cue and cocaine-primed reinstatement. We also examined the effects of 7-OH-DPAT on cocaine self-administration as a positive behavioral control. 7-OH-DPAT decreased cue-and cocaine-primed reinstatement, and reduced the number of cocaine infusions obtained during self-administration; SKF-38393 produced no discernable effects. The results suggest that enhanced stimulation of D2Rs, but not D1Rs, in the CeA is sufficient to inhibit expression of the incentive motivational effects of cocaine priming and cocaine-paired cues. Together with previous findings that D1R blockade attenuates reinstatement of cocaine-seeking behavior, the results suggest that D1R stimulation may be necessary, but not sufficient, to modulate the incentive motivational effects of cues and cocaine priming.
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7-OH-DPAT is a dopamine D2/D3 agonist, which at low doses acts preferentially on D3 receptors but at high doses it acts on D2 and D3 receptors. The present study investigated the contribution of D3 and D2 receptors on latent inhibition (LI) by using two dose levels of 7-OH-DPAT: a low dose, 0.1 mg/kg (D3 receptor activation) and a high dose, 1.0 mg/kg, (D2/D3 receptor activation) in a conditioned emotional response (CER) paradigm. The LI Protocols included CS pre-exposure (10 or 40 CS alone trials), CER induction and a non-drug CER test phase. Additionally, the drug effects upon CER acquisition without LI were assessed using the same treatments and test environment pre-exposure protocols but without the tone CS. The effects of 7-OH-DPAT on crossing, rearing and grooming were also measured in an open field 1 day after the CER test phase. The results showed that the low dose 7-OH-DPAT treatment potentiated LI at 10 but not at 40 CS pre-exposures. The high dose 7-OH-DPAT treatment blocked LI at both the 10 and 40 stimulus pre-exposures; and it also induced hyperactivity. Thus, D3 stimulation induced by a low dose of 7-OH-DPAT can facilitate LI but these effects are contingent upon and are specific to the number of stimulus presentations. Altogether, these findings indicate that D3 stimulation can enhance attentional processes, but D2 stimulation can impair attentional processes.

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Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration

Abstract

Introduction

Section snippets

Animals

Autoshaping

Cocaine intake

Cocaine-seeking behavior

Effects of acute 7-OH-DPAT administration

Acknowledgements

Eur J Pharmacol

Neuropharmacology

Brain Res

Eur J Pharmacol

Brain Res Rev

Drug Alcohol Depend

Pharmacol, Biochem Behav

Pharmacol, Biochem Behav

Prog Neuro-Psychopharmacol Biol Psychiatry

Modulation of cocaine self-administration in the rat through D-3 dopamine receptors

Science

Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose–effects function to the left under different schedules in the rat

Behav Pharmacol

Effects of dopamine D1-like and D2-like agonists in rats that self-administer cocaine

J Pharmacol Exp Ther

Effects of dopamine D1-like and D2-like agonists in rats trained to discriminate cocaine from saline: influence of experimental history

Exp Clin Psychopharmacol

Animal models of relapse

Exp Clin Psychopharmacol

Effects of dopaminergic D3-receptor-preferring ligands on the acquisition of place conditioning in rats

Behav Pharmacol

Behavioral and neurochemical changes in the dopaminergic system after repeated cocaine administration

Mol Neurobiol

Behavioural effects in the rat of the putative dopamine D3 receptor agonist 7-OH-DPAT: comparison with quinpirole and apomorphine

Psychopharmacology

Intracranial self-stimulation under a progressive-ratio schedule in rats: effects of strength of stimulation, d-amphetamine, 7-OH-DPAT and haloperidol

Psychopharmacology

Re-instatement of cocaine-reinforced responding in the rat

Psychopharmacology

Predictive validity of the extinction/re-instatement model of drug craving

Psychopharmacology

Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens

Alcohol Drug Res