1. ¹Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
2. ²Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/US FDA, Jefferson, AR, USA

Correspondence: Dr E French, Department of Pharmacology, University of Arizona, College of Medicine, Tucson, AZ 85724-5050, USA. Fax: +1 520 626-2204; E-mail: efrench@u.arizona.edu

³Current address: Cellular Neurobiology Branch, Section on Neurophysiology, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, MD 21224, USA.

Received 25 October 2002; Revised 21 February 2003; Accepted 25 February 2003; Published online 7 May 2003.

Abstract

The abuse of volatile inhalants remains a prominent, yet poorly understood, form of substance abuse among youth. Nevertheless, the identification of a mechanism underlying the reinforcing properties of inhalants has been hampered by the lack of a clearly identifiable neural substrate upon which these chemicals act. One ingredient that is common to many abused inhalants is toluene, an organic solvent that is self-administered by nonhuman primates and rodents. Most drugs of abuse have been found to elicit forward locomotion in rats, an effect owing to the activation of mesoaccumbal dopamine (DA) pathways. Thus, the present study was undertaken using two different approaches to determine whether toluene-induced locomotor hyperactivity is also ultimately dependent upon DA neurotransmission in the mesolimbic nucleus accumbens (NAC). Here we report on the effects of 6-hydroxydopamine (6-OHDA) lesions of the NAC or pretreatment with the metabotropic mGlu2/3 receptor agonist LY379268 on toluene-induced locomotor activity. Both procedures, which are known to alter neurotransmission within the NAC, significantly attenuated toluene's locomotor stimulatory effects. These results provide strong support for a central mechanism of action of inhalants, which in the past has been more typically attributed to general nonspecific mechanisms throughout the brain. Moreover, as with other drugs of abuse, the NAC may be the final common pathway subserving toluene's abuse liability.