The effect of gliotransmission and stress on behavioral and molecular markers of cocaine-induced synaptic plasticity

A great deal of research has focused on elucidating what makes cocaine so addictive. While cocaine\u27s actions appear simple—dopamine transporter blockade that elicits increases in extracellular dopamine—the downstream signaling pathways that are activated in a myriad of brain regions have a tremendous influence on brain functioning and behavior. Over time, cocaine rewires the synaptic connections in the brain and creates drug-associated memories that are extremely long-lasting and difficult to reverse. Many players are involved in driving this maladaptive learning, including proteins shown to be important for synaptic plasticity, the neural correlate of memory encoding. Synaptic plasticity is in part due to alterations in glutamatergic signaling that act to strengthen or weaken synaptic transmission, as well as the involvement of neurotrophic factors that drive the formation of new synapses and strengthen existing ones. Thus, it is not surprising that some important contributors to cocaine-induced changes in synaptic plasticity include ionotropic glutamate receptors as well as the growth factor brain-derived neurotrophic factor (BDNF). Another less acknowledged candidate is the astrocyte. Drug-induced changes in astrocytes have been linked to the glutamate dysregulation and alterations in synaptic plasticity that occur following cocaine. In addition to other better-known functions of maintaining glutamate homeostasis like transport and exchange, astrocytes are also capable of releasing their own chemical transmitters, termed gliotransmitters. Via generation of a mouse line in which gliotransmission was ablated while leaving neurotransmission intact, we investigated the role of gliotransmission in cocaine-induced behavioral and molecular changes. Ablating gliotransmission using this dnSNARE mouse line impaired reinstatement behavior, an animal model of relapse. Correlated with these changes in behavior, we also observed impairments in the upregulation and trafficking of NMDA and AMPA receptors typically seen in the nucleus accumbens (NAc) following prolonged abstinence from cocaine. Thus, gliotransmission contributes to cocaine-induced alterations in glutamatergic signaling as well as the ability of drugs and cues to reinstate cocaine-associated behaviors. BDNF is also upregulated following prolonged abstinence from cocaine and contributes to drug craving and reinstatement behavior in animal models. We demonstrated that stress during prolonged abstinence from cocaine increased transcription of BDNF in reward-related brain regions. This enhanced BDNF expression was in part due to chromatin remodeling since we observed increases in histone acetylation at one of BDNF\u27s promoters in the NAc. These data indicate that stress has a different molecular signature in a drug-experienced brain, and its ability to elicit drug craving and relapse may be in part due to these increases in BDNF and histone acetylation. Together, these studies demonstrate that both stress and gliotransmitter release from astrocytes can contribute to cocaine-induced changes in molecular markers of synaptic plasticity and in doing so, drive behavioral responses as well. A better understanding of the mechanisms by which these factors strengthen cocaine-associated memories may contribute to the development of novel therapeutics