Toluene-Induced Locomotor Activity is Blocked by 6-Hydroxydopamine Lesions of the Nucleus Accumbens and the mGluR2/3 Agonist LY379268

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.

Long-Term Behavioral Consequences of Prenatal Binge Toluene Exposure in Adolescent Rats

“…In accordance with our results, other studies have shown that acute inhalation and systemic toluene administration increases locomotion [7,13,44]. The sensitization that we observed after postnatal chronic toluene exposure (A/T) is also in line with the observation that sensitization occurs after binge toluene exposure in mice and rats [4,13,14,30].…”

The Metabotropic Glutamate 2/3 Receptor Agonist LY379268 Blocked Nicotine-Induced Increases in Nucleus Accumbens Shell Dopamine only in the Presence of a Nicotine-Associated Context in Rats

“…Thus, actions at these receptors may potentially contribute to the effects of LY379268 at high doses. However, the present results are not likely to be attributable to the action of LY379268 on receptors other than mGlu2/3 receptors because of the low dose (1 mg/kg) of LY379268 used in this study compared doses (3-10 mg/kg) frequently used in the literature to observe reliable behavioral or neurochemical effects (Cartmell et al, 2000a-c; Riegel et al, 2003).…”

“…This hypothesis is supported by the observation that mGlu2/3 receptors are expressed in the NAcc shell (Testa et al, 1998), and these receptors regulate both basal and psychostimulantinduced NAcc dopamine neurotransmission (Greenslade and Mitchell, 2004;Hu et al, 1999;Karasawa et al, 2006;Kim et al, 2005;Manzoni et al, 1997;Uslaner et al, 2009;Xi et al, 2002aXi et al, , 2010a. Furthermore, activation of mGlu2/3 receptors attenuated the dopamine-dependent psychostimulant-induced enhancement of locomotor activity (Kim et al, 2005;Riegel et al, 2003).…”

Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene

“…During at least one of the later sessions, one or more concentrations of toluene increased activity, compared to air and compared to initial toluene exposure, in rats of all ages and both sexes. While a few previous studies have reported the development of sensitization after repeated exposure of adult male rodents to inhaled [62,63] or systemically administered toluene [40][41][42], the present study is perhaps the first to examine the effects of toluene in a sensitization paradigm in adolescent rats. Our results here reveal that development of sensitization to the locomotor stimulant effects of toluene in adolescent rats of both sexes was minimal and did not occur until the second week of exposure sessions.…”

“…Development of the sensitization to the elevated locomotor activity seen in rats treated repeatedly with stimulants has been demonstrated to be mediated by dopaminergic activation [38]. Interestingly, there is now evidence that dopaminergic systems may also play a role in the acute, and possibly the long term, effects of toluene on locomotor activity as well [40][41][42]. Indeed, cross-sensitization has been shown from cocaine to toluene [3].…”