Tobacco addiction and the dysregulation of brain stress systems

Abstract

Tobacco is a highly addictive drug and is one of the most widely abused drugs in the world. The first part of this review explores the role of stressors and stress-associated psychiatric disorders in the initiation of smoking, the maintenance of smoking, and relapse after a period of abstinence. The reviewed studies indicate that stressors facilitate the initiation of smoking, decrease the motivation to quit, and increase the risk for relapse. Furthermore, people with depression or an anxiety disorder are more likely to smoke than people without these disorders. The second part of this review describes animal studies that investigated the role of brain stress systems in nicotine addiction. These studies indicate that corticotropin-releasing factor, Neuropeptide Y, the hypocretins, and norepinephrine play a pivotal role in nicotine addiction. In conclusion, the reviewed studies indicate that smoking briefly decreases subjective stress levels but also leads to a further dysregulation of brain stress systems. Drugs that decrease the activity of brain stress systems may diminish nicotine withdrawal and improve smoking cessation rates.

Figure 1

Role of smoking in developing depression, PTSD, and other anxiety disorders. The left side of the figure shows that there is a bidirectional relationship between smoking and depression and PTSD; smoking increases the risk for developing depression and PTSD and vice versa. The right side of the figure indicates that smoking increases the risk for developing an anxiety disorder (PTSD not included). Most anxiety disorders do not increase the risk for smoking.

Figure 2

Dysregulation of brain stress systems and tobacco addiction. A dysregulation of brain stress systems may play a role in transitioning from experimenting with cigarettes to habitual smoking, the dysphoria associated with smoking cessation, and relapse to smoking. CRF neurons project from the CeA to the prefrontal cortex, BNST, dorsal raphe nucleus, and LC (Swanson et al., 1983). CRF neurons also project from the PVN to the median eminence. NPY neurons project from the arcuate hypothalamic nucleus to the nucleus accumbens, lateral septum, and the LC (Holmes et al., 2003; Kask et al., 2002). Hypocretin neurons project from the later hypothalamus to the prefrontal cortex, thalamus, dorsal raphe nucleus, and the LC (Lambe et al., 2007). Norepinephrine neurons project from the LC to the prefrontal cortex and the CeA and from the A1/A2 region to the BNST (Aston-Jones and Cohen, 2005; Delfs et al., 2000). A2 noradrenergic neurons also play an important role in stimulating CRF neurons in the PVN and thereby activating the HPA axis (Matta et al., 1993b). Corticosterone inhibits the activity of the HPA axis by stimulating glucocorticoid receptors in the pituitary, PVN, and hippocampus (de Kloet et al., 1998a). Inhibitory GABAergic neurons project from the hippocampus to the PVN (de Kloet et al., 1998b). Abbreviations: Arc, arcuate hypothalamic nucleus; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; DR, dorsal raphe nucleus; LC, locus coeruleus; LS, lateral septum; Nacc, nucleus accumbens; PFC, prefrontal cortex; PVN, paraventricular nucleus of the hypothalamus.

Figure 3

Role of corticotropin-releasing factor, norepinephrine, and neuropeptide Y in precipitated nicotine withdrawal in rats. In all figures, brain reward thresholds were assessed with a discrete trial intracranial self-stimulation procedure and were expressed as a percentage of the pre-test day baselines. (A) Effect of the CRF₁/CRF₂ receptor antagonist D-Phe CRF_(12–41) (icv; saline, n = 8; nicotine, n = 7) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of D-Phe CRF_(12–41)). Reproduced with permission from (Bruijnzeel et al., 2007). (B) Effect of the specific CRF₁ receptor antagonist R278995/CRA0450 (icv; saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of R278995/CRA0450). Reproduced with permission from (Bruijnzeel et al., 2009). (C) Effect of the specific CRF₂ receptor antagonist Astressin-2B (icv; saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Reproduced with permission from (Bruijnzeel et al., 2009). (D) Effect of the α1-adrenoceptor antagonist prazosin (ip; saline, n = 9; nicotine, n = 9) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle. Pound signs (## P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle or mecamylamine and 0.0625 mg/kg of prazosin. Reproduced with permission from (Bruijnzeel et al., 2010). (E) Effect of the α2-adrenoceptor antagonist idazoxan (ip; saline, n = 12; nicotine, n = 12) on the elevations in brain reward thresholds associated with DHβE (3 mg/kg, sc) precipitated nicotine withdrawal. The at symbol (@) indicates a statistically significant main effect of precipitated nicotine withdrawal on thresholds (P<0.0001) independent of idazoxan treatment. Reproduced with permission from (Semenova and Markou, 2010). (F) Effect of NPY (icv, saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (+ P<0.05, ++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of NPY). Reproduced with permission from (Rylkova et al., 2008). (G) Effect of the selective Y₁ receptor agonist [D-His²⁶]-NPY (icv, saline, n = 9; nicotine, n = 11) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of [D-His²⁶]-NPY). Reproduced with permission from (Rylkova et al., 2008). In all the figures (A–G), the brain reward thresholds are expressed as means ± SEM.

Figure 3

Role of corticotropin-releasing factor, norepinephrine, and neuropeptide Y in precipitated nicotine withdrawal in rats. In all figures, brain reward thresholds were assessed with a discrete trial intracranial self-stimulation procedure and were expressed as a percentage of the pre-test day baselines. (A) Effect of the CRF₁/CRF₂ receptor antagonist D-Phe CRF_(12–41) (icv; saline, n = 8; nicotine, n = 7) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of D-Phe CRF_(12–41)). Reproduced with permission from (Bruijnzeel et al., 2007). (B) Effect of the specific CRF₁ receptor antagonist R278995/CRA0450 (icv; saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of R278995/CRA0450). Reproduced with permission from (Bruijnzeel et al., 2009). (C) Effect of the specific CRF₂ receptor antagonist Astressin-2B (icv; saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Reproduced with permission from (Bruijnzeel et al., 2009). (D) Effect of the α1-adrenoceptor antagonist prazosin (ip; saline, n = 9; nicotine, n = 9) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle. Pound signs (## P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle or mecamylamine and 0.0625 mg/kg of prazosin. Reproduced with permission from (Bruijnzeel et al., 2010). (E) Effect of the α2-adrenoceptor antagonist idazoxan (ip; saline, n = 12; nicotine, n = 12) on the elevations in brain reward thresholds associated with DHβE (3 mg/kg, sc) precipitated nicotine withdrawal. The at symbol (@) indicates a statistically significant main effect of precipitated nicotine withdrawal on thresholds (P<0.0001) independent of idazoxan treatment. Reproduced with permission from (Semenova and Markou, 2010). (F) Effect of NPY (icv, saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (+ P<0.05, ++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of NPY). Reproduced with permission from (Rylkova et al., 2008). (G) Effect of the selective Y₁ receptor agonist [D-His²⁶]-NPY (icv, saline, n = 9; nicotine, n = 11) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of [D-His²⁶]-NPY). Reproduced with permission from (Rylkova et al., 2008). In all the figures (A–G), the brain reward thresholds are expressed as means ± SEM.

Figure 3

Role of corticotropin-releasing factor, norepinephrine, and neuropeptide Y in precipitated nicotine withdrawal in rats. In all figures, brain reward thresholds were assessed with a discrete trial intracranial self-stimulation procedure and were expressed as a percentage of the pre-test day baselines. (A) Effect of the CRF₁/CRF₂ receptor antagonist D-Phe CRF_(12–41) (icv; saline, n = 8; nicotine, n = 7) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of D-Phe CRF_(12–41)). Reproduced with permission from (Bruijnzeel et al., 2007). (B) Effect of the specific CRF₁ receptor antagonist R278995/CRA0450 (icv; saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of R278995/CRA0450). Reproduced with permission from (Bruijnzeel et al., 2009). (C) Effect of the specific CRF₂ receptor antagonist Astressin-2B (icv; saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Reproduced with permission from (Bruijnzeel et al., 2009). (D) Effect of the α1-adrenoceptor antagonist prazosin (ip; saline, n = 9; nicotine, n = 9) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle. Pound signs (## P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle or mecamylamine and 0.0625 mg/kg of prazosin. Reproduced with permission from (Bruijnzeel et al., 2010). (E) Effect of the α2-adrenoceptor antagonist idazoxan (ip; saline, n = 12; nicotine, n = 12) on the elevations in brain reward thresholds associated with DHβE (3 mg/kg, sc) precipitated nicotine withdrawal. The at symbol (@) indicates a statistically significant main effect of precipitated nicotine withdrawal on thresholds (P<0.0001) independent of idazoxan treatment. Reproduced with permission from (Semenova and Markou, 2010). (F) Effect of NPY (icv, saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (+ P<0.05, ++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of NPY). Reproduced with permission from (Rylkova et al., 2008). (G) Effect of the selective Y₁ receptor agonist [D-His²⁶]-NPY (icv, saline, n = 9; nicotine, n = 11) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of [D-His²⁶]-NPY). Reproduced with permission from (Rylkova et al., 2008). In all the figures (A–G), the brain reward thresholds are expressed as means ± SEM.

Figure 3

Role of corticotropin-releasing factor, norepinephrine, and neuropeptide Y in precipitated nicotine withdrawal in rats. In all figures, brain reward thresholds were assessed with a discrete trial intracranial self-stimulation procedure and were expressed as a percentage of the pre-test day baselines. (A) Effect of the CRF₁/CRF₂ receptor antagonist D-Phe CRF_(12–41) (icv; saline, n = 8; nicotine, n = 7) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of D-Phe CRF_(12–41)). Reproduced with permission from (Bruijnzeel et al., 2007). (B) Effect of the specific CRF₁ receptor antagonist R278995/CRA0450 (icv; saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of R278995/CRA0450). Reproduced with permission from (Bruijnzeel et al., 2009). (C) Effect of the specific CRF₂ receptor antagonist Astressin-2B (icv; saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Reproduced with permission from (Bruijnzeel et al., 2009). (D) Effect of the α1-adrenoceptor antagonist prazosin (ip; saline, n = 9; nicotine, n = 9) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle. Pound signs (## P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle or mecamylamine and 0.0625 mg/kg of prazosin. Reproduced with permission from (Bruijnzeel et al., 2010). (E) Effect of the α2-adrenoceptor antagonist idazoxan (ip; saline, n = 12; nicotine, n = 12) on the elevations in brain reward thresholds associated with DHβE (3 mg/kg, sc) precipitated nicotine withdrawal. The at symbol (@) indicates a statistically significant main effect of precipitated nicotine withdrawal on thresholds (P<0.0001) independent of idazoxan treatment. Reproduced with permission from (Semenova and Markou, 2010). (F) Effect of NPY (icv, saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (+ P<0.05, ++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of NPY). Reproduced with permission from (Rylkova et al., 2008). (G) Effect of the selective Y₁ receptor agonist [D-His²⁶]-NPY (icv, saline, n = 9; nicotine, n = 11) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of [D-His²⁶]-NPY). Reproduced with permission from (Rylkova et al., 2008). In all the figures (A–G), the brain reward thresholds are expressed as means ± SEM.

Figure 3

Role of corticotropin-releasing factor, norepinephrine, and neuropeptide Y in precipitated nicotine withdrawal in rats. In all figures, brain reward thresholds were assessed with a discrete trial intracranial self-stimulation procedure and were expressed as a percentage of the pre-test day baselines. (A) Effect of the CRF₁/CRF₂ receptor antagonist D-Phe CRF_(12–41) (icv; saline, n = 8; nicotine, n = 7) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of D-Phe CRF_(12–41)). Reproduced with permission from (Bruijnzeel et al., 2007). (B) Effect of the specific CRF₁ receptor antagonist R278995/CRA0450 (icv; saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of R278995/CRA0450). Reproduced with permission from (Bruijnzeel et al., 2009). (C) Effect of the specific CRF₂ receptor antagonist Astressin-2B (icv; saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Reproduced with permission from (Bruijnzeel et al., 2009). (D) Effect of the α1-adrenoceptor antagonist prazosin (ip; saline, n = 9; nicotine, n = 9) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle. Pound signs (## P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle or mecamylamine and 0.0625 mg/kg of prazosin. Reproduced with permission from (Bruijnzeel et al., 2010). (E) Effect of the α2-adrenoceptor antagonist idazoxan (ip; saline, n = 12; nicotine, n = 12) on the elevations in brain reward thresholds associated with DHβE (3 mg/kg, sc) precipitated nicotine withdrawal. The at symbol (@) indicates a statistically significant main effect of precipitated nicotine withdrawal on thresholds (P<0.0001) independent of idazoxan treatment. Reproduced with permission from (Semenova and Markou, 2010). (F) Effect of NPY (icv, saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (+ P<0.05, ++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of NPY). Reproduced with permission from (Rylkova et al., 2008). (G) Effect of the selective Y₁ receptor agonist [D-His²⁶]-NPY (icv, saline, n = 9; nicotine, n = 11) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of [D-His²⁶]-NPY). Reproduced with permission from (Rylkova et al., 2008). In all the figures (A–G), the brain reward thresholds are expressed as means ± SEM.

Figure 3

Role of corticotropin-releasing factor, norepinephrine, and neuropeptide Y in precipitated nicotine withdrawal in rats. In all figures, brain reward thresholds were assessed with a discrete trial intracranial self-stimulation procedure and were expressed as a percentage of the pre-test day baselines. (A) Effect of the CRF₁/CRF₂ receptor antagonist D-Phe CRF_(12–41) (icv; saline, n = 8; nicotine, n = 7) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of D-Phe CRF_(12–41)). Reproduced with permission from (Bruijnzeel et al., 2007). (B) Effect of the specific CRF₁ receptor antagonist R278995/CRA0450 (icv; saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of R278995/CRA0450). Reproduced with permission from (Bruijnzeel et al., 2009). (C) Effect of the specific CRF₂ receptor antagonist Astressin-2B (icv; saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Reproduced with permission from (Bruijnzeel et al., 2009). (D) Effect of the α1-adrenoceptor antagonist prazosin (ip; saline, n = 9; nicotine, n = 9) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle. Pound signs (## P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle or mecamylamine and 0.0625 mg/kg of prazosin. Reproduced with permission from (Bruijnzeel et al., 2010). (E) Effect of the α2-adrenoceptor antagonist idazoxan (ip; saline, n = 12; nicotine, n = 12) on the elevations in brain reward thresholds associated with DHβE (3 mg/kg, sc) precipitated nicotine withdrawal. The at symbol (@) indicates a statistically significant main effect of precipitated nicotine withdrawal on thresholds (P<0.0001) independent of idazoxan treatment. Reproduced with permission from (Semenova and Markou, 2010). (F) Effect of NPY (icv, saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (+ P<0.05, ++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of NPY). Reproduced with permission from (Rylkova et al., 2008). (G) Effect of the selective Y₁ receptor agonist [D-His²⁶]-NPY (icv, saline, n = 9; nicotine, n = 11) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of [D-His²⁶]-NPY). Reproduced with permission from (Rylkova et al., 2008). In all the figures (A–G), the brain reward thresholds are expressed as means ± SEM.

Figure 3

Role of corticotropin-releasing factor, norepinephrine, and neuropeptide Y in precipitated nicotine withdrawal in rats. In all figures, brain reward thresholds were assessed with a discrete trial intracranial self-stimulation procedure and were expressed as a percentage of the pre-test day baselines. (A) Effect of the CRF₁/CRF₂ receptor antagonist D-Phe CRF_(12–41) (icv; saline, n = 8; nicotine, n = 7) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of D-Phe CRF_(12–41)). Reproduced with permission from (Bruijnzeel et al., 2007). (B) Effect of the specific CRF₁ receptor antagonist R278995/CRA0450 (icv; saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 µg of R278995/CRA0450). Reproduced with permission from (Bruijnzeel et al., 2009). (C) Effect of the specific CRF₂ receptor antagonist Astressin-2B (icv; saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (3 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Reproduced with permission from (Bruijnzeel et al., 2009). (D) Effect of the α1-adrenoceptor antagonist prazosin (ip; saline, n = 9; nicotine, n = 9) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle. Pound signs (## P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle or mecamylamine and 0.0625 mg/kg of prazosin. Reproduced with permission from (Bruijnzeel et al., 2010). (E) Effect of the α2-adrenoceptor antagonist idazoxan (ip; saline, n = 12; nicotine, n = 12) on the elevations in brain reward thresholds associated with DHβE (3 mg/kg, sc) precipitated nicotine withdrawal. The at symbol (@) indicates a statistically significant main effect of precipitated nicotine withdrawal on thresholds (P<0.0001) independent of idazoxan treatment. Reproduced with permission from (Semenova and Markou, 2010). (F) Effect of NPY (icv, saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (+ P<0.05, ++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of NPY). Reproduced with permission from (Rylkova et al., 2008). (G) Effect of the selective Y₁ receptor agonist [D-His²⁶]-NPY (icv, saline, n = 9; nicotine, n = 11) on the elevations in brain reward thresholds associated with mecamylamine (2 mg/kg, sc) precipitated nicotine withdrawal. Asterisks (** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Crosses (++ P<0.01) indicate elevations in brain reward thresholds compared to those of rats chronically treated with saline and acutely treated with vehicle (0 µg of [D-His²⁶]-NPY). Reproduced with permission from (Rylkova et al., 2008). In all the figures (A–G), the brain reward thresholds are expressed as means ± SEM.