Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2004 Sep 22;24(38):8198-204.
doi: 10.1523/JNEUROSCI.0425-04.2004.

Noradrenaline triggers GABAA inhibition of bed nucleus of the stria terminalis neurons projecting to the ventral tegmental area

Eric C Dumont  1 , John T Williams
Affiliations

Noradrenaline triggers GABAA inhibition of bed nucleus of the stria terminalis neurons projecting to the ventral tegmental area

Eric C Dumont et al. J Neurosci. .

Abstract

The lateral part of the ventral bed nucleus of the stria terminalis (vlBNST) is a critical site for the antiaversive effects of noradrenergic drugs during opioid withdrawal. The objective of the present study is to identify the cellular action(s) of noradrenaline in the vlBNST after withdrawal from a 5d treatment with morphine. The vlBNST is a heterogeneous cell group with multiple efferent projections. Therefore, neurons projecting to the midbrain were identified by retrograde transport of fluorescent microspheres injected in the ventral tegmental area (VTA). Whole-cell voltage clamp recordings of these neurons and of those sharing physiological properties were done in brain slices. Noradrenaline activated alpha1-adrenergic receptors to increase GABA(A)-IPSC frequency. Noradrenaline produced a similar increase in GABA(A)-IPSCs during acute opioid withdrawal, but this increase resulted from activation of beta-adrenergic receptors, adenylyl cyclase, and protein kinase A, as well as alpha1-adrenergic receptors. Given that neurons in the vlBNST send an excitatory projection to the VTA, noradrenaline may reduce excitatory drive to mesolimbic dopamine cells. This mechanism might contribute to the withdrawal-induced inhibition of dopamine neurons and explain how noradrenergic drugs microinjected into the vlBNST reduce aversive aspects of opioid withdrawal.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Anatomical (A-C) and electrophysiological (D-G) identification of neurons in the vlBNST projecting to the VTA. A, Recordings were restricted to the vlBNST where most labeling was observed (adapted from Paxinos and Watson, 1998). B, Neurons (arrows) in the vlBNST filled with fluorescent microspheres transported retrograde to their cell bodies after being microinjected in the VTA. C, Focus on one labeled neuron showing individual fluorescent beads in both the cell body and processes. D, Superimposed steady-state currents in response to voltage steps, ranging from +10 to -50 mV, applied from rest (-60 mV). E, The current-voltage plot revealed an inwardly rectifying potassium conductance observed in labeled neurons. Bath application of noradrenaline produced small outward currents in the voltage-clamp configuration (F) and a corresponding hyperpolarization in the current-clamp conditions (G). In this particular neuron, noradrenaline also blocked the spontaneous firing (G). ac, Anterior commissure.
Figure 2.
Figure 2.
Chronic morphine sensitized GABA synapses to morphine in the vlBNST. Morphine (A, B) and the selective μ-opioid receptor agonist DAMGO (C) reduced electrically evoked (0.1 Hz) GABAA-IPSCs in slices from control and morphine-treated rats. Slices from morphine-treated rats were washed with morphine-free solution for 60 min such that they were in withdrawal. A, Each trace is the average of five evoked GABAA-IPSCs before (left traces), during superfusion with morphine (1 μm, 20 min; middle traces), and after the addition of naloxone (1 μm; right traces). B, Summary of the effect of 1 μm morphine on the amplitude of evoked GABAA-IPSCs from 15 neurons- groups (10 rats in each group). C, Dose-response curves of the effect of cumulative concentrations of the μ-opioid receptor agonist DAMGO on evoked GABAA-IPSCs. Inset shows representative traces, averaged from 5-10 evoked GABAA-IPSCs in a slice from a control rat, before (left), after DAMGO (1 μm; middle), and after reversing the effect of DAMGO with naloxone (1 μm; right). S2, Stimulus 2; S1, stimulus 1. Error bars indicate SEM.
Figure 3.
Figure 3.
Acute morphine withdrawal increased evoked (A, B) and spontaneous miniature (C) GABAA-IPSCs through the AC-PKA pathway. A1, Traces represent the average of five evoked GABAA-IPSCs in the presence of morphine (1 μm) and at the peak effect of naloxone in slices from control (top) and morphine-treated rats (bottom). A2, Summary of the effect of acute naloxone-precipitated morphine withdrawal on evoked GABAA-IPSCs (n = 10 and 14, control andmorphine-treated,respectively). B, Summary of the effect of adenylyl cyclase blockade with H89 (10 μm; n = 5 and 7) and activation with forskolin (10 μm; n = 5 per group) on evoked GABAA-IPSCs during naloxone-precipitated morphine withdrawal. C, Top, representative recordings of miniature GABAA-IPSCs recorded in tetrodotoxin (0.5 μm) in slices from control (left trace) and morphine-treated (right trace) rats. Summary of the frequency (left) and amplitude (right) of miniature GABAA-IPSCs in slices from control (n = 9) and morphine-treated (n = 15) rats after acute morphine withdrawal. * p < 0.05. Error bars indicate SEM. Rectangles in A2 refer to 1 and 2 in A1.
Figure 4.
Figure 4.
Noradrenaline increased spontaneous GABAA-IPSCs in the vlBNST. A, Representative recording of spontaneous GABAA-IPSCs in a slice from a control rat. Inset, Noradrenaline-driven spontaneous GABAA-IPSCs at a larger time scale. B, Representative recordings of spontaneous GABAA-IPSCs in a slice from a morphine-treated rat after naloxone-precipitated withdrawal. C, Summary of the effect of naloxone-precipitated morphine withdrawal and of α1-, β-adrenergic receptor blockade on the noradrenaline-induced increase of GABAA-IPSCs. D, Effects of adenylyl cyclase blockade (H89, 10 μm) on the noradrenaline-induced increase of spontaneous GABAA-IPSCs in slices from control or morphine-treated slices spontaneously withdrawn (at least 60 min) from morphine. * p < 0.05, before versus after noradrenaline; ap < 0.05, before versus after naloxone 1 μm. Error bars indicate SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acquas E, Carboni E, Di Chiara G (1991) Profound depression of mesolimbic dopamine release after morphine withdrawal in dependent rats. Eur J Pharmacol 193: 133-134. - PubMed
    1. Acquas E, Carboni E, de Ree RH, Da Prada M, Di Chiara G (1992) Extracellular concentrations of dopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methyltransferase inhibitor Ro 40-7592. J Neurochem 59: 326-330. - PubMed
    1. Aghajanian GK (1978) Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature 276: 186-188. - PubMed
    1. Akaoka H, Aston-Jones G (1991) Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input. J Neurosci 11: 3830-3839. - PMC - PubMed
    1. Alheid GF, de Olmos JS, Baltramino CA (1995) Amygdala and extended amygdala. In: The rat nervous system, Ed 2 (Paxinos G, ed), pp 495-578. San Diego: Academic.

Publication types

MeSH terms

LinkOut - more resources

-