Abstract Body: It is well documented that neuronal glutamate release plays a critical role in cocaine- or cue-induced reinstatement of drug-seeking behavior. However, it remains unclear whether glia-derived glutamate similarly regulates cocaine-taking and cocaine-seeking behavior. In the present study, we evaluated the effects of TBOA, a selective glial glutamate transporter (GLT-1) inhibitor, and NPPB, a glial anion channel blocker, on cocaine self-administration and reinstatement of drug-seeking behavior. We found that: 1) local perfusion of TBOA into the NAc significantly elevated, while NPPB lowered extracellular glutamate in a dose-dependent manner; 2) microinjections of TBOA into the NAc, but not the dorsal striatum, inhibited cocaine self-administration under both fixed-ratio (FR2) and progressive-ratio (PR) reinforcement, while microinjections of NPPB into the NAc had no effect on cocaine self-administration; 3) this effect on cocaine self-administration was blocked by co-administration of TBOA and AP-5 (a NMDA receptor antagonist), ifenprodil or Ro25-6981 (selective NMDA-NR2B receptor inhibitors), but not by DNQX (an AMPA receptor blocker) or NVP-AAM007 (a NMDA-NR2A receptor antagonist), suggesting a NMDA-NR2B-mediated effect; 4) conditioned knockdown of GLT-1 in the NAc by antisense oligonucleotides also decreased cocaine self-administration in rats in a dose-dependent manner; 5) microinjections of TBOA, but not NPPB, into the NAc, but not the dorsal striatum, reinstated drug-seeking behavior in rats extinguished from cocaine self-administration. Taken together, the present findings suggest that elevation of extracellular glutamate in the NAc by inhibiting glial GLT-1 inhibits cocaine-taking behavior in rats during self-administration, and reinstates cocaine-seeking behavior in rats during reinstatement testing. In contrast, attenuation of glial glutamate release via anion channels has no effect on cocaine-taking and cocaine-seeking behavior. Supported by NIDA-IRP.
Lay Language Summary: Substance abuse and addiction is characterized by a loss of control over drug-taking and drug-seeking. However, it is not clear how such behavior occurs. Recent research suggests that glutamate, a chemical released from nerve cells in the reward circuitry of the brain, plays an important role in drug-taking and drug-seeking. In addition to nerve cells, the brain contains massive numbers of glial cells that also release glutamate and modulate nerve cell activity. The question thus arises - does glial-released glutamate regulate drug-taking and drug-seeking behaviors? To address this question, we first allowed experimental animals to work (press a wall-mounted lever in a test chamber) to receive drug reward (intravenous cocaine) or electrical brain-stimulation reward (tiny electrical pulses delivered to the “pleasure/reward” circuitry of the brain). We then examined whether modulation of glial glutamate release or clearance in the brain reward area called the nucleus accumbens altered cocaine self-administration or brain-stimulation behavior. There are two important ways by which glial cells modulate extracellular glutamate levels. One is by altering glutamate release from glial cells; the second is by altering glutamate transporter, which removes glutamate from the extracellular space into glial cells. We found that reducing glutamate release failed to alter intravenous cocaine self-administration. However, elevating extracellular glutamate by inactivating glutamate reuptake into glial cells produced a significant reduction in cocaine self-administration and electrical brain-stimulation reward. Decreasing expression of the glutamate transporter gene in the nucleus accumbens produced a similar inhibitory effect on cocaine self-administration. These findings suggest that glial-derived glutamate attenuates cocaine-taking behavior and brain reward; this differs from previous findings that nerve cell-released glutamate is rewarding as assessed by intracranial optical self-stimulation. Why does glial-derived glutamate produce an effect opposite from nerve cell-released glutamate in modulating brain reward function? To answer this question, we used multiple drugs to selectively block different glutamate receptor subtypes that mediate neuronal (via synaptic receptors) or glial (via extra-synaptic receptors) glutamate transmission. We found that blocking extra-synaptic AMPA receptors or synaptic NMDA receptor subtypes failed to alter the reduction in cocaine self-administration produced by inactivation of the glial glutamate transporter. However, blocking extra-synaptic NMDA receptor subtypes prevented the reduction in cocaine self-administration produced by inactivation of glial glutamate transporter, suggesting an effect that is mediated by activation of extra-synaptic NMDA receptors. We further examined whether modulation of glial glutamate release or clearance alters relapse to drug-seeking behavior. In this experiment, animals were first allowed to self-administer cocaine, and then the drug-taking behavior was extinguished by removing cocaine and cocaine-associated stimuli. We found that decreasing glial glutamate release in the nucleus accumbens did not induce any behavioral response, while elevating extracellular glutamate by inactivating glial glutamate transporter induced robust relapse to cocaine-seeking behavior in a manner similar to re-exposure to cocaine. This effect was preventable by co-administration of an AMPA receptor blocker, suggesting an AMPA receptor-mediated effect. This finding is consistent with previous reports that nerve cell-released glutamate also triggers relapse to cocaine-seeking behavior by activation of AMPA receptors. In summary, the present findings, for the first time, suggest that: 1) glial-derived glutamate plays different roles in cocaine-taking and cocaine-seeking behavior; and 2) different glutamate receptor mechanisms may underlie these actions - extra-synaptic NMDA receptor activation inhibits cocaine self-administration, while extra-synaptic AMPA receptor activation potentiates relapse to drug-seeking behavior. Thus, glial glutamate transporter proteins and extra-synaptic (NMDA and AMPA) glutamate receptors may constitute new therapeutic targets in medication development for treatment of cocaine addiction. 1
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit