Elevations In Brain Reward Thresholds Research Articles

Sex differences in the reward deficit and somatic signs associated with precipitated nicotine withdrawal in rats

Female smokers are more likely to relapse than male smokers, but little is known about sex differences in nicotine withdrawal. Therefore, male and female rats were prepared with minipumps that contained nicotine or saline and sex differences in precipitated and spontaneous nicotine withdrawal were investigated. The intracranial self-stimulation (ICSS) procedure was used to assess mood states. Elevations in brain reward thresholds reflect a deficit in reward function. Anxiety-like behavior was investigated after the acute nicotine withdrawal phase in a large open field and the elevated plus maze test. The nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-treated rats but did not affect those of the saline-treated control rats. A low dose of mecamylamine elevated the brain reward thresholds of the nicotine-treated male rats but not those of the females. Mecamylamine also precipitated more somatic withdrawal signs in the nicotine-treated male than female rats. Minipump removal elevated the brain reward thresholds of the nicotine-treated rats for about 36 h but did not affect those of the saline-treated rats. There was no sex difference in the reward deficit during spontaneous nicotine withdrawal. In addition, the nicotine-treated male and female rats did not display increased anxiety-like behavior three to four days after minipump removal. In conclusion, these studies suggest that relatively low doses of a nicotinic receptor antagonist induce a greater reward deficit and more somatic withdrawal signs in male than female rats, but there is no sex difference in the reward deficit during spontaneous withdrawal.

Chronic treatment with the vasopressin 1b receptor antagonist SSR149415 prevents the dysphoria associated with nicotine withdrawal in rats

Nicotine addiction is a chronic brain disorder that is characterized by dysphoria upon smoking cessation and relapse after brief periods of abstinence. It has been hypothesized that the negative mood state associated with nicotine withdrawal is partly mediated by a heightened activity of brain stress systems. Animal studies suggest that blockade of vasopressin 1b (V1b) receptors diminishes high levels of drug intake in dependent animals and attenuates the emotional response to stressors. The goal of the present studies was to investigate the effect of acute and chronic treatment with the V1b receptor antagonist SSR149415 on the negative mood state associated with nicotine withdrawal in rats. An intracranial self-stimulation (ICSS) procedure was used to assess mood states and nicotine dependence was induced using minipumps. The nicotinic receptor antagonist mecamylamine was used to precipitate withdrawal. Mecamylamine elevated the brain reward thresholds of the nicotine dependent rats, which reflects a negative mood state. Mecamylamine did not affect the brain reward thresholds of the saline-treated control rats. Chronic treatment with SSR149415 completely prevented the elevations in brain reward thresholds associated with nicotine withdrawal while acute treatment only partly prevented nicotine withdrawal. These data suggest that chronic treatment with V1b receptor antagonists may prevent the dysphoria associated with smoking cessation and thereby improve relapse rates.

Investigation of the role of corticotropin‐releasing factor receptors within the central amygdala and basolateral amygdala during nicotine withdrawal in rats

Abrupt cessation of tobacco smoking in humans is associated with negative affective symptoms such as depressed mood and anxiety. Evidence indicates that this dysphoric state associated with nicotine withdrawal is one of the motivational factors for the continuation of tobacco smoking. Cessation of chronic nicotine administration in rodents induces affective withdrawal signs which can be investigated using the intracranial self‐stimulation (ICSS) procedure. The amygdala is hypothesized to play a key role in both the positive and negative reinforcing properties of drugs of abuse. Injections of the specific CRF1 antagonist R278995/CRA0450 into the central amygdala attenuated elevations in brain reward thresholds, whereas injections into the basolateral amygdala showed no effect. Funded by NIDA Grant # DA023575

Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats

The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA.

Effects of insulin and leptin in the ventral tegmental area and arcuate hypothalamic nucleus on food intake and brain reward function in female rats

There is evidence for a role of insulin and leptin in food intake, but the effects of these adiposity signals on the brain reward system are not well understood. Furthermore, the effects of insulin and leptin on food intake in females are underinvestigated. These studies investigated the role of insulin and leptin in the ventral tegmental area (VTA) and the arcuate hypothalamic nucleus (Arc) on food intake and brain reward function in female rats. The intracranial self-stimulation procedure was used to assess the effects of insulin and leptin on the reward system. Elevations in brain reward thresholds are indicative of a decrease in brain reward function. The bilateral administration of leptin into the VTA (15–500 ng/side) or Arc (15–150 ng/side) decreased food intake for 72 h. The infusion of leptin into the VTA or Arc resulted in weight loss during the first 48 (VTA) or 24 h (Arc) after the infusions. The administration of insulin (0.005–5 mU/side) into the VTA or Arc decreased food intake for 24 h but did not affect body weights. The bilateral administration of low, but not high, doses of leptin (15 ng/side) or insulin (0.005 mU/side) into the VTA elevated brain reward thresholds. Neither insulin nor leptin in the Arc affected brain reward thresholds. These studies suggest that a small increase in leptin or insulin levels in the VTA leads to a decrease in brain reward function. A relatively large increase in insulin or leptin levels in the VTA or Arc decreases food intake.

Effects of prazosin, clonidine, and propranolol on the elevations in brain reward thresholds and somatic signs associated with nicotine withdrawal in rats

Tobacco withdrawal is characterized by a negative mood state and relatively mild somatic symptoms. Increased noradrenergic transmission has been reported to play an important role in opioid withdrawal, but little is known about the role of noradrenergic transmission in nicotine withdrawal. The aim of these experiments was to investigate the effects of prazosin, clonidine, and propranolol on the negative mood state and somatic signs associated with nicotine withdrawal in rats. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, the nicotinic acetylcholine receptor antagonist mecamylamine (3 mg/kg) elevated the brain reward thresholds of the nicotine-treated rats and did not affect those of the control rats. The α1-adrenergic receptor antagonist prazosin (0.0625 and 0.125 mg/kg) dose-dependently attenuated the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. The α2-adrenergic receptor agonist clonidine (10-40 μg/kg) and the nonselective β-adrenergic receptor antagonist propranolol (2.5-10 mg/kg) did not attenuate the elevations in brain reward thresholds associated with nicotine withdrawal. Furthermore, mecamylamine (2 mg/kg) induced more somatic signs in the nicotine-treated rats than in the control rats. Clonidine and propranolol, but not prazosin, decreased the total number of somatic signs associated with nicotine withdrawal. Blockade of α1-adrenergic receptors attenuates the deficit in brain reward function associated with nicotine withdrawal. Antagonism of β-adrenergic receptors or stimulation of α2-adrenergic receptors attenuates the somatic symptoms of nicotine withdrawal.

Somatostatin-28 modulates prepulse inhibition of the acoustic startle response, reward processes and spontaneous locomotor activity in rats

Somatostatins have been shown to be involved in the pathophysiology of motor and affective disorders, as well as psychiatric disorders, including schizophrenia. We hypothesized that in addition to motor function, somatostatin may be involved in somatosensory gating and reward processes that have been shown to be dysregulated in schizophrenia. Accordingly, we evaluated the effects of intracerebroventricular administration of somatostatin-28 on spontaneous locomotor and exploratory behavior measured in a behavioral pattern monitor, sensorimotor gating, prepulse inhibition (PPI) of the acoustic startle reflex, and brain reward function (measured in a discrete trial intracranial self-stimulation procedure) in rats. Somatostatin-28 decreased spontaneous locomotor activity during the first 10 min of a 60 min testing session with no apparent changes in the exploratory activity of rats. The highest somatostatin-28 dose (10 microg/5 microl/side) induced PPI deficits with no effect on the acoustic startle response or startle response habituation. The somatostatin-induced PPI deficit was partially reversed by administration of SRA-880, a selective somatostatin 1 (sst(1)) receptor antagonist. Somatostatin-28 also induced elevations in brain reward thresholds, reflecting an anhedonic-like state. The non-peptide sst(1) receptor antagonist SRA-880 had no effect on brain reward function under baseline conditions. Altogether these findings suggest that somatostatin-28 modulates PPI and brain reward function but does not have a robust effect on spontaneous exploratory activity. Thus, increases in somatostatin transmission may represent one of the neurochemical mechanisms underlying anhedonia, one of the negative symptoms of schizophrenia, and sensorimotor gating deficits associated with cognitive impairments in schizophrenia patients.

Preadolescent tobacco smoke exposure leads to acute nicotine dependence but does not affect the rewarding effects of nicotine or nicotine withdrawal in adulthood in rats

Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21–35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood.

Corticotropin-releasing factor mediates the dysphoria-like state associated with alcohol withdrawal in rats

This study investigated the role of CRF in the dysphoria-like state associated with alcohol withdrawal in rats. The intracranial self-stimulation procedure was used to assess brain reward thresholds. Cessation of chronic alcohol administration led to an elevation in brain reward thresholds in the alcohol dependent rats. The CRF receptor antagonist d-Phe CRF (12–41) dose-dependently prevented the elevations in brain reward thresholds associated with alcohol withdrawal. This indicates that the dysphoria associated with alcohol withdrawal is at least partly mediated by the activation of central CRF receptors.

Corticotropin-Releasing Factor-1 Receptor Activation Mediates Nicotine Withdrawal-Induced Deficit in Brain Reward Function and Stress-Induced Relapse

Tobacco addiction is a chronic brain disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that blockade of corticotropin-releasing factor (CRF) receptors with a nonspecific CRF1/CRF2 receptor antagonist prevents the deficit in brain reward function associated with nicotine withdrawal and stress-induced reinstatement of extinguished nicotine-seeking in rats. The aim of these studies was to investigate the role of CRF1 and CRF2 receptors in the deficit in brain reward function associated with precipitated nicotine withdrawal and stress-induced reinstatement of nicotine-seeking. The intracranial self-stimulation (ICSS) procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. Stress-induced reinstatement of nicotine-seeking was investigated in animals in which responding for intravenously infused nicotine was extinguished by substituting saline for nicotine. In the ICSS experiments, the nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-dependent rats but not those of the control rats. The CRF1 receptor antagonist R278995/CRA0450 but not the CRF2 receptor antagonist astressin-2B prevented the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. Furthermore, R278995/CRA0450 but not astressin-2B prevented stress-induced reinstatement of extinguished nicotine-seeking. Neither R278995/CRA0450 nor astressin-2B affected operant responding for chocolate-flavored food pellets. These studies indicate that CRF(1) receptors but not CRF(2) receptors play an important role in the anhedonic-state associated with acute nicotine withdrawal and stress-induced reinstatement of nicotine-seeking.

Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats.

Tobacco addiction is a chronic disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that an increased central release of corticotropin-releasing factor (CRF) at least partly mediates the deficit in brain reward function associated with nicotine withdrawal in rats. The aim of these studies was to investigate the role of CRF in the central nucleus of the amygdala (CeA), the lateral bed nucleus of the stria terminalis (BNST), and the nucleus accumbens shell (Nacc shell) in the deficit in brain reward function associated with precipitated nicotine withdrawal. The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all experiments, the nicotinic receptor antagonist mecamylamine (3 mg/kg) elevated the brain reward thresholds of the nicotine dependent rats (9 mg/kg/day of nicotine salt) and did not affect the brain reward thresholds of the saline-treated control rats. The administration of the nonspecific CRF1/2 receptor antagonist D-Phe CRF(12–41) into the CeA and the Nacc shell prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine dependent rats. Blockade of CRF1/2 receptors in the lateral BNST did not prevent the mecamylamine-induced elevations in brain reward thresholds in the nicotine dependent rats. These studies indicate that the negative emotional state associated with precipitated nicotine withdrawal is at least partly mediated by an increased release of CRF in the CeA and Nacc shell.

Effects of fentanyl dose and exposure duration on the affective and somatic signs of fentanyl withdrawal in rats

Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of chronic pain. The aim of the present study was to investigate the effect of the dose of fentanyl and the exposure duration on the affective and somatic signs of fentanyl withdrawal in rats. Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function and somatic signs were recorded from a checklist of opioid abstinence signs. The opioid receptor antagonist naloxone elevated the brain reward thresholds of the rats chronically treated with high doses of fentanyl (0.3 and 0.6 mg/kg/day), but not those of rats treated with low doses of fentanyl (0.006 and 0.06 mg/kg/day). Fentanyl had a dose-dependent effect on the naloxone-induced elevations in brain reward thresholds. On a similar note, the discontinuation of the administration of high doses of fentanyl was associated with elevations in brain reward thresholds and the discontinuation of the administration of low doses of fentanyl did not lead to an elevation in brain reward thresholds. The results also demonstrated that the duration of fentanyl administration does not affect naloxone-induced elevation in brain reward thresholds. In contrast, the somatic withdrawal syndrome gradually developed over time; maximum somatic signs were observed 120 h after pump implantation. These studies suggest that the magnitude and duration of the negative affective signs of fentanyl withdrawal depend on the dose of fentanyl administered and not on the duration of fentanyl administration.

Effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats.

Tobacco addiction is a chronic disorder that is characterized by dysphoria upon smoking cessation and relapse after periods of abstinence. Previous research suggests that Neuropeptide Y (NPY) and Y1 receptor agonists attenuate negative affective states and somatic withdrawal signs. The aim of the present experiments was to investigate the effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats. The intracranial self-stimulation procedure was used to assess the effects of nicotine withdrawal on brain reward function as this procedure can provide a quantitative measure of emotional states in rodents. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In the first experiment, NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Similar to NPY, [D-His(26)]-NPY did not prevent the elevations in brain reward thresholds associated with precipitated nicotine withdrawal and elevated the brain reward thresholds of the saline-treated control rats. Neither NPY nor [D-His(26)]-NPY affected the response latencies. In a separate experiment, it was demonstrated that the specific Y1 receptor antagonist BIBP-3226 prevented the NPY-induced elevations in brain reward thresholds. NPY attenuated the overall somatic signs associated with precipitated nicotine withdrawal. [D-His(26)]-NPY did not affect the overall somatic signs associated with precipitated nicotine withdrawal, but decreased the number of abdominal constrictions. Both NPY and [D-His(26)]-NPY attenuated the overall somatic signs associated with spontaneous nicotine withdrawal. These findings indicate that NPY and [D-His(26)]-NPY attenuate somatic nicotine withdrawal signs, but do not prevent the deficit in brain reward function associated with precipitated nicotine withdrawal. In addition, NPY decreases the sensitivity to rewarding electrical stimuli via an Y1 dependent mechanism.

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Pretreatment with a single moderate dose of morphine (e.g. 5.6-10 mg/kg) 4-24 hr prior to challenge with an opioid antagonist such as naloxone results in reliable expression of behaviors that resemble aversive or emotional consequences of withdrawal from chronic opioid exposure, including suppression of operant responding, elevations in brain reward thresholds, and conditioned place aversion. Repeated daily or weekly treatment with these same morphine doses results in a progressive increase in naloxone potency to elicit these withdrawal signs. The current study sought to determine whether increased anxiety-like behavior during withdrawal from chronic opioid dependence is also seen after acute morphine exposure, and progresses with repeated intermittent treatment. Male Wistar rats were handled and injected with either vehicle or morphine for 4 consecutive days. Three injection regimens were employed: Morphine Naive (4 vehicle injections), Acute Morphine (3 vehicle injections, 4th injection 5.6 or 10 mg/kg morphine), or Repeat Morphine (all 4 injections with 5.6 or 10 mg/kg morphine). Acute pretreatment with 5.6 mg/kg or 10 mg/kg morphine resulted in time-dependent increases in exploration of the open arms of the plus maze in naloxone-naive rats when tested at 2, 4 or 8 hr after the final pretreatment injection, with the effects at the higher dose appearing later (4 hr) than after the lower dose (2 hr). This pattern of results, in combination with a separate study which confirmed a significant anxiolytic-like effect of a low dose of morphine (0.56 mg/kg) administered 15 min prior to test, suggested that low residual morphine levels remaining in plasma at 2-4 hr after 5.6 and 10 mg/kg morphine may be sufficient to elicit anxiolytic-like effects. Repeat treatment with either dose of morphine resulted in a further increase in the magnitude and duration of this anxiolytic-like effect. These effects had dissipated by 8 hr post-morphine, and therefore precipitation of withdrawal by one of several doses of naloxone (0.10-3.3 mg/kg) was assessed in separate cohorts of rats 8 hr after the final pretreatment under Morphine Naïve, Acute Morphine, or Repeat Morphine conditions. Naloxone resulted in a significant dose-dependent expression of anxiety-like behavior with no effects on general activity after Acute Morphine pretreatment at either 5.6 or 10 mg/kg morphine. A further significant shift in naloxone potency was observed after Repeat Morphine pretreatment at the 10 mg/kg but not the 5.6 mg/kg dose. Thus, anxiety-like behavior is a prominent feature of the negative emotional consequences of naloxone-precipitated withdrawal from acute opioid dependence.

Dose‐ and Time‐Dependent Expression of Anxiety‐Like Behavior in the Elevated Plus‐Maze During Withdrawal From Acute and Repeated Intermittent Ethanol Intoxication in Rats

Withdrawal from acute bolus intraperitoneal (IP) injection of high doses of ethanol elicits anxiety-like behavior (e.g. Doremus et al., 2003; Gauvin et al., 1989, 1992) and conditioned place aversion (Morse et al., 2000). More recently we demonstrated that withdrawal from a single moderate dose of ethanol (2.0 g/kg) is accompanied by elevations in brain reward thresholds, and that repeated intermittent treatment with this dose results in a significant potentiation of reward deficit (Schulteis and Liu, 2006). In the current study, the time- and dose-dependent emergence of anxiety-like behavior was measured in the elevated plus-maze at various times (3 to 24 hours) after acute or 3 daily IP injections of ethanol (1.0, 2.0, or 3.0 g/kg). Rats receiving daily handling for 2 days, and a single anxiety opportunity to explore the maze on a third day were divided into 1 of several treatment protocols: (1) NAIVE conditions: vehicle IP on all 3 days; (2) ACUTE conditions: vehicle on the first 2 days, ethanol on the third day; or (3) REPEAT conditions: ethanol on all 3 days. ACUTE ethanol elicited reduced exploration of the open arms of the elevated plus-maze in a dose- and time-dependent fashion: 1.0 g/kg failed to elicit any significant effects, whereas 2.0 and 3.0 g/kg ethanol elicited a significant anxiety-like response at 6 hours and 9 to 12 hours postinjection, respectively. REPEAT treatment was still without effect at any time point tested following 1.0 g/kg ethanol, but extended the time course of anxiety-like behavior after treatment with either 2.0 or 3.0 g/kg doses. REPEAT treatment with 2.0 and 3.0 g/kg ethanol also produced significant hypoactivity in the maze at some time points postinjection. Withdrawal from a single exposure to ethanol produces transient but significant anxiety-like behavior, and repeated intermittent bouts of intoxication result in a significant extension of the duration of effect. The rapid emergence and progression of negative emotional signs of withdrawal may be a significant factor in determining susceptibility to transition from casual drinking to loss of control and escalating patterns of consumption that result in alcoholism.

Chronic bupropion attenuated the anhedonic component of nicotine withdrawal in rats via inhibition of dopamine reuptake in the nucleus accumbens shell

Bupropion, a dopamine reuptake inhibitor, is an effective therapy for smoking cessation, but the behavioral and neurochemical mechanisms mediating its antismoking properties are relatively unknown. To explore the hypothesis that bupropion ameliorates nicotine withdrawal partly by a dopamine-dependent mechanism, we investigated the effects of chronic bupropion on potassium-stimulated dopamine overflow in the nucleus accumbens shell in nicotine-withdrawing rats. We also assessed the effects of chronic bupropion on behavioral aspects of nicotine withdrawal measured by elevations in brain reward thresholds and somatic signs of withdrawal. Rats were treated with nicotine or saline for 7 days and then coadministration of bupropion or saline was initiated. After 14 days of coadministration of bupropion/saline and nicotine/saline, nicotine/saline administration was terminated, whereas bupropion/saline administration continued. These conditions mimic bupropion administration in human smokers. Cessation of nicotine administration in non-bupropion-treated rats elevated reward thresholds reflecting a reward deficit, increased somatic signs and diminished potassium-evoked dopamine overflow in the nucleus accumbens shell. Chronic bupropion lowered reward thresholds and increased potassium-evoked dopamine release regardless of previous nicotine exposure, possibly by inhibition of dopamine reuptake, and thus attenuated the anhedonic and neurochemical effects of nicotine withdrawal. Chronic bupropion blocked withdrawal-associated increased somatic signs. Finally, acute experimenter-administered nicotine enhanced brain reward function equally in all groups, indicating that bupropion does not alter the reward-facilitating effects of experimenter-administered nicotine. In conclusion, the bupropion-induced increase in extracellular dopamine in the nucleus accumbens shell may ameliorate the anhedonia associated with nicotine withdrawal, which in turn may facilitate smoking cessation.

Antagonism of CRF Receptors Prevents the Deficit in Brain Reward Function Associated with Precipitated Nicotine Withdrawal in Rats

Nicotine dependence is a chronic mental illness that is characterized by a negative affective state upon tobacco smoking cessation and relapse after periods of abstinence. It has been hypothesized that cessation of nicotine administration results in the activation of brain corticotropin-releasing factor (CRF) systems that leads to the negative affective state of withdrawal. The aim of our experiments was to investigate the role of brain CRF systems in the deficit in brain reward function associated with the cessation of nicotine administration in rats. The intracranial self-stimulation procedure was used to assess to negative affective aspects of nicotine withdrawal as this procedure can provide a quantitative measure of emotional distress in rats. In the first experiment, mecamylamine induced a dose-dependent elevation in brain reward thresholds in nicotine-treated rats. In the follow-up experiment, it was shown that pretreatment with the corticotropin-receptor antagonist D-Phe CRF((12-41)) prevents the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. In the third experiment, the effect of D-Phe CRF((12-41)) on the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal was investigated. Administration of D-Phe CRF((12-41)) 6 h after the explantation of the nicotine pumps, did not result in a lowering of the brain reward thresholds. These findings indicate that antagonism of CRF receptors prevents, but not reverses, the deficit in brain associated with nicotine withdrawal. These data provide support for the hypothesis that a hyperactivity of brain CRF systems may at least partly mediate the initiation of the negative affective aspects of nicotine withdrawal.

Decreased sensitivity to the effects of dopamine D1-like, but not D2-like, receptor antagonism in the posterior hypothalamic region/anterior ventral tegmental area on brain reward function during chronic exposure to nicotine in rats

Chronic administration of nicotine induces adaptations in central nervous system function to counteract nicotine's acute effects. When nicotine administration ceases, these adaptations remain unopposed and may lead to drug withdrawal. The present studies were conducted to assess the effects of chronic nicotine administration on dopamine D1- and D2-like receptor activity in the posterior hypothalamus/anterior ventral tegmental area (VTA). An intracranial self-stimulation discrete trial procedure that provides current intensity thresholds was used to provide a measure of brain reward function in rats. Previous studies showed that systemic administration of dopamine D1- or D2-like receptor antagonists induced elevations in brain reward thresholds in drug-free rats, indicative of a decrease in brain reward function. We show here that injections of the D1-like receptor antagonist SCH 23390 (1–4 μg total bilateral dose) into the posterior hypothalamus/anterior VTA differentially elevated brain reward thresholds in rats chronically treated with nicotine (9 mg/kg/day, salt) versus saline-treated rats. The nicotine-treated rats were less sensitive to the threshold elevating effects of D1-like receptor antagonism. By contrast, the D2-like receptor antagonist eticlopride (1–4 μg total bilateral dose) injected into the posterior hypothalamus/anterior VTA significantly elevated brain reward thresholds in saline- and nicotine-treated rats. No differential effect of eticlopride on brain reward thresholds in saline- and nicotine-treated rats was observed. Decreased sensitivity to D1-like receptor antagonism in the posterior hypothalamus/anterior VTA may partly mediate the development of tolerance to the reinforcing effects of nicotine and the manifestation of negative affective signs associated with cessation of nicotine administration.

Adaptations in cholinergic transmission in the ventral tegmental area associated with the affective signs of nicotine withdrawal in rats

Chronic administration of nicotine induces adaptations in the brain reward circuit to counteract the acute drug effects; when nicotine administration ceases, these adaptations remain unopposed and lead to drug withdrawal. The present studies were conducted to assess the effects of chronic nicotine administration on nicotinic acetylcholine receptor (nAChR) activity in the ventral tegmental area (VTA) and the nucleus accumbens (Nacc) shell. A discrete-trial intracranial self-stimulation procedure that provides current-intensity thresholds as measures of brain reward function was used in rats. Previous studies have shown that withdrawal from nicotine-induced elevations in brain reward thresholds that are indicative of a decrease in brain reward function. We show here that injections of the nAChR antagonist dihydro-β-erythroidine (DHβE; 0.6–20 μg total bilateral dose) into the VTA, but not outside the VTA, resulted in significant elevations in brain reward thresholds in nicotine dependent rats (9 mg/kg/day nicotine hydrogen tartrate) while having no effect in saline-treated controls. By contrast, DHβE (0.6–20 μg total bilateral dose) injected into the Nacc shell had no effect on brain reward thresholds of nicotine- or saline-treated rats. The adaptations in cholinergic transmission in the VTA are likely to mediate, at least partly, the affective signs of nicotine withdrawal in humans.

Withdrawal from chronic amphetamine induces Depressive-Like behavioral effects in rodents

Background Amphetamine withdrawal and major depression share many behavioral commonalties in humans. Therefore, the examination of the behavioral effects of amphetamine withdrawal in rodents may provide insights into the neurobiological mechanisms underlying both disorders and aid in the development of animal models of depression that are sensitive to antidepressant agents. Methods We examined the behavioral effects of withdrawal from chronic continuous infusion of amphetamine (via minipump) in three behavioral paradigms: the intracranial self-stimulation (ICSS) procedure in rats, the modified forced swim test in rats, and the tail suspension test in mice. Results Amphetamine withdrawal resulted in a prolonged (5 day) deficit in brain reward function as assessed by elevations in ICSS thresholds. Using a similar regimen of amphetamine administration, we examined the behavioral effects of withdrawal in a modified rat forced swim test. Animals that were treated with the highest dose of amphetamine (10 mg/kg/day) exhibited increased climbing behavior and decreased immobility 24 hours after withdrawal; by the 48-hour testing time point, this effect had dissipated. In contrast, animals that had been pretreated with 5 mg/kg/day amphetamine exhibited a pronounced increase in immobility indicative of an increase in “depressive-like” behavior, coupled with decreases in swimming and climbing. In the mouse tail suspension test, both regimens of amphetamine pretreatment induced increases in immobility scores, also indicative of “depressive-like” behavior, 24 hours following withdrawal. Conclusions Withdrawal from chronic amphetamine administration results in behavioral changes that may be analogous to some aspects of depression in humans, such as reward deficits (i.e., elevations in brain reward thresholds) and behaviors opposite to those seen after treatment with antidepressant drugs, such as decreased immobility in the forced swim test and the tail suspension test.