Single and repeated baclofen treatment attenuates the discriminative stimulus effects of morphine in rats

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Abstract

The GABAB agonists block the rewarding properties of opiates. However, the role of GABAB receptors in the discriminative properties of these drugs has received little attention. In this line, the present study was performed to investigate the effects of acute (Experiment 1) and chronic (Experiment 2) pretreatment with baclofen on the discriminative stimulus effects of morphine. Rats were trained to discriminate morphine (5 mg/kg i.p.) from saline under a two-lever fixed-ratio schedule of food reinforcement. Experiment 1: a morphine generalization curve was obtained under standard conditions in control and baclofen (1 and 2 mg/kg i.p.) pretreated animals. Acute baclofen pretreatment attenuated morphine-lever responding and response rate at both doses. Experiment 2: the animals were randomly divided in two groups and a morphine generalization curve was obtained in daily consecutive test sessions before (TEST1) and after (TEST2) chronic saline (Group I) or chronic baclofen (2 mg/kg) (Group II) administration. As expected, chronic saline pretreatment was ineffective, while chronic baclofen pretreatment attenuated the stimulus properties of morphine, without modifying the rate-decreasing effect of the drug.The data support a role for GABAergic neurotransmission in the discriminative effects of opiates and demonstrate that a short-term treatment with baclofen is useful for decreasing the sensitivity to narcotic cue.

Research Highlights

► Rats are trained to discriminate morphine from saline. ► Acute or chronic baclofen pre-treatment attenuates morphine stimulus properties. ► Acute, but not chronic, baclofen pre-treatment decreases response rate. ► Baclofen might be a promising medication for opiate addiction.

Introduction

Several lines of evidence support the hypothesis that the mesocorticolimbic dopamine system has a role in mediating opiate discrimination (Krivsky et al., 2006, Shaham and Stewart, 1995) as well as opiate reinforcement (Bardo, 1998). However, the dopaminergic system is only one component of the neural circuitry underlying the behavioural properties of opiates. GABAB receptors have been found both in the nucleus accumbens (NA), one of the main projection sites of the mesolimbic dopamine system, and in the ventral tegmental area (VTA) (Kalivas et al., 1990) and may play a primary role in decreasing dopamine release (Klitenick et al., 1992). Actually, intra-ventral tegmental area administration of the GABAB agonist baclofen decreases extracellular dopamine in the NA and in the medial prefrontal cortex (Westerink et al., 1998). Therefore, activation of GABAB receptors localized on dopaminergic and glutamatergic neurons in the VTA is expected to modulate the motivational as well the discriminative properties of opiates by regulating mesolimbic circuitry and its afferent inputs. In this regard it is worth noting that the GABAB agonist baclofen blocks the rewarding effect of morphine, as measured by conditioned place preference (Kaplan et al., 2003, Tsuji et al., 1996), and heroin self-administration (Brebner et al., 2002, Xi and Stein, 1999) (see Filip and Frankowska, 2008 for a review). However, the role of GABAB receptors in the discriminative properties of opiates has received little attention. Actually, the only available study, to our knowledge, has given conflicting results, since selective inhibition of GABA reuptake, but not inhibition of GABA transaminase or direct stimulation of GABAA and GABAB receptors, attenuated the discriminative stimulus effects of heroin in rats (Solecki et al., 2005). Thus, the present study was performed to further investigate the effects of a GABAB agonist (baclofen) on the discriminative stimulus effects of morphine.

Medications to treat addictive disorders are administered chronically (Montoya and Vocci, 2008); thus, since the effect of acute and chronic drug treatments may differ (Matto and Allikmets, 1999), a further experiment was performed to evaluate the effect of repeated baclofen on the discriminative stimulus effects of morphine in rats. In this case, as usual (Emmett-Oglesby, 1990, Wood et al., 1984), training was halted during the chronic baclofen treatment.

Section snippets

Materials and methods

The Principles of Laboratory Animal Care (NIH publication No. 85-23, revised 1985) were followed. The experimental protocol was approved by a local bioethical committee, whereas the University Veterinary Service controlled the procedures and animal comfort.

Experiment 1: effect of baclofen co-administration on the discriminative stimulus effects of morphine

The effects of baclofen co-administration on the discriminative stimulus effects of morphine are shown in Fig. 1. As regards drug-lever responding, the ANOVA revealed significant effects of morphine [F(3,135) = 7.73, P < 0.01] and baclofen [F(2,135) = 5.97, P < 0.01], but no morphine × baclofen interaction (F < 1). Further comparisons indicated that baclofen significantly attenuates morphine-lever responding at both doses (1 mg/kg: t135 = 2.32, P < 0.05; 2 mg/kg: t135 = 3.14, P < 0.01). The ANOVA relative to

Discussion

Baclofen co-administration reduced the potency of morphine as a discriminative stimulus. The data are in keeping with previous reports supporting the role of GABAergic neurotransmission in the reinforcing (Brebner et al., 2002, Kaplan et al., 2003, Tsuji et al., 1996, Xi and Stein, 1999, Xi and Stein, 2000, Xi and Stein, 2002) and discriminative (Solecki et al., 2005) effects of opiates. Actually, Solecki et al. (2005) found that the enhancement of GABAergic transmission by GABA uptake

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