Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: vulnerability to relapse to heroin-seeking in rats.

paper Cited Public

Authors: Zhou, Yan; Leri, Francesco; Cummins, Erin; Kreek, Mary Jeanne
Year: 2015
Journal: Physiology & behavior
PMID: 25446223
DOI: 10.1016/j.physbeh.2014.11.002
PMCID: PMC4275356

Figure 1

Comparison of heroin self-administration (SA) behavioral responses. The panels show the mean (sem) actual self-infusions obtained (A, B) and the mean (sem) heroin total intake (mg/kg) (C, D) over the seven 3-h sessions of heroin SA (0.05 mg/kg/infusion, continuous schedule of reinforcement) in all heroin or saline SA rats (A, C) or each of the 3 groups (B, D). Three groups of animals: (1) H-RI, the heroin SA rats with “high” reinstatement induced by acute foot shock stress, n = 10; (2) L-RI, the heroin SA rats with “low” reinstatement induced by acute foot shock stress, n = 10; and (3) NR, the rats below the criterion for acquisition of heroin SA (20 infusions on days 5–7 of SA testing, 0.05 mg/kg/infusion), n = 6. * p<0.001 vs. Session 1 within the group; # p<0.05 vs. NR group.

Figure 2

Comparison of extinction and reinstatement behavioral responses. The same 3 groups of animals: (1) H-RI, the heroin SA rats with “high” reinstatement induced by acute foot shock stress, n = 10; (2) L-RI, the heroin SA rats with “low” reinstatement induced by acute foot shock stress, n = 10; and (3) NR, the rats below the criterion for acquisition of heroin SA, n = 6. The upper panels show the mean (sem) responses on the active lever (A) and inactive lever (B) during the four 3-h extinction sessions. * p<0.001 vs. Session 4 within the group; + p<0.05 vs. L-RI group; # p<0.05 vs. NR group. The middle panels (C, D) show individual responses and the lower panels (E, F) show the mean (sem) responses on both the active and inactive levers following exposure to 15-min intermittent foot shock stress (C, E) and to heroin (0.25 mg/kg, s.c.) (D, F) during the 3-h session of two reinstatement tests. * p<0.05 vs. inactive lever within the group; ++ p<0.001 vs. L-RI group; # p<0.05, ## p<0.01 vs. NR group.

Figure 3

(A) Comparison of arginine vasopressin (AVP) mRNA levels in the medial/basolateral amygdala (Me/BLA) and medial hypothalamus (MH). The same 3 groups of animals: (1) H-RI, the heroin SA rats with “high” reinstatement induced by acute foot shock stress; (2) L-RI, the heroin SA rats with “low” reinstatement induced by acute foot shock stress; and (3) NR, the rats below the criterion for acquisition of heroin SA (n=6–10). The dotted line represents basal mean mRNA level in each brain region of rats with saline SA without acute foot shock stress (heroin/stress control, n = 8). The panels show the mean (sem) mRNA levels (attomole/µg total RNA) measured 45 min after 15-min intermittent foot shock stress on day 16 (9 days after the last heroin SA). + p<0.05 vs. H-RI group; ## p<0.01 vs. NR group. (B) Regression of AVP mRNA levels in the Me/BLA and the foot shock stress-induced lever responding during 3-hour reinstatement session in the H-RI and L-RI rats. There was a significant correlation between the AVP mRNA level in the Me/BLA and the stress induced responding in all heroin SA rats, both the H-RI (•) (n = 10) and L-RI (○) animals (n = 10).

Figure 4

Comparison of pro-opiomelanocortin (POMC) mRNA levels in the medial hypothalamus (A) and orexin mRNA levels in the lateral hypothalamus (B). The same 3 groups of animals: (1) H-RI, the heroin SA rats with “high” reinstatement induced by acute foot shock stress; (2) L-RI, the heroin SA rats with “low” reinstatement induced by acute foot shock stress; and (3) NR, the rats below the criterion for acquisition of heroin SA (n = 6–9). The dotted line represents basal mean mRNA level for each gene in each brain region of the rats with saline SA without acute foot shock stress (heroin/stress control, n = 8). The panels show the mean (sem) mRNA levels (attomole/ug total RNA) measured 45 min after 15-min intermittent foot shock stress on day 16 (9 days after the last heroin SA). # p<0.05 vs. NR group.

Figure 5

Regression of dopamine D2 receptor mRNA levels in the caudate putamen (CPu) and foot shock stress-induced lever responding during 3-hour reinstatement session in the H-RI rats (heroin SA rats with “high” reinstatement induced by acute foot shock stress) and the L-RI rats (heroin SA rats with “low” reinstatement induced by acute foot shock stress). There was a significant correlation between the D2 mRNA level in the CPu and the stress induced responding in all heroin SA rats, both the H-RI (•) (n = 9) and L-RI (○) animals (n = 9).

#	Section	Preview
0	Introduction	There have been numeral animal studies on drug addiction that explored individual propensities to…
1	Introduction	Heroin addiction is a chronic relapsing disease of the brain caused by drug-induced neuroadaptations…
2	Introduction	stress-related behaviors in rodents [15]. Increased AVP gene expression in the amygdala is…
3	Introduction	Heroin, morphine and other short-acting opiates regulate the activity of endogenous opioid systems,…
4	Introduction	The objective of this study is explore whether individual differences in the vulnerability to drug…
5	Introduction	specificity of the stress-defined H-RI and L-RI groups, all rats were also tested for reinstatement…
6	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement	As mentioned in the self-administration section below, we used an acquisition criterion to identify…
7	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 1. Subjects	Twenty six adult male out-bred Sprague-Dawley rats (Charles River, QC), weighing 225–250g at the…
8	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 2. Surgery	Rats were surgically implanted with intravenous silastic catheters (Dow Corning, Midland, MI) in the…
9	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 3. Apparatus	Twenty-six Plexiglas operant chambers (model ENV-008CT, Med Associates, Georgia, VT) were each…
10	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 4. Procedure	The behavioral experiment consisted of three phases: self-administration, extinction, and…
11	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 4. Procedure — (A) Self-administration:	One 3-h self-administration session occurred every day for 7 consecutive days. Rats were transferred…
12	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 4. Procedure — (A) Self-administration:	During heroin self-administration, we noted individual variability in heroin intake that was not…
13	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 4. Procedure — (A) Self-administration:	An additional control group (n=8) was comprised of rats were trained to self-administer saline. On…
14	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 4. Procedure — (B) Extinction	Forty-eight hours after the last heroin self-administration session, extinction occurred over four…
15	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 4. Procedure — (C) Reinstatement	Twenty-four hours after the last extinction session (day 13), rats were tested for foot…
16	Material and methods — I. Heroin self-administration, extinction, foot shock- and heroin- induced reinstatement — 4. Procedure — (C) Reinstatement	As mentioned above, the “heroin/stress control” received saline during self-administration, no…
17	Material and methods — II. Preparation of RNA extracts	Nine days after the last heroin self-administration session, all rats (except the heroin/stress…
18	Material and methods — II. Preparation of RNA extracts	Each brain was removed from the skull and placed in a chilled rat brain matrix (ASI Instruments,…
19	Material and methods — III. Solution hybridization ribonuclease protection-trichloroacetic acid precipitation assay	The protocol for the solution hybridization ribonuclease protection-trichloroacetic acid…

Citation	PMID	DOI	Status
Aguilera, G et al., Regul Pept, 2000, Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis: implications for stress adaptation	11102648	10.1016/s0167-0115(00)00196-8	Cited
Bardo, MT et al., Behav Brain Res, 1996, Psychobiology of novelty seeking and drug-seeking behavior	8762157	10.1016/0166-4328(95)00203-0	Cited
Besson, M et al., Neuropsychopharmacology, 2013, Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats	23632436	10.1038/npp.2013.95	Cited
Boutrel, B et al., Proc Natl Acad Sci USA, 2005, Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior	16357203	10.1073/pnas.0507480102	Cited
Brady, KT et al., Arch Gen Psychiatry, 2009, Response to corticotropin-releasing hormone infusion in cocaine-dependent individuals	19349312	10.1001/archgenpsychiatry.2009.9	Cited
Bronstein, DM et al., Brain Res, 1990, Effects of morphine treatment on pro-opiomelanocortin systems in rat brain	2144463	10.1016/0006-8993(90)90066-k	Cited
Brown, RM et al., Neurochem Res, 2009, Neurochemistry underlying relapse to opiate seeking behavior	19418222	10.1007/s11064-009-9967-y	Cited
Chen, SA et al., Neuropsychopharmacology, 2006, Unlimited access to heroin self-administration: independent motivational markers of opiate dependence	16452993	10.1038/sj.npp.1301008	Cited
Cooper, ZD et al., J Pharmacol Exp Ther, 2008, Morphine deprivation increases self-administration of the fast- and short-acting mu-opioid receptor agonist remifentanil in the rat	18515643	10.1124/jpet.108.139196	Cited
Deminiere, JM et al., Neurosci Biobehav Rev, 1989, Experimental approach to individual vulnerability to psychostimulant addiction	2682400	10.1016/s0149-7634(89)80023-5	Cited
Edwards, S et al., Addict Biol, 2012, Evidence that vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-dependent rats	21309953	10.1111/j.1369-1600.2010.00291.x	Cited
Erb, S et al., Neuropsychopharmacology, 2000, Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking	10882840	10.1016/S0893-133X(99)00158-X	Cited
Fuchs, RA et al., Psychopharmacology, 1998, Predictive validity of the extinc- tion/reinstatement model of drug craving	9497020	10.1007/s002130050496	Cited
Georgescu, D et al., J Neurosci, 2003, Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal	12716916	10.1523/JNEUROSCI.23-08-03106.2003	Cited
Griebel, G et al., Proc Natl Acad Sci USA, 2002, Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders	11959912	10.1073/pnas.092012099	Cited
Harris, GC et al., Nature, 2005, A role for lateral hypothalamic orexin neurons in reward seeking	16100511	10.1038/nature04071	Cited
Koob, GF et al., Am J Psychiatry, 2007, Stress, dysregulation of drug reward pathways, and the transition to drug dependence	17671276	10.1176/appi.ajp.2007.05030503	Cited
Koob, GF, Neuron, 2008, A role for brain stress systems in addiction	18614026	10.1016/j.neuron.2008.06.012	Cited
Kreek, MJ et al., Cur Opin Pharmacol, 2009, Opiate and cocaine addiction: from bench to clinic and back to bench	19155191	10.1016/j.coph.2008.12.016	Cited
Le Merrer, L et al., Physiol Rev, 2009, Reward processing by the opioid system in the brain	19789384	10.1152/physrev.00005.2009	Cited
Leri, F et al., Eur Neuropsychopharmacol, 2009, Steady-state methadone blocks cocaine seeking and cocaine-induced gene expression alterations in the rat brain	18990547	10.1016/j.euroneuro.2008.09.004	Cited
Leri, F et al., Exp Clin Psychopharmacol, 2001, Drug-induced reinstatement to heroin and cocaine seeking: a rodent model of relapse in poly-drug use	11534540	10.1037//1064-1297.9.3.297	Cited
Leri, F et al., J Neurosci, 2002, Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala	12097523	10.1523/JNEUROSCI.22-13-05713.2002	Cited
Li, Y et al., J Neurosci, 2008, Mu-opioid receptor-mediated depression of the hypothalamic hypocretin/orexin arousal system	18337411	10.1523/JNEUROSCI.5447-07.2008	Cited
Lolait, SJ et al., Proc Natl Acad Sci USA, 1995, Extrapituitary expression of the rat V1b vasopressin receptor gene	7624319	10.1073/pnas.92.15.6783	Cited
Negus, S, J Pharmacol Exp Ther, 2006, Choice between heroin and food in nondependent and heroin-dependent rhesus monkeys: effects of naloxone, buprenorphine and methadone	16456085	10.1124/jpet.105.095380	Cited
Paxinos, G et al., The rat brain in stereotaxic coordinates (Ed 2), 1998	6110810	10.1016/0165-0270(80)90021-7	Cited
Peltier, RL et al., J Pharmacol Exp Ther, 2001, Effects of saline substitution on responding and plasma corticosterone in rats trained to self-administer different doses of cocaine	11561070	—	Cited
Quirarte, GL et al., Brain Res, 1998, Norepinephrine release in the amygdala in response to foot shock and opioid peptidergic drugs	9767150	10.1016/s0006-8993(98)00795-1	Cited
Robinson, TE et al., Brain Res Rev, 1993, The neural basis of drug craving: an incentive-sensitization theory of addiction	8401595	10.1016/0165-0173(93)90013-p	Cited
Roper, JA et al., Stress, 2011, The vasopressin AVPr1b receptor: molecular and pharmacological studies	20828336	10.3109/10253890.2010.512376	Cited
Salome, N et al., Psychopharmacology, 2006, Differential roles of amygdaloid nuclei in the anxiolytic and antidepressant-like effects of the V1b receptor antagonist, SSR149415, in rats	16779555	10.1007/s00213-006-0424-1	Cited
Self, DW et al., Drug Alcohol Depend, 1998, Relapse to drug seeking: neural and molecular mechanisms	9716929	10.1016/s0376-8716(98)00065-9	Cited
Shaham, Y et al., Psychopharmacology, 2003, The reinstatement model of drug relapse: history, methodology and major findings	12402102	10.1007/s00213-002-1224-x	Cited
Sharf, R et al., Brain Res, 2010, Role of orexin/hypocretin in dependence and addiction	19699189	10.1016/j.brainres.2009.08.028	Cited
Sinha, R et al., Psychopharmacology, 1999, Stress induced craving and stress response in cocaine dependent individuals	10229058	10.1007/s002130050898	Cited
Sinha, R et al., Psychopharmacology, 2011, Translational and reverse translational research on the role of stress in drug craving and relapse	21494792	10.1007/s00213-011-2263-y	Cited
Van Ree, JM et al., Life Sci, 1979, Dependence creating properties of lipotropin C-fragment (b-endorphin): Evidence for its internal control of behavior	571036	10.1016/0024-3205(79)90170-x	Cited
Wang, GJ et al., Neuropsychopharmacology, 1997, Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal	9015800	10.1016/S0893-133X(96)00184-4	Cited
Zhou, Y et al., J Endocrinol, 2006, Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal	17065397	10.1677/joe.1.06960	Cited
Zhou, Y et al., Neurochem Res, 2013, Suppression of hypothalamic-pituitary-adrenal axis by acute heroin challenge in rats during acute and chronic withdrawal from chronic heroin administration	23771528	10.1007/s11064-013-1091-3	Cited
Zhou, Y et al., Neuropsychopharmacology, 2008, Involvement of arginine vasopressin and V1b receptor in heroin withdrawal and heroin seeking precipitated by stress and by heroin	17443128	10.1038/sj.npp.1301419	Cited
Zhou, Y et al., Neuropsychopharmacology, 2011, Persistent increase in hypothalamic arginine vasopressin gene expression during protracted withdrawal from chronic escalating-dose cocaine in rodents	21677651	10.1038/npp.2011.97	Cited
Zijlstra, F et al., Eur Neuropsychopharmacol, 2008, Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males	18077142	10.1016/j.euroneuro.2007.11.002	Cited

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