Research ReportInjection of oxotremorine in nucleus accumbens shell reduces cocaine but not food self-administration in rats
Introduction
The mesolimbic dopamine (DA) system has been the primary focus of research on the neurochemical substrates of drug reward and addiction. Terminals of DA cells projecting from the ventral midbrain are susceptible to the action of psychostimulants that potentiate DA transmission by acting as substrates for (e.g., amphetamines) or inhibitors of (e.g., cocaine) the DA reuptake transporter (Gulley and Zahniser, 2003). A key projection site of DA cells from the ventral tegmental area (VTA) is the nucleus accumbens (NAcc), where DA terminals synapse on medium spiny gamma-aminobutyric acid (GABA)-containing cells and a smaller population of large, aspiny acetylcholine (ACh)-containing interneurons (Smith and Bolam, 1990). Cholinergic interneurons have large dendritic arbors and an extensive network of axons that contact many cell bodies and terminals within the NAcc (Kawaguchi et al., 1995, Meredith and Chang, 1994). In conjunction with DA inputs from VTA, ACh interneurons can modulate the activity of the GABA projection neurons, the primary output neurons of the NAcc (de Rover et al., 2002, Di Chiara et al., 1994).
Several lines of evidence suggest that stimulation of both nicotinic and muscarinic cholinergic receptors can affect mesolimbic DA levels and modify the reinforcing value of self-administered drugs. In this regard, the action of nicotine (the prototypical agonist at nicotinic ACh receptors) on the mesolimbic DA system has been studied extensively (Mansvelder et al., 2003, Mansvelder and McGehee, 2002) as has its interaction with other drugs of abuse such as alcohol (Le et al., 2003, Soderpalm et al., 2000) and cocaine (Bechtholt and Mark, 2002, Corrigall et al., 2002, Zachariou et al., 2001). These studies demonstrate that nicotinic activation increases extracellular DA in the NAcc, stimulates locomotor activity with repeated exposure and can potentiate the rewarding value of cocaine.
In comparison to the rather clear-cut situation for nicotinic activation, the role of muscarinic receptors in mediating reward processes is less clear. Muscarinic M5 receptors in the VTA are necessary for slow onset depolarization of dopamine neurons, increased dopamine levels in the NAcc and brain stimulation reward (Yeomans et al., 2001). In addition, there is evidence that systemic administration of muscarinic agonists can decrease amphetamine-induced hyperactivity (Shannon and Peters, 1990) and inhibit amphetamine-induced DA release in the NAcc (Ichikawa et al., 2002). Conversely, muscarinic antagonists enhance the locomotor stimulating effects of amphetamine and cocaine (Bymaster et al., 1993, Hagan et al., 1987, Shannon and Peters, 1990). Systemic administration of muscarinic agonists and partial agonists has been reported to decrease cocaine self-administration rates in mice (Rasmussen et al., 2000) whereas co-administration of the muscarinic antagonist scopolamine with cocaine decreases cocaine self-administration in rhesus monkeys (Ranaldi and Woolverton, 2002). In addition, mice lacking the muscarinic M5 receptor subtype self-administer less cocaine and show reduced cocaine conditioned place preference (CPP) compared to their wild-type counterparts (Fink-Jensen et al., 2003), suggesting that M5 receptors potentiate cocaine reward.
Identifying the precise location of cholinergic effects on psychostimulant reward has been difficult because systemic administration of drugs and genetic deletion models affect receptors throughout the nervous system. However, recent work has focused attention on the NAcc as a site of interaction between cholinergic mechanisms and cocaine reinforcement. ACh interneurons in the NAcc are known to be responsive to cocaine self-administration (Berlanga et al., 2003, Mark et al., 1999) and ablation of cholinergic interneurons within the NAcc using immunotoxin-mediated cell targeting results in increased cocaine-induced locomotor activity and enhanced cocaine reward, as measured by CPP (Hikida et al., 2001). In contrast, augmentation of ACh levels with acetylcholinesterase inhibitors following cholinergic lesions has the opposite effect (Hikida et al., 2001, Hikida et al., 2003). These studies suggest that ACh in the NAcc may have an overall inhibitory effect on cocaine reward.
In humans, a clinical study of the acetylcholinesterase inhibitor, donepezil (Aricept) did not find a significant effect on the abuse of cocaine by addicts as measured by quantitative urinary benzoylecognine (Winhusen et al., 2005). However, this study had a limited number of subjects per group, perhaps insufficient (given the variability in quantitative cocaine metabolite levels) to detect a modest decrease in abuse. Still, the use of cholinergic drugs remains an appealing approach given the number of muscarinic, nicotinic and broad-spectrum cholinergic agents in clinical development as nootropic/cognitive enhancing agents (Narahashi et al., 2004). Cognitive deficits are believed to complicate stimulant abusers' attempts at abstinence and rehabilitation, perhaps by increasing impulsivity (Goldstein et al., 2005). Medications that directly modulate reinforcement of self-administration may be appealing under these conditions. Pre-clinical studies provide strong evidence that cholinergic cells in the NAcc play an important role in modulating the reinforcing value of psychostimulants but the nature of the cholinergic receptors that are critical for this effect remains unclear. To address this question, the aim of the present study was to examine the role of muscarinic receptors on cocaine reinforcement within the NAcc using the self-administration model combined with microinjections of the muscarinic agonist oxotremorine in rats (Fig. 1).
Section snippets
Oxotremorine effects on cocaine self-administration
The initial analysis examined the effect of OXO, PIRENZ, or OXO + PIRENZ on the number of cocaine infusions across all 5 time points (Fig. 2, Fig. 3). There was a significant interaction between time and treatment [F(20,116) = 5.06, p < 0.001], indicating that treatment differentially altered cocaine infusions. Follow-up ANOVAs across treatment at each time point confirmed that treatment significantly affected cocaine infusions only on the test day [F(5,31) = 11.5, p < 0.001]. Treatment did not
Discussion
The major finding of this study was a dose-related reduction in cocaine self-administration in rats following intra-NAcc injections of the muscarinic receptor agonist oxotremorine. Because we measured these reductions in cocaine intake on a progressive ratio (PR) reinforcement schedule, we interpret the reduction in intake (i.e., lowered BP and fewer cocaine infusions per session) to reflect a reduction in reward value of cocaine in the presence of the muscarinic agonist. The interpretation is
Animals
Thirty-three male Sprague-Dawley rats weighing 350–400 g were used in these studies and were maintained according to the guidelines set forth in the “Principles of Laboratory Animal Care” (National Research Council, 2003) and under the approval of the Oregon Health & Science University's Institutional Animal Care and Use Committee. Animals were housed individually following surgery in a temperature-controlled environment (22° C) with a 12-h day/night schedule (lights on 0700–1900). All animals
Acknowledgments
This research was supported by NIH grants DA11203 and DA14639. M.C.G. was supported by individual NRSA F32 DA05965. A.J.B. was supported by grant T32 DA07262. We thank James Welch for excellent technical assistance with histological preparations.
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- 1
Present address: One River Grants, 8 Winter Street, Troy, NY 12180, USA.
- 2
Present Address: Dept of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.