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Repeated Cocaine Injections Have No Influence on Tyrosine Hydroxylase Activity in the Rat Nucleus Accumbens Core Or Shell

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Repeated Cocaine Injections Have No Influence on Tyrosine Hydroxylase Activity in the Rat Nucleus Accumbens Core Or Shell Brain Research 1012 (2004) 119–126 www.elsevier.com/locate/brainres Research report Repeated cocaine injections have no influence on tyrosine hydroxylase activity in the rat nucleus accumbens core or shell Stephanie C. Licataa,*, R. Christopher Piercea,b a Laboratory of Neuropsychopharmacology, Department of Pharmacology, Boston University School of Medicine, Boston, MA 02118, USA b Laboratory of Neuropsychopharmacology, Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA Accepted 31 March 2004 Available online 10 May 2004 Abstract Numerous reports have demonstrated augmented cocaine-evoked release of dopamine in the nucleus accumbens of rats pre-treated with cocaine. However, the extent to which repeated cocaine injections affect basal levels of dopamine is unclear. There have been reports of increases, decreases, or no change in basal levels of extracellular accumbal dopamine resulting from repeated psychostimulant administration. The present study assessed the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the nucleus accumbens following either acute or repeated cocaine administration. The in vivo microdialysis technique was used to measure accumulation of the dopamine precursor DOPA following intra-accumbal administration of the DOPA decarboxylase inhibitor NSD 1015 through the microdialysis probe. This method provides an estimate of tyrosine hydroxylase activity within the nucleus accumbens. Results indicate that neither acute nor repeated cocaine administration produced any change in DOPA accumulation in either the nucleus accumbens shell or core. These data indicate that dopamine synthesis is not altered by cocaine administration. D 2004 Elsevier B.V. All rights reserved. Theme: Neural basis of behavior Topic: Drugs of abuse: cocaine Keywords: Cocaine; Microdialysis; DOPA; Tyrosine hydroxylase; Nucleus accumbens; Rat 1. Introduction sensitization [32]. Repeated injections of cocaine in partic- ular lead to persistent alterations in structure [27,39], neuro- Within the past few decades, research in the field of drugs nal activity [45,54], and gene expression [6,53] within the of abuse has supported the notion that addiction to psycho- mesoaccumbens dopamine system. motor stimulants such as cocaine is a disease of the brain Neurochemical modifications associated with psycho- [21]. Therefore, studies examining the neural mechanisms stimulant-induced behavioral sensitization include changes that contribute to cocaine-induced changes in the brain may in dopamine transmission. Microdialysis studies have dem- lead to identifying potential therapeutics for the treatment of onstrated that there is a consistent enhancement of drug- cocaine addiction. Several lines of evidence suggest that the evoked dopamine efflux in the nucleus accumbens of rats mesoaccumbens dopamine system is a critical neural sub- that display behavioral sensitization to psychostimulants strate for the rewarding properties of addictive drugs (Refs. [1,15,29,35], but see also [42]). However, it is [5,8,19,37,38,44,51], and plays a role in the neuroadapta- unclear if there are changes in basal levels of extracellular tions that contribute to psychostimulant-induced behavioral dopamine following repeated exposure to psychostimu- lants. Reports have shown increases [10,45], decreases [13,22], or no change [9,15,26,37] in basal dopamine * Corresponding author. Current address: New England Primate levels in the accumbens within the first 24–48 h after Research Center, Harvard Medical School, Behavioral Biology, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772, USA. Tel.: +1-508- cessation of repeated psychostimulant administration. 624-8162; fax: +1-508-624-8197. There is similar confusion when basal levels of dopamine E-mail address: [email protected] (S.C. Licata). are examined after a protracted abstinence. Decreases 0006-8993/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2004.03.043 120 S.C. Licata, R.C. Pierce / Brain Research 1012 (2004) 119–126 [11,13,29,41] or no change [16,49] in basal extracellular displayed behavioral sensitization when a challenge injec- dopamine are observed 5–22 days following the last of tion of amphetamine [31] or cocaine [56] was administered daily psychostimulant injections. directly into the shell, but not the core of the nucleus The mechanisms responsible for the psychostimulant- accumbens. Taken together, these studies indicate that induced changes in dopamine neurotransmission are not cocaine administration results in enhanced dopamine trans- completely understood, but may be a result of differential mission specifically in the shell subregion of the nucleus regulation of the activity of tyrosine hydroxylase, the rate- accumbens following a cocaine challenge. limiting enzyme in dopamine biosynthesis [55]. One in vitro The present experiments were designed to investigate the study demonstrated a decrease in tyrosine hydroxylase hypothesis that enhanced tyrosine hydroxylase activity in phosphorylation in the nucleus accumbens following twice the nucleus accumbens shell alters dopamine synthesis daily injections of cocaine over 14 consecutive days [3], following repeated injections of cocaine. NSD 1015 was which may be due to a cocaine-induced reduction in neuro- perfused directly into the shell or core and tyrosine hydrox- filament protein levels in the ventral tegmental area (VTA) ylase activity was estimated as a function of DOPA accu- leading to compromised axonal transport of tyrosine hy- mulation following either acute or repeated cocaine droxylase from the VTA to the nucleus accumbens [4]. administration. However, other studies reported no change in accumbal tyrosine hydroxylase immunoreactivity or enzymatic activ- ity following repeated cocaine administration [25,29]. 2. Materials and methods Westerink et al. [50] first utilized and verified the validity of the brain microdialysis technique to determine tyrosine 2.1. Surgery hydroxylase activity indirectly in the brain of the rat. DOPA decarboxylase, the enzyme that converts DOPA to dopa- All experimental protocols were consistent with guide- mine, can be inhibited via administration of NSD 1015. lines issued by the National Institutes of Health and were Following perfusion of NSD 1015 through the microdialysis approved by Boston University School of Medicine’s Insti- probe, the amount of DOPA measured in the dialysate is a tutional Animal Care and Use Committee. Male Sprague– reliable index of tyrosine hydroxylase activity. Systemic Dawley rats (251–275 g; Taconic Farms, Germantown, administration of the tyrosine hydroxylase inhibitor a-meth- NY) were anesthetized with 80 mg/kg ketamine HCl and yl-p-tyrosine caused a rapid decline of DOPA concentration 12 mg/kg xylazine HCl (i.m.) and mounted in a stereotaxic in the dialysate, demonstrating the validity of this method apparatus. A stainless steel microdialysis guide cannula (13 [50]. Using this approach, a reduction in DOPA accumula- mm, 20 guage; Plastics One, Roanoke, VA) was implanted tion after perfusion of NSD 1015 through a microdialysis unilaterally 1 mm dorsal to the shell ( + 1 A/P, + 1.0 M/L, probe located in the nucleus accumbens of rats was dem- À 5.5 D/V) or core ( + 1 A/P, + 2.5 M/L, À 5.5 D/V) of the onstrated after 10 daily administrations of cocaine [7]. left nucleus accumbens relative to bregma [30]. The guide These data suggest a reduction in tyrosine hydroxylase cannula was cemented in place by affixing dental acrylic to activity, and thus a reduction in dopamine synthesis, in three stainless steel screws secured in the skull. Following the nucleus accumbens following repeated psychostimulant surgery, animals were allowed to recover for 3–5 days prior administration. to the start of the experiment. These studies of tyrosine hydroxylase levels and activity all lacked a distinction between subregions of the nucleus 2.2. Drug treatment accumbens. Histochemical studies have revealed two major subregions of the nucleus accumbens, the core and shell After recovering from surgery, animals were subjected to [52]. Differential anatomical connectivity between the core either an acute or repeated injection regimen (see Table 1). and the shell indicates that each subregion has a specific The acute group received one intraperitoneal injection of function. It has been suggested that the shell primarily modulates limbic input, while the core receives information Table 1 about motor processes [2,12,52]. Recent studies indicate Drug treatment schedule that cocaine administration produces different neurochemi- A single Seven daily Seven daily cal changes in the core and shell of the nucleus accumbens. injection, injections, injections, Extracellular glutamate levels were elevated in the core of microdialysis microdialysis microdialysis cocaine-pretreated rats following a challenge injection of 24 h later 24 h later 2 weeks later cocaine [17,21], as well as during the reinstatement of drug- Treatment Cocaine Cocaine Cocaine seeking behavior in animals trained to self-administer co- Brain region Core (6) Core (4) Core (4) Shell (5) Shell (4) Shell (4) caine [23]. In contrast, there is a preferential increase in Treatment Saline Saline Saline dopamine in the shell associated with cocaine-induced Brain region Core (4) Core (5) Core (6) behavioral sensitization [31] or a single intravenous injec- Shell (5) Shell (5) Shell (4) tion of cocaine [35]. In addition, cocaine-pretreated
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