ELSEVIER Pharmacology Biochemistry and Behavior, Vol. 53, No. 4, pp. 809-816, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/96 $15.00 + .oO SSDIOO91-3057(95)02078-O Morphine and Naloxone, IP or Locally, Affect Extracellular Acetylcholine in the Accumbens and Prefrontal Cortex zyxwvutsrqponmlkjih PEDRO V. RADA,*t GREGORY P. MARK,*$ KATHLEEN M. TAYLOR* AND BARTLEY G. HOEBEL*’ zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPO *Department of Psychology, Princeton University, Princeton, NJ 08544-1010, TLaboratory of Behavioral Physiology, Universidad de Los Andes, MPrida 5101A, Venezuela and SDepartment of Medical Psychology, Oregon Health Science University, Portland, OR 97201 Received 26 July 1994 RADA, P. V., G. P. MARK, K. A. M. TAYLOR AND B. G. HOEBEL. M orphine and naloxone, IP or locally, af- fect extracellular acety lcholine in the accumbens and prefrontal cortex. PHARMACOL BIOCHEM BEHAV 53(4) 809- 816, 1996. -In rats with microdialysis probes in the nucleus accumbens (NAc) or prefrontal cortex (PFC), intraperitoneally (IP) delivered morphine on the 8th day of escalating doses decreased extracellular ACh in the NAc. On day 9, naloxone (5 mg/kg) precipitated withdrawal and increased the release of ACh. When morphine and methylnaloxonium were given locally into the NAc by reverse dialysis, the opiate again decreased extracellular ACh, and the opiate antagonist increased it. These effects were proportional to the dose of local infusions. Local morphine had the same ACh-lowering effect in morphine- dependent and nondependent rats, whereas local methylnaloxonium increased extracellular ACh significantly more in mor- phine-dependent animals. Systemic and local effects on ACh systems in the PFC were more complicated and showed some relation to locomotor activity. The results suggest that intrinsic ACh neurons in the NAc have a special relationship to opiate reinforcement such that extracellular ACh is low in response to morphine and high during withdrawal. Thus, low ACh may correlate with opiate reward, and high ACh with aversion. Microdialysis Acetylcholine Morphine Opiates Methylnaloxonium Addiction Withdrawal Nucleus accumbens Prefrontal cortex Rats THE NUCLEUS ACCUMBENS (NAc) receives input from limbic structures such as the hippocampus, amygdala, septal nuclei, and prefrontal cortex and projects mainly to the ven- tral globus pallidus and substantia nigra (9,30,52). It has been suggested that the NAc serves, in part, as an integrative area between sensory and motor systems (31) for motivated behav- iors, such as obtaining positive reinforcers and getting away from negative reinforcers (21,22,27,49). The importance of dopamine (DA) in drug abuse is demonstrated by 6-OHDA lesions that are sufficient to block psychostimulant self-ad- ministration; however, morphine can reinforce behavior even in DA-depleted rats by acting directly in the NAc (34). Mi- crodialysis studies show that most drugs of abuse induce a significant increase in extracellular DA in the NAc (16,19,35), and many such drugs including amphetamine, phencyclidine, cocaine, nicotine, and morphine act directly on the NAc to increase extracellular DA (21,35). The mechanism of opiate reinforcement in the NAc may also involve acetylcholine (ACh). Earlier studies have shown that morphine increases stores of ACh and decreases its release in various brain regions (3,6,12,17,24,28,32,33,40,50). Our in vivo microdialysis re- search revealed that intraperitoneal (IP) morphine not only can raise extracellular DA in the NAc but can also decrease extracellular ACh (36). The decrease in accumbens ACh disappeared after repeated administration of equal daily doses of morphine. This raised the first question addressed here: Can extracellular ACh be kept at a low level during daily IP morphine injections if, instead of equal daily doses, the dose is progressively in- creased? This paradigm would mimic the escalating doses that drug addicts use to maintain subjective reward properties. Such a result might imply that addicts escalate their dose in part to keep ACh low in the NAc. The NAc has been implicated as a neural substrate involved ’ To whom requests for reprints should be addressed. E-mail: hoebel@princeton.edu 809