Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence - PubMed (original) (raw)

Review

Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence

Rachel J Smith et al. Brain Struct Funct. 2008 Sep.

Abstract

Studies reviewed here implicate the extended amygdala in the negative affective states and increased drug-seeking that occur during protracted abstinence from chronic drug exposure. Norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling in the extended amygdala, including the bed nucleus of the stria terminalis, shell of the nucleus accumbens, and central nucleus of the amygdala, are generally involved in behavioral responses to environmental and internal stressors. Hyperactivity of stress response systems during addiction drives many negative components of drug abstinence. In particular, NE signaling from the nucleus tractus solitarius (NTS) to the extended amygdala, along with increased CRF transmission within the extended amygdala, are critical for the aversiveness of acute opiate withdrawal as well as stress-induced relapse of drug-seeking for opiates, cocaine, ethanol, and nicotine. NE and CRF transmission in the extended amygdala are also implicated in the increased anxiety that occurs during prolonged abstinence from chronic opiates, cocaine, ethanol, and cannabinoids. Many of these stress-associated behaviors are reversed by NE or CRF antagonists given systemically or locally within the extended amygdala. Finally, increased Fos activation in the extended amygdala and NTS is associated with the enhanced preference for drugs and decreased preference for natural rewards observed during protracted abstinence from opiates and cocaine, indicating that these areas are involved in the altered reward processing associated with addiction. Together, these findings suggest that involvement of the extended amygdala and its noradrenergic afferents in anxiety, stress-induced relapse, and altered reward processing reflects a common function for these circuits in stress modulation of drug-seeking.

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Figures

Fig. 1

Darkfield photomicrograph of a frontal section through ventral BNST showing very dense NE innervation, as revealed by dopamine beta-hydroxylase staining (yellow). Ventral BNST lies beneath the anterior commissure in this section; left is medial

Fig. 2

Noradrenergic drugs infused into BNST blocked CPA while having minimal effects on somatic signs associated with acute opiate withdrawal. Effects of the beta antagonists betaxolol + ICI 118,551 (a, b) or propranolol (c, d), or the alpha-2 agonist ST-91 (e, f) on aversion scores and somatic withdrawal (TC teeth chattering; ET eye twitch; WDS wet dog shakes; JUMP jumping; WR writhing; PG penile grooming; PT paw tremor). Aversion score for the withdrawal-paired environment is the mean time in seconds spent in the withdrawal side minus the non-withdrawal side on test day. n = 6 – 8 animals per dose; * P < 0.05. Taken from Delfs et al. (2000)

Fig. 3

BNST-projecting noradrenergic cells in NTS were stimulated by acute opiate withdrawal. The retrograde tracer WGA-gold was injected into BNST, and the A2 region of NTS was triple-labeled for WGA-gold (small black particles in cell body), Fos-related antigens (dark purple-black nuclei), and tyrosine hydroxylase (light brown). Arrows indicate triple-labeled cells. Similar results were seen in A1 and LC, but fewer cells were retrogradely labeled. XII hypoglossal nucleus; scale bar: 40 um. Taken from Delfs et al. (2000)

Fig. 4

Beta adrenoceptor antagonists reduced the increased anxiety observed in the defensive burying paradigm 48 h after forced abstinence from chronic cocaine or morphine. Withdrawn animals showed a shorter latency to begin burying a shock-prod (a) and longer duration of burying (b) after chronic treatment with cocaine or morphine, as compared to chronic saline. Pre-treatment with propranolol (5 mg/kg) or atenolol (5 mg/kg) reduced this anxiety, as compared to saline pre-treatment. Asterisks denote statistically significant differences from saline/saline group; * P < 0.05; ** P < 0.01. Morphine/atenolol is significantly different from morphine/saline, P < 0.05; no other between group comparisons are different. Modified from Harris and Aston-Jones (1993b)

Fig. 5

Stress-induced reinstatement was reduced by local administration of beta antagonists in BNST or CeA, or local unilateral administration of CRF antagonists in BNST combined with contra-lateral CeA inactivation. a Effects of the beta antagonists betaxolol + ICI 118,551 on footshock-induced reinstatement when infused locally into BNST (P < 0.05) or CeA (P < 0.001). Mean responses on the active and inactive lever during 3-h test sessions. Modified from Leri et al. (2002). b Effects of unilateral injection of CRF antagonists (D-Phe CRF12–41) into BNST and/or contralateral injection of TTX into CeA during 3-h test sessions preceded by footshock or no shock. Mean responses on the active and inactive lever. Only combined D + T injections effectively reduced reinstatement; * different from no shock, # different from D + T shock, P < 0.05. Taken from Erb et al. (2001)

Fig. 6

Previously morphine-dependent animals (M) showed decreased CPP for food after 2–5 weeks of abstinence, as compared to non-dependent animals (P) (upper graph), and increased CPP for morphine after 5 weeks of abstinence (lower graph). Preference for food- or morphine- paired environments is expressed as the mean time in seconds spent in the rewarded side minus the non-rewarded side on test day. *P < 0.01. Taken from Harris and Aston-Jones (2003a)

Fig. 7

Previously morphine-dependent animals showed an increase in Fos-activated neurons in ventrolateral BNST, CeA, and NTS following a food CPP test after 5 weeks of abstinence, as compared to non-dependent animals (placebo). Graphs show mean Fos counts for conditioned and non-conditioned animals. † significantly different from non-conditioned rats, P < 0.01; * significantly different between conditioned groups, P < 0.01. Photomicrographs of frontal sections of brain areas show representative animals in morphine-withdrawn (left) and placebo (right) groups following food CPP test. Medial is to the right; arrows on NTS section indicate cells double-labeled for Fos and TH. Modified from Harris and Aston-Jones (2007)

Fig. 8

Morphine exposure after 7 weeks of abstinence stimulated more noradrenergic cells in NTS of post-dependent rats (morphine withdrawn) than non-dependent rats (placebo). Animals were exposed to a CPP environment following an acute morphine injection (8 mg/ kg), and then sacrificed 2 h later for Fos and TH double-labeling. Post-dependent rats showed a significantly greater percentage of NTS TH+ cells with Fos double-labeling (P < 0.05, n = 3–4), with no differences in the total number of TH cells or number of TH-negative cells expressing Fos. Graph shows mean Fos counts ± S.E.M.

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Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence - PubMed (original) (raw)