Differential Effects of Caffeine on Dopamine and Acetylcholine Transmission in Brain Areas of Drug-Naive and Caffeine-Pretreated
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Differential Effects of Caffeine on Dopamine and Acetylcholine Transmission in Brain Areas of Drug-naive and Caffeine-pretreated Rats Elio Acquas, Ph.D., Gianluigi Tanda, Ph.D., and Gaetano Di Chiara, M.D. The effects of caffeine on extracellular dopamine and effects of a dose of 1 and 2.5 mg/kg i.v. of caffeine; these acetylcholine have been studied in freely moving rats doses, however, still increased dialysate acetylcholine but implanted with concentric microdialysis probes in the did not affect dopamine in the prefrontal cortex. Therefore, nucleus accumbens shell and core and in the medial in rats made tolerant to the locomotor stimulant effects of prefrontal cortex. Intravenous administration of caffeine caffeine, tolerance developed to the dopamine stimulant but (0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg) dose-dependently not to the acetylcholine stimulant effect of caffeine in the increased dopamine and acetylcholine dialysate prefrontal cortex. The lack of acute stimulation of dopamine concentrations in the medial prefrontal cortex, while it did release in the nucleus accumbens shell by caffeine is not affect dialysate dopamine in the shell and core of the relevant to the issue of its addictive properties and of the nucleus accumbens. Intraperitoneal administration of role of DA in drug- and substance-addiction. On the other caffeine (1.5, 3, 10, 30 mg/kg) also failed to affect DA in the hand, the dissociation between tolerance to the locomotor shell and core of the nucleus accumbens. Such effects were effects of caffeine and stimulation of acetylcholine release in duplicated by intravenous administration of DPCPX, a the prefrontal cortex suggests that this effect might be selective antagonist of adenosine A1 receptors, and of SCH correlated to the arousing effects of caffeine as distinct from 58261, an antagonist of A2a receptors. The effect of caffeine its locomotor stimulant properties. on prefrontal dopamine and acetylcholine transmission was [Neuropsychopharmacology 27:182–193, 2002] also studied in rats chronically administered with caffeine © 2002 American College of Neuropsychopharmacology. (25 mg/kg, twice a day for seven days). At the end of this Published by Elsevier Science Inc. treatment rats became tolerant to the locomotor stimulating KEY WORDS: Acetylcholine; Caffeine; Dopamine; Caffeine is the active psychostimulant ingredient of Microdialysis; Nucleus Accumbens; Prefrontal cortex widely consumed beverages. Although the large con- sumption of caffeine-containing beverages could be taken as indicative of its reinforcing properties, no con- From the Department of Toxicology, University of Cagliari, and sistent self-administration of caffeine has been obtained Centre for Neuropharmacology – CNR, Via Ospedale72, I-09124 Cagliari, Italy. in laboratory animals including rats and non-human pri- Address correspondence to: Prof. Gaetano Di Chiara, Depart- mates (Garrett and Griffiths 1998; Griffiths and Mumford ment of Toxicology & Centre for Neuropharmacology – CNR, Uni- 1995; Nehlig 1999). On the other hand, although toler- versity of Cagliari, Via Ospedale 72 - I-09124, Cagliari, Italy. Tel.: ϩ39 70 675 8666/8667, fax: ϩ39 70 675 8612/86, E-mail: diptoss@ ance and physical dependence can develop in humans tin.it after prolonged intake of caffeine, this drug is currently Received August 6, 2001; revised January 9, 2002; accepted Janu- not included in the list of drugs that fulfill DSM-IV crite- ary 16, 2002. Online publication: 1/17/02 at www.acnp.org/citations/Npp ria for addiction (APA 1994; Chou et al. 1985; Fredholm 011702226. et al. 1999; Nehlig 1999; Svenningsson et al. 1999). NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 2 © 2002 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/02/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(02)00290-7 NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 2 Caffeine Stimulates PFCx DA and ACh but not NAc Shell DA 183 Caffeine’s central effects are known to be due to properties, the relationship between tolerance to caf- blockade of adenosine A1 and A2A receptors. These re- feine’s psychostimulant effects and changes in DA and ceptors are widely distributed through the brain (Dixon ACh transmission was also studied. The effects of caf- et al. 1996; Lee and Reddington 1986; Palmer and Stiles feine were compared with those of selective antagonists 1995), adenosine A1 receptors being present mostly in for adenosine A1 or A2A receptors. Caffeine was admin- cortical layers, hippocampus and striatum (Dixon et al. istered by two routes: intravenous, through subchroni- 1996; Palmer and Stiles 1995) and A2a receptors being cally implanted catheters, and intraperitoneal. The in- co-localized with DA receptors in the striatum (Dixon travenous route was utilized in experiments involving et al. 1996; Palmer and Stiles 1995). monitoring DA and ACh in the PFCX so as to avoid ma- Acetylcholine (ACh) might be involved in the stimu- nipulating the animals during drug-injection and to ar- lant properties of caffeine. Cholinergic nerve terminals tifactually stimulate cortical DA and ACh transmission. in the prefrontal cortex, originating in the Ch1–Ch4 nu- The intraperitoneal route of administration was uti- clei of the basal forebrain cholinergic complex (Mesu- lized, comparatively with the intravenous one, in ex- lam et al. 1983; Schwaber et al. 1987) have been in- periments involving monitoring of DA in the NAc shell volved in arousal and attentional processes (Fibiger and core areas, where this manuever induces only mi- 1991; Sarter and Bruno 2000). Cortical ACh release is in- nor changes in DA and ACh transmission. The intra- creased following presentation of novel, behaviorally peritoneal route was also utilized in order to allow relevant stimuli (Acquas et al. 1996; Moore et al. 1993) comparison of the results with those of previous place- but also as a consequence of an attentional load during preference studies utilizing the same route (Patkina and performance in a 5-choice serial reaction time task (Pas- Zvartau 1998; Bedginfield et al. 1998). setti et al. 2000). Adenosine exerts a strong control over ascending ACh projections to the thalamus and cortex. Thus, cho- EXPERIMENTAL PROCEDURE linergic nuclei of the mesopontine tegmentum (Ch –Ch 5 6 Animals nuclei, according to the nomenclature of Mesulam et al. (1983)) are tonically inhibited by adenosine through an Male Sprague-Dawley rats (275–300 g) were housed in action onto A1 receptors (Rainnie et al. 1994). Prolonged groups of two or three per cage for at least three days wakefulness is associated to enhanced adenosine con- before use and were maintained on a 12:00/12:00 h centrations in the basal forebrain (Porkka-Heiskanen et light/dark cycle (lights on at 7:30 A.M.) with food and al. 1997) as a result of local brain metabolism; moreover, water available ad libitum. After surgery the rats were induction of SW sleep is associated to increased levels housed individually in plexiglas hemispherical bowls of adenosine in brain (Strecker et al. 2000). On this basis (50 cm of diameter) which also served as the experi- it has been suggested that adenosine is an endogenous mental environment, where they recovered for 24–30 h sleep factor (Strecker et al. 2000) and modulates EEG- prior to the microdialysis experiments. Experiments arousal through ACh projections to the cortex (Portas et were carried out between 9:00 A.M. and 4:00 P.M. Animal al. 1997; Rainnie et al. 1994; Strecker et al. 2000). care and experimental protocol were conducted in ac- Dopamine (DA) transmission is thought to be in- cordance with guidelines of national (D.L. 116, Suppl. volved in the psychostimulant properties of drugs of G.U. 40, 18/2/1992 and circolare no. 8 G.U. 14/7/1994) abuse. Thus, microdialysis studies have shown that a and international (EEC council Directive 86/609, OJ L neurochemical property common to psychostimulant 358/1, Dec. 12, 1987) policies. and reinforcing drugs is the ability of preferentially stimulating DA release in the shell subdivision of the Surgery and Microdialysis nucleus accumbens (Cadoni and Di Chiara 1999, 2000; Di Chiara 1999; Pontieri et al. 1995, 1996; Tanda et al. Rats were anesthetized with ketamine HCl (Ketalar, 1997). Given the psychostimulant properties of caffeine, Parke Davis Spa, Italy) (100 mg/kg i.p.) and stereotaxi- its debated reinforcing and addictive properties and the cally implanted with a vertical concentric microdialysis postulated involvement of ACh in its arousing effects, it probe in the left medial prefrontal cortex, and in differ- was of interest to investigate the effects of caffeine on ent subjects in their left nucleus accumbens shell and DA and ACh transmission. right nucleus accumbens core. The coordinates, mea- With these premises we studied with microdialysis sured from bregma, were AP ϭ ϩ3.6 mm, ML ϭ Ϫ0.7, in freely-moving rats the effect of caffeine on extracellu- DV ϭ Ϫ4.8 mm from dura, for the medial prefrontal lar DA and ACh levels in the shell and in the core of the cortex, and AP ϭ ϩ2.2 mm, ML ϭ Ϫ1.1, DV ϭ Ϫ8.0 mm NAc (Heimer et al. 1991; Heimer and Alheid 1991) and from dura, and AP ϭ ϩ1.6 mm, ML ϭ ϩ2.0, DV ϭ Ϫ7.8 in the prefrontal cortex (PFCX). In order to investigate mm, for the nucleus accumbens shell and core, respec- the relationship between the psychostimulant proper- tively, according to (Paxinos and Watson 1998). For in- ties of caffeine, as estimated by its locomotor stimulant travenous administration, under halothane anesthesia 184 E. Acquas et al. NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 2 rats were implanted, in the same day, with a polyethyl- (50 mM), Na2HPO4 (5 mM), Na2EDTA (0.1 mM), octane- ene catheter in the left femoral vein and tunneled sub- sulfonic acid (0.5 mM) (Eastman Kodak Co., NY), and cutaneously to exit at the nape of the neck according to methanol 15% v/v, pH ϭ 5.5.