SHORTCOMMUNICATION Transplantation of glial cell line-derived neurotrophic factor-expressing cells into the striatum and nucleus accumbens attenuates acquisition of cocaine self-administration in rats Tamar Green-Sadan, Noa Kinor, Ilana Roth-Deri, Revital Geffen-Aricha, Cheryl J. Schindler and Gal Yadid Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel Keywords: astrocytes, neurotrophic factors, plasticity, simian virus-40 glia (SVG) cells Abstract Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), may play a role in drug-induced biochemical and behavioural adaptations that characterize addiction. We found that GDNF mRNA levels are lower in the striatum of rats that chronically self-administered cocaine. Therefore, we examined the effect of transplanted cells used as a biodelivery system for GDNFon cocaine self-administration in rats. A human astrocyte-like cell line, which produces and excretes GDNF, was transplanted into the striatum and nucleus accumbens of rats. These rats showed a signi®cantly lower number of active lever presses in the cocaine self-administration paradigm compared with control rats. Moreover, rats that received a chronic infusion of GDNF via a micro-osmotic pump also exhibited weak cocaine self-administration. Therefore, we conclude that exogenous augmentation of GDNF repositories may be useful in suppressing cocaine self-administration. Introduction Chronic exposure to substances of abuse induces changes in neu- ron morphology concurrently with biochemical and behavioural adaptations in the dopaminergic (DAergic) system (Nestler & Aghajanian, 1997; Koob et al., 1998). Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain- derived neurotrophic factor, are also implicated in inducing neu- ronal plasticity (Pierce & Bari, 2001) in addition to growth and development (Nagtegaal et al., 1998). Intra-ventral tegmental area (VTA) infusion of neurotrophic factors alters drug-induced mor- phological and physiological effects (Berhow et al., 1995; Sklair- Tavron et al., 1996). However, there are contrasting effects of GDNF and brain-derived neurotrophic factor on the behavioural responses to abused substances. Brain-derived neurotrophic factor dramatically augments (Horger et al., 1999) while GDNF decreases the response to cocaine administration (Messer et al., 2000). Chronic exposure to cocaine alters GDNF production and signal- ling levels. Chronic cocaine exposure decreases VTA levels of tyrosine-phosphorylated Ret (Messer et al., 2000), which mediates the physiological actions of GDNF (Airaksinen et al., 1999). Furthermore, prenatal cocaine exposure reduces striatal GDNF production in rat fetuses, which may impair DAergic neuronal differentiation and decrease DAergic neuron levels (Lipton et al., 1999). Cell transplantation may be used to deliver peptide-based ther- apeutics such as neurotrophic factors, overcoming such dif®culties as short half-lives, chemical instability, low oral bioavailability and poor blood±brain barrier penetration (Tresco et al., 2000). This technique repairs neurodegenerative and neuroplastic damage and improves neurotoxin-induced behavioural de®cits (Gash et al., 1996; Yadid et al., 1999). Astrocytes, especially fetal (Sullivan et al., 1998), can be successfully transplanted into the central nervous system without tumour formation (Blakemore & Franklin, 1991) and integrate well into brain parenchyma (Tornatore et al., 1996). The immortalized, but not malignant, human astrocyte-like cell line [simian virus-40 glia (SVG)] secretes GDNF tonically and following DAergic stimulation (Kinor et al., 2001). In a rat model of Parkin- son's disease, SVG cells grafted into the brain remained in the tract at the transplantation site (Tornatore et al., 1996) and, in primate brain, were not rejected up to 9 months post-transplantation (Torna- tore et al., 1993). Thus, SVG cells are potential tools for the introduction of GDNF into the brain and may be a novel approach to provide protection against biochemical and behavioural damage caused by abused substances. Other methods for treating cocaine addiction have been examined, but with limited ef®cacy (Carroll et al., 1999). In the present study, we examined the effect of cocaine self- administration on GDNF mRNA levels in the striatum and nucleus accumbens (NAc). We then studied the effect of GDNF application on cocaine self-administration. The SVG cells were injected into the striatum and (NAc) and cocaine self-administration was examined. To clarify the role of GDNF in transplantation ef®cacy, exogenous GDNF was chronically infused into the NAc/striatal border and self-admin- istration examined. European Journal of Neuroscience, Vol. 18, pp. 2093±2098, 2003 ß Federation of European Neuroscience Societies doi:10.1046/j.1460-9568.2003.02943.x Correspondence: Dr Gal Yadid, as above. E-mail: yadidg@mail.biu.ac.il Received 22 June 2003, revised 22 July 2003, accepted 28 July 2003