Nervenkitt or neuroglia, literally “nerve-glue” in English, were merely considered connective tissue that served only as scaffolding between neurons when first identified in the early 1900s. However, in the 1980s one subtype of glial cells, astrocytes, were shown to exhibit voltage-gated channels and neurotransmitter receptors leading to increased interest in their function. Glial cells, specifically astrocytes and microglia, are now described as having a significant role in homeostatic processes, synaptogenesis and guiding neuronal development, neuroplasticity, and regulating the immune responses in the CNS by releasing pro-inflammatory cytokines and chemokines. Glial cells can elicit their own signals, termed gliotransmission, and regulate synapse formation and strength via the release of pro-inflammatory cytokines by astrocytes and microglia. Activated glial cells have been correlated with altering synaptic transmission and drug abuse behavior and an examination of glial cell function should highlight the importance of glial cell activity in behavior and suggest a unique target for novel drug abuse pharmacotherapies.
While neuroinflammation is commonly associated with neurodegenerative conditions, decades of evidence indicate that some CNS-active drugs can induce neuroinflammatory processes via activation of glial cells as well. Glial cells can be separated into two main groups, macroglia and microglia. One sub-type of macroglia, astrocytes, are the most prevalent cell type in the CNS and have a variety of functions including the response to injury by stimulating proinflammatory cytokine release and immune function activity. Microglia work as macrophages to degrade foreign debris and are also associated with immune response by responding to and secreting inflammatory cytokines. Following methamphetamine administration, activated microglia and astrocytes release pro-inflammatory cytokines. Methamphetamine increases levels of cytokines and inflammatory factors, such as tumor necrosis factor (TNFα), interleukin 6 (IL-6), interleukin 1β (IL-1β) mRNA levels, monocyte chemo-attractant protein 1 (MCP-1), and cellular adhesion molecule (ICAM-1)
Glial cells can elicit both excitatory and inhibitory signals, known as gliotransmission, giving rise to the idea of the tripartite synapse in which neurotransmitters released from the pre-synaptic neuron not only bind and affect the post-synaptic neuron, but also glial cells, which in turn can release their own gliotransmitters or neutralize synaptic neurotransmitters. First, glial cells are activated as they exhibit many ionic and metabotropic receptor complexes on their membranes such as those for norepinephrine, glutamate, GABA, acetylcholine, histamine, adenosine, and ATP. They do not produce action potentials, but rather signal via oscillations in intracellular Ca2+. Following activation, glial cells may also release neurotransmitters, known as gliotransmitters, glutamate, D-serine, and ATP which may modulate synaptic transmission and neuronal excitability. For example, release of glutamate from glial cells can excite glutamatergic NMDA and AMPA receptors on the post-synaptic neuron. Furthermore, glial cells also play an active role in maintaining the extracellular glutamate concentration to prevent excitotoxicity to the neurons. Thus, neurotransmitter signaling is no longer isolated to neuronal receptors. Further, as a function of chronic gliotransmission signaling, glial cells also have the capability to modulate synapses.