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Nicotine self-administration induces CB1-dependent LTP in the bed nucleus of the stria terminalis - PubMed

  • ️Wed Jan 01 2014

Nicotine self-administration induces CB1-dependent LTP in the bed nucleus of the stria terminalis

Anne-Ruth Reisiger et al. J Neurosci. 2014.

Abstract

Nicotine addiction is characterized by repetitive drug taking and drug seeking, both tightly controlled by cannabinoid CB1 receptors. The responsiveness of neurons of the bed nucleus of the stria terminalis (BNST) to infralimbic cortex (ILCx) excitatory inputs is increased in rats with active, but not passive, nicotine taking. Therefore, we hypothesize that acquisition of the learned association between nicotine infusion and a paired cue light permits the strengthening of the ILCx-BNST synapses after ILCx tetanic stimulation. We exposed rats to intravenous nicotine self-administration for 2 months. Using a combination of in vivo protocols (electrical stimulations, extracellular recordings, and pharmacological manipulations), we characterized the effects of 10 Hz stimulation of the ILCx on BNST excitatory responses, under different conditions of exposure to nicotine. In addition, we tested whether the effects of the stimulation were CB1 receptor-dependent. The results show that nicotine self-administration supports the induction of evoked spike potentiation in the BNST in response to 10 Hz stimulation of ILCx afferents. Although not altered by nicotine abstinence, this cellular adaptation was blocked by CB1 receptor antagonism. Moreover, blockade of BNST CB1 receptors prevented increases in time-out responding subsequent to ILCx stimulation and decreased cue-induced reinstatement. Thus, the synaptic potentiation within the BNST in response to ILCx stimulation seems to contribute to the cue-elicited responding associated with nicotine self-administration and is tightly controlled by CB1 receptors.

Keywords: CB1 receptor; addiction; bed nucleus of the stria terminalis; in vivo electrophysiology; intravenous self-administration; nicotine.

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Figures

Figure 1.
Figure 1.

Operant behavior before electrophysiological recordings. A, Timeline of experiment. Animals were recorded 24 h after the following: (1) a single nicotine self-administration session (NIC-1 d, n = 5), (2) eight sessions of nicotine self-administration (NIC-8 d, n = 8), (3) extended training (NIC-60 d, n = 8; SAL-60 d, n = 7; yoked, n = 5), (4) extinction (Ext, n = 6), or (5) abstinence (Abst, n = 7). B, Number of visits in the active hole. Each bar represents the average number over the 3 last days before electrophysiological recording for each experimental group (except the “1 day” group). C, NIC-60 d rats showed a strong preference for the active hole. ***p < 0.001. Data are mean + SEM.

Figure 2.
Figure 2.

Effect of the 10 Hz ILCx stimulation onto BNST neurons at different stages of nicotine acquisition and maintenance. A, Stimulation and recording protocol. B, Histological control of stimulation (ILCx, *) and recording (BNST, arrow) sites. Scale bar, 1 mm. C, LTP seen in NIC-60 d rats but not in NIC-1 d, NIC-8 d, SAL-60 d, or yoked rats. D, Baseline and post-tetanic stimulation responses of ILCx–BNST projection neurons in NIC-60 d rats. Stimulus delivered at time = 0 (arrow). Each histogram consists of 100 trials individually illustrated in the associated raster. Bin width, 5 ms. E, The 10 Hz ILCx stimulation induces NMDA-dependent LTP within the BNST. Microinjection of the NMDA antagonist AP5 (400 μ

m

, 60 nl) blocks the induction of LTP. Data are mean ± SEM.

Figure 3.
Figure 3.

Effect of the 10 Hz ILCx stimulation onto BNST neurons after abstinence versus extinction. A, Decreasing active responses during extinction training. B, Extinction (Ext, n = 6) but not abstinence (Abst, n = 7) blocks LTP. *p < 0.05. ***p < 0.001. Data are mean ± SEM.

Figure 4.
Figure 4.

In Nic-60 d rats, 10 Hz stimulation of ILCx inputs evokes LTP that is CB1 receptor mediated. A, In vivo ILCx stimulation (1 min, 10 Hz) in anesthetized rats. CB1 antagonist AM251 (60 nl, 400 μ

m

) or vehicle was infused into the BNST before stimulation. B, AM251 blocks electrically induced LTP in NIC-60 d rats (Veh, n = 5; AM251, n = 5). *p < 0.05. Data are mean ± SEM.

Figure 5.
Figure 5.

Effects of 10 Hz ILCx stimulation on active responding during nicotine self-administration and on cue-induced reinstatement. A, Timeline of experiment. Rats were: (1) trained for nicotine self-administration (60 d), (2) anesthetized, received ILCx electrical stimulation 24 h after the last session (1 d) and CB1 antagonist pretreatment (Veh or AM251, 400 μ

m

; 60 nl), (3) tested for nicotine taking (4 d), (4) trained for extinction (2 d), and (5) tested for cue-induced nicotine seeking. Effects of ILCx and sham stimulation in vehicle and AM251-treated rats on the following: B, Total number of visits in active hole during the whole session. C, Total nicotine intake over the whole session. D, Total number of visits in active hole during time-out. E, Total number of visits in the active hole during the cue-induced reinstatement period. Post hoc active hole Veh Session 1 versus Session 2 and Veh Session 1 versus Session 3, **p < 0.01. @@p < 0.01, main effect stimulation versus sham stimulation. ++p < 0.02. B–D, Data are mean ± SEM. E, Data are mean + SEM.

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