NEURONAL ACTIVITY IN THE NUCLEUS ACCUMBENS IS NECESSARY FOR PERFORMANCE-RELATED INCREASES IN CORTICAL ACETYLCHOLINE RELEASE G. N. NEIGH, a H. M. ARNOLD, a1 R. L. RABENSTEIN, a M. SARTER a,b AND J. P. BRUNO a,b * a Department of Psychology, 31 Townshend Hall, The Ohio State University, Columbus, OH 43210, USA b Department of Neuroscience, 31 Townshend Hall, The Ohio State University, Columbus, OH 43210, USA Abstract—In vivo microdialysis was used to determine the necessity of neuronal activity in the nucleus accumbens (NAC) for task-induced increases in cortical acetylcholine (ACh) efflux. Rats were trained in a behavioral task in which they were required to perform a defined number of licks of a citric acid solution in order to gain access to a palatable, cheese-flavored food. Upon reaching a consistent level of performance, rats were implanted with microdialysis cannula in the medial prefrontal cortex (mPFC) and either the ipsilat- eral shell of the NAC or in the dorsal striatum (STR; control site). Dialysis samples from the mPFC were analyzed for ACh concentrations and samples from the NAC were analyzed for dopamine (DA) concentrations. Performance in the task was associated with increases in both ACh efflux in the cortex (150 –200%) and DA efflux in the NAC (50 –75%). These in- creases were blocked by administration of tetrodotoxin (TTX; 1.0 M) via reverse dialysis into the NAC. Administration of TTX into the dorsal STR control site was ineffective in block- ing performance-associated increases in cortical ACh. The D2 antagonist sulpiride (10 or 100 M) administered into the NAC via reverse dialysis was ineffective in blocking in- creases in cortical ACh efflux. The present data reveal that neuronal activity in the NAC is necessary for behaviorally induced increases in cortical ACh efflux and that this activa- tion does not require increases in D2 receptor activity. © 2003 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: dopamine, TTX, reward, microdialysis, prefrontal cortex, incentive. The basal forebrain cholinergic system (BFCS) projects to practically all areas and layers of the cerebral cortex (Woolf and Butcher, 1986; Woolf, 1991) and is critically involved in the mediation of attentional functions such as the detection, selection, and processing of stimuli (for re- views see Everitt and Robbins, 1997; Sarter and Bruno, 1997; Sarter et al., 2001). Several decades of psychophar- macological research in laboratory animals (Everitt and Robbins, 1997; Sarter and Bruno, 1997; Sarter et al., 2001) and in humans (Dunne and Hartley, 1986; Vitiello et al., 1997; Witte et al., 1997; Mancuso et al., 1999; Thiel et al., 2002) have substantiated this role for cholinergic trans- mission in attentional processes. Numerous studies have demonstrated that activity within the BFCS is necessary for performance in tasks designed to explicitly measure atten- tion (Muir et al., 1992, 1994; McGaughy et al., 1996). In addition, recent experiments have revealed that perfor- mance in attentional tasks is sufficient to increase cortical ACh efflux (Himmelheber et al., 2000, 2001; Passetti et al., 2000; Dalley et al., 2001; Arnold et al., 2002). Based on these data, some have suggested that impairments in attentional processing could contribute to the development of cognitive deficits in a variety of neuropsychiatric disor- ders (Jones et al., 1991; Greenwood et al., 1993; Berntson et al., 1998; Sarter and Bruno, 1999). These hypotheses have promoted interest in neuronal systems that regulate the excitability of the basal forebrain corticopetal cholinergic projections, particularly by the me- dium spiny GABAergic projection originating from the shell region of the nucleus accumbens (NAC; Zaborszky and Cullinan, 1992; Zahm and Heimer, 1993). The functional modulation of basal forebrain activity by this pathway was first demonstrated in the classical work of Mogenson and colleagues (Yang and Mogenson, 1984, 1989) in anesthe- tized rats. Although the precise circuitry underlying the ability of NAC efferents to regulate the excitability of the BFCS remains unresolved (see Zahm et al., 1999) recent studies have demonstrated that pharmacological manipu- lations of neurotransmission within the NAC modulate cor- tical acetylcholine (ACh) efflux (Moore et al., 1999; Neigh- McCandless et al., 2002). If, as proposed, the NAC serves to integrate cortical and limbic information in order to modulate subsequent stimulus selection and processing, then one might expect that perfor- mance in certain behavioral tasks would reveal a concomitant activation of accumbens and basal forebrain. A test of the functional relationships between these two regions during performance requires a task that markedly enhances accum- bens and basal forebrain activity. The literature suggests that behavioral procedures that would be most effective in pro- ducing marked and persistent activation of these two regions would be characterized by specific task attributes, including: highly activating and arousing conditions (Muir et al., 1995; Sarter and Bruno, 2000), performance on operant schedules (Cousins et al., 1999), the requirement that the subject ac- 1 Present address: CNS Research, Johnson & Johnson Pharmaceu- tical Research and Development, Welsh and McKean Roads, Spring House, PA 19477, USA. *Corresponding author. Tel: +1-614-292-1770; fax: +1-614-688- 4733. E-mail address: bruno.1@osu.edu (J. P. Bruno). Abbreviations: ACh, acetylcholine; aCSF, artificial cerebrospinal fluid; ANOVA, analysis of variance; BFCS, basal forebrain cholinergic system; DA, dopamine; Glu, glutamate; mPFC, medial prefrontal cortex; NAC, nucleus accumbens; STR, dorsal striatum; SULP, sulpiride; TTX, tetrodotoxin. Neuroscience 123 (2004) 635– 645 0306-4522/04$30.00+0.00 © 2003 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2003.10.006 635