Neuroscience Letters 401 (2006) 125–129 Augmented cocaine-induced accumbal dopamine efflux, motor activity and place preference in rats fed with a tryptophan-deficient diet M. Carta a , M. Collu b , F. Fadda a,* , R. Stancampiano a a Department of Applied Sciences for Biosystems, Section of Physiology and Human Nutrition, University of Cagliari, Via Porcell 4, Cagliari 09124, Italy b Department of Neuroscience, University of Cagliari, Via Porcell 4, Cagliari 09124, Italy Received 23 November 2005; received in revised form 24 February 2006; accepted 1 March 2006 Abstract In the present study we demonstrate that consumption of a tryptophan-deficient diet for a period of 14 days decreased the striatal serotonin and 5-hydroxyindolacetic acid tissue content in rats, whereas the level of dopamine remained unchanged. Under this condition of diminished serotonergic tone, a challenge dose of cocaine (10 mg/kg, i.p.) significantly increased motor activity and dopamine extracellular content in the nucleus accumbens compared to rats fed with a balanced diet. We moreover found that pretreatment with cocaine (7 and 10 mg/kg, i.p.) produced a significant increase in preference for a cocaine-associated environment in the tryptophan-deficient group compared to control rats. Our experiments show that a low tone of serotonergic system, augments the behavioural reinforcing effect of cocaine and that this effect may be due to a increased cocaine-induced accumbal dopamine release. These data indicate that a tryptophan-deficient diet alters the behavioural and neurochemical effect of psychostimulants, such as cocaine, and suggest an important role of serotonin in modulation of these effects. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Cocaine; Tryptophan; Nucleus accumbens; Serotonin; Dopamine release; Place preference Cocaine dependence presents serious medical, social and crim- inal problems throughout the world. Abuse of this substance is on an increase, in part due to an increased financial availabil- ity and in part to the difficulties encountered in treating craving associated to withdrawal from this drug of abuse. Cocaine binds with high affinity to dopamine (DA), serotonin (5-HT) and norepinephrine (NA) transporter sites and inhibits the presynaptic reuptake of these neurotransmitters [19,26]. Enhanced DA neurotransmission and activation of D1 and D2 receptors play a central role in the positive reinforcing effect of psychomotor stimulants [30]. Augmented DA neurotransmis- sion, particularly in the nucleus accumbens (NAcc) is important in mediating the locomotor, discriminative stimulus and rein- forcing effects of cocaine. [1,4,8,30]. The serotonergic system is also implicated in the behavioural and neurochemical effects of cocaine and other psychostimulants. Indeed, pharmacological interventions which decrease central serotonergic transmission potentiate locomotor stimulant, reinforcing, and discriminative effect of cocaine in rats, whereas activation of the serotonergic * Corresponding author. Tel.: +39 070 6758938; fax: +39 070 6758917. E-mail address: ffadda@unica.it (F. Fadda). system appears to inhibit these effects [6,16,22,23,29]. In fact, treatment with 5-HT agonists reduces self-administration of both cocaine and amphetamine in rats [5,6,28] while a reduction in brain 5-HT content, following destruction of serotonergic neu- rons by neurotoxic lesions induced by 5,7-dihydroxytryptamine increases self-administration of these psychostimulants in rats [20,21]. Thus, serotonergic tone appears to be strongly impli- cated in the effect of psychostimulant drugs. The brain content of 5-HT can be changed by dietary manipu- lation of l-tryptophan (TRP) [10] the precursor of 5-HT. Admin- istration of a TRP-free or TRP-deficient diet produces a specific and long lasting reduction of 5-HT content and the release of this neurotransmitter in the rat brain [2,11,13]. The advantage of this method lies in its high specificity and non-toxicity and, thus, it has been intensively used as a physiological tool to study brain 5-HT function (for review, see [10]). We used a TRP-deficient diet to decrease the central sero- tonergic tone in order to investigate the net effect of decreased brain 5-HT levels on cocaine-induced motor activity, condi- tioned place preference (CPP), and DA efflux in the NAcc. Male Sprague–Dawley rats (Harlan, Nossan, Italy) weighing ∼300 g were used. Animals were kept at constant temperature (22 ± 2 ◦ C) and relative humidity (60%) with a 12 light/dark 0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.03.002