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Effects of Co-Administration of the GABAB Receptor Agonist Baclofen

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Effects of Co-Administration of the GABAB Receptor Agonist Baclofen Pharmacological Reports Copyright © 2013 2013, 65, 11321143 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Effectsofco-administrationoftheGABAB receptoragonistbaclofenandapositiveallosteric modulatoroftheGABAB receptor,CGP7930,on thedevelopmentandexpressionofamphetamine- inducedlocomotorsensitizationinrats LauraN.Cedillo,FlorencioMiranda FESIztacala,NationalAutonomousUniversityofMéxico,Av. delosBarrios1,LosReyesIztacalaTlalnepantla, Edo.deMéxico54090,México Correspondence: FlorencioMiranda,e-mail:[email protected] Abstract: Background: Several of the behavioral effects of amphetamine (AMPH) are mediated by an increase in dopamine neurotransmis- sion in the nucleus accumbens. However, evidence shows that g-aminobutyric acid B (GABAB) receptors are involved in the behav- ioral effects of psychostimulants, including AMPH. Here, we examined the effects of co-administration of the GABAB receptor agonist baclofen and a positive allosteric modulator of the GABAB receptor, CGP7930, on AMPH-induced locomotor sensitization. Methods: In a series of experiments, we examined whether baclofen (2.0, 3.0 and 4.0 mg/kg), CGP7930 (5.0, 10.0 and 20.0 mg/kg), or co-administration of CGP7930 (5.0, 10.0 and 20.0 mg/kg) with a lower dose of baclofen (2.0 mg/kg) could prevent the develop- mentandexpressionoflocomotorsensitizationproducedbyAMPH(1.0mg/kg). Results: The results showed that baclofen treatment prevented both the development and expression of AMPH-induced locomotor sensitization in a dose-dependent manner. Furthermore, the positive allosteric modulator of the GABAB receptor, CGP7930, in- creasedtheeffectsofalowerdoseofbaclofenonAMPH-inducedlocomotorsensitizationunderbothconditions. Conclusion: These data provide further evidence that GABAB receptor ligands may modulate psychostimulant-induced behaviors. Keywords: amphetamine, sensitization, GABAB receptors Introduction synaptic vesicles, promoting an increase in the cyto- plasmic concentrations of these monoamines. As the levels of cytoplasmic monoamines increase, they exit Cocaine and amphetamine (AMPH) are indirect neurons via reversal of the direction of plasma mem- monoamine agonists that exhibit an affinity for dopa- brane transporters, which leads to an increase in synap- mine (DA), norepinephrine (NE), and serotonin (5-HT) tic DA, NE, and 5-HT levels [1, 28, 52]. transporters, which are involved in neurotransmitter re- The mesolimbic DAergic system, particularly the uptake and vesicular storage systems [52]. Cocaine in- projection from the ventral tegmental area (VTA) to hibits the reuptake of DA, NE, and 5-HT, thereby in- the nucleus accumbens (NAcc), is an important locus creasing the synaptic levels of these neurotransmitters. for the production of the locomotor, reinforcement, AMPH blocks the uptake of DA, NE, and 5-HT into reward, and discriminative stimulus effects of psy- 1132 Pharmacological Reports, 2013, 65, 11321143 EffectsofBCF andCGP onAMPH-inducedlocomotor sensitization Laura N. Cedillo and Florencio Miranda chostimulants [17, 20, 35]. The administration of useful for studying DA-GABA interactions. The pres- AMPH or cocaine rapidly increases DAergic neuro- ent study was designed to examine the effects of co- transmission by interfering with the function of DA administration of the GABAB receptor agonist BCF transporters, as described above. Consequently, psy- and CGP, a positive allosteric modulator of the chostimulant administration produces an increase in GABAB receptor, on the development and expression DAergicsignalinginthelimbicareas[35,36]. ofAMPH-inducedlocomotorsensitization. Recent evidence also suggests a potential role for g-aminobutyric acid (GABA) neurotransmission in modulating some of the behavioral effects of psycho- stimulants. GABAB receptor agonists are reportedly MaterialsandMethods effective in attenuating some of the behavioral effects of psychostimulants that may be related to the abuse Animals of these drugs. For example, the selective GABAB re- ceptor agonist baclofen (BCF) reduces the reinforcing A total of 400 male Wistar rats that were 120 days old effects of cocaine [49], nicotine [19], methAMPH and weighed 20–250 g at the beginning of the experi- [48], and AMPH [9]. Furthermore, BCF administra- ments were obtained from the breeding colony of the tion decreases the conditioned locomotion elicited by FES-Iztacala-UNAM, México. They were individu- cues associated with cocaine [25]. Other GABAB re- ally housed in stainless steel cages with freely avail- ceptor agonists also reduce psychostimulant-related able food (Teklad LM485 Rat Diet by Harlan, México behaviors. Brebner et al. [10] reported that the selec- City, México) and water and were maintained under tive GABAB receptor agonist CPG44532 was effec- a 12 h light/dark cycle, with the lights turned on at tive in attenuating cocaine self-administration in rats 08:00 h. The room was maintained at a temperature of subjectedtoaprogressiveratioschedule. 21 ± 1°C. All experiments were conducted during the Although some findings have indicated that light phase (between 11:00 a.m. and 1:00 p.m.). Ani- GABAB agonists, such as BCF, may be useful in the mal care and handling procedures were performed in treatment of drug abuse, other results have suggested accordance with the Official Mexican Norm (NOM- that the muscle-relaxant properties of BCF, in con- 062-ZOO-1999) entitled “Technical Specifications junction with its sedative and hypothermic effects, for the Production, Care, and Use of Laboratory Ani- limit its widespread application as a therapeutic agent mals” and all procedures were approved by the local in humans and as a tool for behavioral research [16, bioethicscommittee. 26]. However, a novel alternative approach, allosteric modulation of GABAB receptors, has been suggested. Drugs Positive allosteric modulators of GABAB receptors display no intrinsic activity of their own but can inter- The drugs used in this study were D-amphetamine act synergistically with GABAB agonists, including sulfate, (±)-baclofen (Sigma-Aldrich, St. Louis, MO, BCF, to enhance their effects. One strategy for at- USA), and CGP7930 (Tocris, Ballwin, MO, USA). tempting to overcome the side effects of BCF is to use (±)-Baclofen and D-AMPH were dissolved in water, lower dosages to reduce unwanted effects of the drug, and CGP7930 was dissolved in 2 drops (20 µl/drop) in combination with positive allosteric modulators of of ethanol and then in 1% Tween 80. All drugs were GABAB receptors,suchasCGP7930(CGP). prepared fresh daily and were administered via Locomotor sensitization is the progressive and per- intraperitonealinjection(1ml/kg). sistent enhancement of a behavioral response to a drug after repeated and intermittent administration. Apparatus This phenomenon has been well characterized for psychostimulant and cannabinoid drugs [32, 60, 63] Locomotor activity was measured with an open-field and is thought to reflect neuroadaptations that contrib- activity monitoring system (ENV-515 model; Med ute to drug addiction and model some aspects of ad- Associates, St. Albans, VT. USA). Each Plexiglas dictive behaviors, such as drug craving [51]. There- cage (40 × 40 × 30 cm) was equipped with 2 sets of 8 fore, locomotor sensitization may reflect neurobio- photobeams that were placed 2.5 cm above the sur- logical changes related to drug addiction and may be face of the floor on opposite walls to record x–y am- Pharmacological Reports, 2013, 65, 11321143 1133 bulatory movements. Photobeam interruptions were Experiment1: EffectsofBCFandCGPco- recorded and translated by software to yield the hori- administrationonthedevelopmentofAMPH- zontal distance traveled (in cm), which was the de- inducedlocomotorsensitization(seeTab.1for thescheduleofdrugtreatmentforExperiment1 pendentmeasureusedforanalysis. andExperiment2) Experimentalprocedure a) Effects of BCF on the development of AMPH- induced locomotor sensitization. On the days where The timeline of the general procedure is shown in Figure the development of sensitization was examined, 1. Each day or session started with a 10 min period of groups of rats (n = 10 rats per group) received one of habituation to the cages, followed by administration of the following treatments: VEH + VEH (group 2V), drug(s) or vehicle (VEH). The rats were returned to the VEH + AMPH (1.0 mg/kg; group VA), BCF (2.0 mg/ cages, and their locomotor activity was recorded for 1 h. kg) + AMPH (1.0 mg/kg; group B2A), BCF (3.0 mg/ On day 1, the rats were habituated to the open-field kg) + AMPH (1.0 mg/kg; group B3A), or BCF cages and injection procedures (habituation session). On (4.0mg/kg)+AMPH(1.0mg/kg;groupB4A). day 2, locomotor activity after VEH administration (lo- b) Effects of CGP on the development of AMPH- comotor activity baseline) was evaluated. On days 3–7, induced locomotor sensitization. On the days where the rats received pharmacological compounds and/or the development of sensitization was examined, AMPH (for development of AMPH-induced locomotor groups of rats (n = 10 rats per group) received one of sensitization; see Tab. 1). On days 8–9, the rats were left the following treatments: VEH + VEH (group 2V), undisturbed (resting days). In the experiments examin- VEH + AMPH (1.0 mg/kg; group VA), CGP (5.0 mg/ ing the development of AMPH sensitization, the rats kg) + AMPH (1.0 mg/kg; group C5A), CGP (10.0 mg/ were injected with VEH and AMPH on days 10 and 11, kg) + AMPH (1.0 mg/kg; group C10A), or CGP respectively (test days), while in the experiments exam- (20.0mg/kg)+AMPH(1.0mg/kg;groupC20A).
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