Chronic Morphine Treatment and Withdrawal Increase Extracellular Levels of Norepinephrine in the Rat Bed Nucleus of the Stria Terminalis

Abstract

Extracellular levels of norepinephrine (NE) and glutamate (Glu) in the ventral bed nucleus of the stria terminalis (vBNST) of saline-and chronic morphine-treated rats, with or without withdrawal, were studied by means of the in vivo microdialysis technique in anesthetized rats. In addition, the tissue concentration of NE was studied at different rostrocaudal levels of the vBNST. Chronic morphine treatment significantly increased extracellular levels of NE, but not Glu, in vBNST. At 48 h after naloxone-induced morphine withdrawal there was a further significant increase in the extracellular levels of NE, but not Glu, in vBNST. The presence of UK 14304, an ␣ 2 -adrenergic agonist, induced a significant decrease in NE extracellular levels in all experimental groups. In contrast, UK 14304 induced a significant decrease in Glu extracellular levels only in saline-treated rats. The results also show that the vBNST presents a rostrocaudal gradient of NE and contains 9.4% of total brain NE. The increase in NE extracellular levels in vBNST induced by chronic morphine treatment and the further increase in NE levels 48 h after naloxone-induced morphine withdrawal suggest that NE in vBNST may be involved in the pharmacological effects of chronic morphine and withdrawal. Key Words: Norepinephrine -Ventral bed nucleus of the stria terminalis-Morphine-Naloxone-Withdrawal-Microdialysis.

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

“…The vBNST receives dense noradrenergic projections from the NTS (Forray and Gysling, 2004), and thus is a likely downstream target for norepinephrine's actions in morphine reward. However, we did not detect norepinephrine release in the vBNST during morphine, although elevated norepinephrine in the BNST may develop following chronic drug exposure (Fuentealba et al, 2000). Alternatively, NTS norepinephrine may instead modulate drug-reward through its projections to the NAc (Delfs et al, 1998) where it can regulate dopamine efflux, and presumably the rewarding property of abused drugs through α 1 receptors (Mitrano et al, 2012).…”

“…Although few studies emphasize the noradrenergic component of drug use, norepinephrine in the bed nucleus of the stria terminalis (BNST) has been clearly implicated in drug withdrawal (Aston-Jones et al, 1999). The ventral BNST (vBNST) receives dense innervation from the nucleus of the solitary tract (NTS) (Forray and Gysling, 2004), the source of norepinephrine critical for withdrawal aversion , and chronic morphine treatment increases basal norepinephrine in the BNST (Fuentealba et al, 2000). However, no work addresses the effect of acute drug exposure or withdrawal on phasic release.…”

Prolonged Activation of Mesolimbic Dopaminergic Neurons by Morphine Withdrawal Following Clonidine: Participation of Imidazoline and Norepinephrine Receptors

“…At least certain withdrawal signs involve activation of noradrenergic transmission in the BNST originating in the NTS and A1 (Aston-Jones et al, 1999;Delfs et al, 2000). In addition, an increase of noradrenergic extracellular levels in vBNST in morphinewithdrawn rats has been shown in vivo (Fuentealba et al, 2000). In view of these findings, we propose that clonidine pretreatment may prevent the withdrawal-induced increase of noradrenaline in the BNST, which may disinhibit the glutamatergic BNST projection to the VTA.…”

“…However, interactions between the two pathways remain poorly understood (De Vries and Shippenberg, 2002;Delfs et al, 2000;Gobbi et al, 2001;Harris and Aston-Jones, 1994;Maldonado, 1997). Withdrawal from chronic morphine is associated with opposite changes in noradrenergic and dopaminergic neuronal activities: noradrenergic neurons are activated and noradrenaline release is increased in the cortex and the bed nucleus of the stria terminalis (BNST) (Aghajanian, 1978;Akaoka and AstonJones, 1991;Fuentealba et al, 2000;Rossetti et al, 1993), and conversely ventral tegmental area dopaminergic (VTA DA) neurons are inhibited (Diana et al, 1995;Nowycky et al 1978) and DA release in the nucleus accumbens is consistently reduced (Acquas et al, 1991).…”

β1 Adrenergic Receptors in the Bed Nucleus of Stria Terminalis Mediate Differential Responses to Opiate Withdrawal

“…Retrograde tract-tracing studies in morphine-dependent rats after NTX-precipitated opiate withdrawal show that noradrenergic cells stimulated by opioid withdrawal and projecting to the BST are prominently located in the nucleus tractus solitarius (NTS) (Aston-Jones et al, 1999). As a consequence of the noradrenergic system activation, NE extracellular levels in the BST are elevated during withdrawal (Fuentealba et al, 2000) and produce an activation of the dorsolateral and ventral parts of the BST that is blockable by b antagonists (Aston-Jones et al, 1999; Gracy et al, 2001). We studied basal expression of several catecholamine-related molecules in the locus coeruleus and NTS of HR and LR animals (in preparation).…”