Interactions of Glutamatergic Neurotransmission and Brain-Derived Neurotrophic Factor in the Regulation of Behaviors after Nicotine Administration

Abstract

Nicotine causes tobacco dependence, which may result in fatal respiratory diseases. The striatum is a key structure of forebrain basal nuclei associated with nicotine dependence. In the striatum, glutamate release is increased when α7 nicotinic acetylcholine receptors expressed in the glutamatergic terminals are exposed to nicotine, and over-stimulates glutamate receptors in gamma amino-butyric acid (GABA)ergic neurons. These receptor over-stimulations in turn potentiate GABAergic outputs to forebrain basal nuclei and contribute to the increase in psychomotor behaviors associated with nicotine dependence. In parallel with glutamate increases, nicotine exposure elevates brain-derived neurotrophic factor (BDNF) release through anterograde and retrograde targeting of the synapses of glutamatergic terminals and GABAergic neurons. This article reviews nicotine-exposure induced elevations of glutamatergic neurotransmission, the bidirectional targeting of BDNF in the striatum, and the potential regulatory role played by BDNF in behavioral responses to nicotine exposure.

Keywords: TrkB; glutamate receptor; neurotrophic factor; nicotine dependence; striatum.

Figure 1

(A) Changes in glutamatergic neurotransmission, bidirectional BDNF release, BDNF-mediated signaling cascades, and behavioral sensitization after repeated exposure to nicotine and nicotine withdrawal. (B,C) Proposed cellular mechanisms underlying repeated nicotine exposure and nicotine withdrawal mediated effects in GABAergic neurons are schematically depicted and compared. Exogenous BDNF infusion into the striatum during nicotine withdrawal returned hypoactivated GABAergic neurons to the basal level by activating TrkB-linked signaling cascades [91,96,97]. Switched neural activity caused by BDNF does not alter after challenge nicotine administration. Putative interactions are discussed in the text. Solid and broken arrows represent direct and indirect stimulations of downstream molecules or behaviors, respectively. AP, action potential; [Ca²⁺], Ca²⁺ concentration; EPSP, excitatory postsynaptic potential; IP₃R, inositol trisphosphate receptor; mV, membrane potential; [Na⁺], Na⁺ concentration; PKC, protein kinase C; RyR, ryanodine receptor; SYT, synpatotagamin; tPAs, tissue-plasminogen activators; VGCC, voltage-gated calcium channel.