Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Apr 16;236:220-32.
doi: 10.1016/j.neuroscience.2012.12.071. Epub 2013 Jan 18.

Proopiomelanocortin (POMC) Expression and Conditioned Place Aversion During Protracted Withdrawal From Chronic Intermittent Escalating-Dose Heroin in POMC-EGFP Promoter Transgenic Mice

Affiliations
Free PMC article

Proopiomelanocortin (POMC) Expression and Conditioned Place Aversion During Protracted Withdrawal From Chronic Intermittent Escalating-Dose Heroin in POMC-EGFP Promoter Transgenic Mice

K Niikura et al. Neuroscience. .
Free PMC article

Abstract

In heroin-dependent individuals, the drive to avoid or ameliorate the negative affective/emotional state associated with the discontinuation of heroin contributes to the chronic relapsing nature of the disease. Here, we investigate changes in proopiomelanocortin (POMC) expression at three time points across an extended period of heroin withdrawal in a clinically relevant rodent model of addiction using conditioned place aversion (CPA) in POMC-EGFP (POMC-enhanced green fluorescent protein) bacterial artificial chromosome (BAC) transgenic mice. Neurons expressing POMC-EGFP were found in the medial nucleus of the amygdala (MeA), basomedial amygdala (BMA) and dentate gyrus of hippocampus (DG), as well as the arcuate nucleus of hypothalamus (ARC). Heroin-treated mice displayed robust CPA after acute spontaneous withdrawal (12h), which persisted across the extended (14days) withdrawal period. After 12-h withdrawal, heroin-treated mice showed lower signal intensity of POMC-EGFP-positive cells in the ARC, higher levels of POMC mRNA in the amygdala but lower levels in the hippocampus than saline controls. After 7-d withdrawal, heroin-treated mice showed fewer POMC-EGFP-positive cells in the MeA and lower POMC mRNA in the amygdala than saline controls. After extended (14days) withdrawal, heroin-treated mice showed more POMC-EGFP-positive cells in BMA and DG, increased intensity of POMC-EGFP signal in DG, and higher POMC mRNA levels in the hippocampus compared to controls. Our results show dynamic changes in POMC in hypothalamic and extra-hypothalamic regions that may contribute to the negative affective/emotional state of heroin withdrawal shown by CPA from acute to extended periods of heroin withdrawal.

Conflict of interest statement

The authors have no conflicts of interest, financial or otherwise, pertaining to any aspect of the work reported in this manuscript.

Figures

Figure 1
Figure 1
POMC-EGFP fluorescence in the midbrain region including the hippocampus, hypothalamus and amygdala (A). High magnification images show that POMC-EGFP fluorescence-expressing cells exist in the dentate gyrus of the hippocampus (DG) (B), the medial nucleus of the amygdala (MeA) and the basomedial amygdala (BMA) (C), and the arcuate nucleus of the hypothalamus (ARC) (D). There is strong and bright fluorescence in the ARC. Although with a weaker signal, POMC-EGFP fluorescence-positive cells exist in the DG (arrows in B), MeA and BMA (arrows in C). Scale bar = 500 um (A), 50 um (B–D). 3V: third ventricular
Figure 2
Figure 2
(A) Schedule of exposure to escalating doses of heroin, timing of the conditioning sessions during withdrawal state and timing of the post-test session in different groups. (B and C) Heroin withdrawal-induced Conditioned Place Aversion (CPA) after chronic intermittent escalating-dose heroin. Negative scores [downward bars] indicate an avoidance of the conditioned environment, due to its pairing with the aversive heroin withdrawal state. Both POMC-EGFP positive (B) and negative (C) mice showed strong CPA on acute spontaneous withdrawal (12 hours after receiving their final injection of chronic escalating dose of heroin). This CPA persists into extended spontaneous withdrawal (14 days after receiving their final injection of chronic escalating-dose of heroin). (D and E) Body weight loss induced by chronic escalating dose of heroin. Body weight changes (caluculated as percentage of baseline) displayed by POMC-EGFP positive (D) and negative (E) mice during received escalating-dose of heroin or saline and its withdrawal. Values are expressed as mean ± SEM (n=6/group). ***p<0.001, *p<0.05 vs matched saline control group.
Figure 3
Figure 3
Change in POMC-EGFP positive cells and POMC mRNA in the hypothalamus in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal (WD) from the last injection of chronic escalating doses of heroin administration. The total number of POMC-EGFP positive cells in POMC-EGFP positive mice in the arcuate nucleus of the hypothalamus (ARC) in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal are shown in A, D and G, respectively. The total relative intensity of POMC-EGFP positive cells in POMC-EGFP positive mice in ARC in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal are shown in B, E and H, respectively. The level of POMC mRNA in the hypothalamus in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal in POMC-EGFP negative mice are shown in C, F and I, respectively. Values are expressed as mean ± SEM. *p<0.05 vs saline group.
Figure 4
Figure 4
Change in POMC-EGFP positive cells and POMC mRNA in the amygdala in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal from the last injection of chronic escalating doses of heroin administration. In acute spontaneous withdrawal, the total number of POMC-EGFP positive cells in POMC-EGFP positive mice in the basomedial amygdala (BMA) and the medial nucleus of the amygdala (MeA) are shown in A and C, respectively. The total relative intensity of POMC-EGFP positive cells in POMC-EGFP positive mice in BMA and MeA are shown in B and D, respectively. The level of POMC mRNA in POMC-EGFP negative mice in amygdala is shown in E. In mid-range spontaneous withdrawal, the total number of POMC-EGFP positive cells in POMC-EGFP positive mice in BMA and MeA are shown in F and H, respectively. The total relative intensity of POMC-EGFP positive cells in POMC-EGFP positive mice in BMA and MeA are shown in G and I, respectively. The level of POMC mRNA in POMC-EGFP negative mice in amygdala is shown in J. In extended spontaneous withdrawal, the total number of POMC-EGFP positive cells in POMC-EGFP positive mice in BMA and MeA are shown in K and M, respectively. The total relative intensity of POMC-EGFP positive cells in POMC-EGFP positive mice in BMA and MeA are shown in L and N, respectively. The level of POMC mRNA in POMC-EGFP negative mice in amygdala is shown in O. Values are expressed as mean ± SEM. *p<0.05 vs saline group.
Figure 5
Figure 5
Change in POMC-EGFP positive cells and POMC mRNA in the hippocampus in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal (WD) from the last injection of chronic escalating doses of heroin administration. The total number of POMC-EGFP positive cells in POMC-EGFP positive mice in DG in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal are shown in A, D and G, respectively. The total relative intensity of POMC-EGFP positive cells in POMC-EGFP positive mice in DG in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal are shown in B, E and H, respectively. The level of POMC mRNA in the hypothalamus in acute (12 hours), mid-range (7 days) or extended (14 days) spontaneous withdrawal in POMC-EGFP negative mice are shown in C, F and I, respectively. Values are expressed as mean ± SEM. *p<0.05 vs saline group.

Similar articles

See all similar articles

Cited by 8 articles

See all "Cited by" articles

Publication types

Substances

Feedback