Double-dissociation of D1 and opioid receptor antagonism effects on the acquisition of sucrose-conditioned flavor preferences in BALB/c and SWR mice

Sugar appetite is influenced by unlearned attractions to sweet taste and learned responses to sugars' taste and post-ingestive actions. In rats, sugar-conditioned flavor preferences (CFP) are attenuated by dopamine D1 (SCH23390: SCH), but not by opioid (naltrexone: NTX), receptor antagonism. Sucrose-CFP occurs in BALB/c and SWR inbred mice that differ in their suppressive effects of SCH and NTX on sucrose intake. The present study examined whether SCH and NTX altered expression of previously learned sucrose-CFP and acquisition (learning) of sucrose-CFP in these strains. In Experiment 1, food-restricted mice were trained (10 one-bottle sessions) to drink a more-preferred flavored (e.g., cherry) 16% sucrose solution (CS +/Sucrose) on odd-numbered days, and a less-preferred flavored (e.g., grape) 0.05% saccharin solution (CS −/Saccharin) on even-numbered days. Two-bottle tests with the flavors mixed in 0.2% saccharin occurred 30 min following vehicle (Veh), SCH (50-800 nmol/kg) or NTX (1-5 mg/kg) assessing preference expression. CS + preference expression in BALB/c and SWR mice following Veh were significantly reduced by SCH and NTX. In Experiment 2, separate groups of BALB/c and SWR mice received Veh, SCH (50 nmol/kg) or NTX (1 mg/kg) injections 30 min prior to daily one-bottle training sessions with the CS +/Sucrose and CS −/Saccharin solutions assessing preference acquisition. Subsequent two-bottle tests with the CS + vs. CS − solutions were conducted without injections. CS +/Sucrose training intakes were reduced by SCH in both strains and by NTX in BALB/c mice. In the initial two-bottle test, sucrose-CFP acquisition was significantly reduced in BALB NTX (54%), but not in BALB SCH (77%) groups relative to the BALB Veh group (85%). In contrast, sucrose-CFP acquisition was significantly reduced in SWR SCH (61%), but not in SWR NTX (83%) groups relative to the SWR Veh group (86%). DA D1 and opioid receptor signaling modulate acquisition and/or expression of sucrose-CFP in mice with significant strain differences observed.     

Naltrexone fails to block the acquisition or expression of a flavor preference conditioned by intragastric carbohydrate infusions

The effects of naltrexone on the expression and acquisition of flavor preferences conditioned by the postingestive actions of carbohydrates were investigated. Food-restricted rats (Experiment 1) were given one-bottle training with one flavored saccharin solution (CS+) paired with intragastric (IG) infusions of 16% sucrose, and another flavored saccharin solution (CS-) paired with water infusions. In two-bottle tests CS+ was preferred to CS-, and naltrexone (1.0-5.0 mg/kg) reduced total intake but not CS+ preference. In Experiment 2 food-restricted rats that received naltrexone (0.1 or 1.0 mg/kg; NTX group) throughout one-bottle training consumed less CS+ and CS- than did saline-treated control rats. Yet, the NTX and control groups displayed similar CS+ preferences during two-bottle tests when treated with saline or naltrexone (0.1-5.0 mg/kg). In Experiment 3, rats were trained to accept more CS+ than CS- in one-bottle tests. Naltrexone (0.1-2.5 mg/kg) reduced the one-bottle intakes of both solutions, and the rats continued to consume more CS+ than CS-. We conclude that the opioid system modulates the consumption of flavored solutions, but is not critically involved in the acquisition or expression of flavor preferences conditioned by IG carbohydrate.     

Flavor preferences conditioned by intragastric ethanol with limited access training

In a prior study, ad libitum fed rats learned a strong preference (90%) for a flavored saccharin solution (conditioned stimulus, CS+) paired with concurrent intragastric (IG) infusions of 5% ethanol over another flavor (CS-) paired with water infusions in unlimited access sessions (22 h/day). The present study expanded the investigation of ethanol-conditioned preferences to limited access sessions (30 min/day). Experiment 1 revealed that ad lib or food-restricted rats failed to develop a CS+ preference using the same CS solutions (0.05% Kool-Aid+0.2% saccharin) and IG infusions that were effective with long-term training. Experiments 2 and 3 mimicked the parameters from a report of successful ethanol conditioning in deprived rats: ethanol (0.5 g/kg) or water was infused intragastrically 5 min before access to sweetened CS solutions flavored with HCl or NaCl. Rats learned to prefer the ethanol-paired CS+ when the flavors were mixed with 5% sucrose but not when mixed with 0.2% saccharin. Experiment 4 revealed that 5% sucrose solutions flavored with 0.25% Kool Aid also supported flavor preference conditioning by IG ethanol (0.5 g/kg). CS+ preferences were obtained in rats trained with ethanol infused 5 min before or concurrent with CS+ intake, but not in rats trained with ethanol infused 30 min before CS+ intake. These data confirm that flavor preferences can be conditioned by IG ethanol using a limited access procedure. However, in contrast to 22 h/day training, 30 min/day training requires more intense CS flavors and a nutritive sweetener. The preference reinforcing actions of ethanol may develop slowly and are thus most effective with long training sessions or when intense CS flavors are used in short training sessions.     

Opioid mediation of starch and sugar preference in the rat

In our prior studies, administration of the opioid receptor antagonist naltrexone did not block conditioned preferences for a flavor paired with a preferred sugar solution over a flavor paired with saccharin. This may be because both training solutions were sweet, and their attractiveness was reduced by naltrexone. The present study compared the effects of naltrexone on preferences for flavors paired with sugar or starch drinks that have distinctive tastes to rats. Experiment 1 assessed naltrexone's effect on the preference for unflavored 8% cornstarch and 8% sucrose aqueous solutions/suspensions. The food-restricted rats displayed a significant sucrose preference which increased following systemic treatment with naltrexone (1 or 3 mg/kg) even though total intake of both solutions declined. In Experiment 2, rats were trained to drink flavored (cherry or grape) starch and sucrose solutions in separate one-bottle sessions. In a two-bottle choice test with both flavors presented in a sucrose-starch mixture, the rats significantly preferred the starch-paired flavor. Naltrexone treatment blocked the expression of this starch-conditioned preference. In Experiment 3, rats were treated with saline or naltrexone throughout one-bottle training with flavored sucrose and starch solutions. In a subsequent choice test, both the saline and naltrexone groups displayed significant preferences for the starch-paired flavor, indicating that opioid antagonism failed to alter the acquisition of this conditioned preference. In summary, novel outcomes of this study included the increased rather than the predicted decrease in sucrose preference produced by naltrexone. Also, starch unexpectedly conditioned the stronger flavor preference, although this can be explained by the differential post-oral reinforcing actions of starch and sucrose, and naltrexone blocked the expression, but not the acquisition, of this preference. These findings suggest that the reward value of starch in liquid form is more dependent upon opioid signaling than is that of sugar.     

Flavor quality and ethanol concentration affect ethanol-conditioned flavor preferences

A previous report showed that outbred rats acquired preferences for a sweetened conditioned stimulus (CS) flavor paired with intragastric ethanol. To evaluate the role of sweet taste in ethanol conditioning, this study compared training with sweetened and unsweetened flavors. In Experiment 1, nondeprived rats were trained to drink one flavored solution (CS+, e.g., grape) paired with intragastric infusion of 5% ethanol and another (CS-, e.g., cherry) paired with intragastric water on alternate days. The volume of ethanol solution infused was matched to the volume of flavored solution the rats consumed. The sweet group's flavors initially contained 0.2% saccharin, reduced to 0.1%, 0.05%, and 0% over days; the plain group's flavors were unsweetened. The sweet group drank more and self-infused more ethanol during training and its preference for the CS+ over the CS- (without saccharin) exceeded that of the plain group (75% versus 62%). Experiment 2 equated total ethanol intake in rats trained with two combinations of flavor quality and ethanol concentration. The Sweet5 group drank flavors with 0.2% saccharin throughout training and tests and received 5% ethanol when they drank CS+, while the Plain10 group drank unsweetened flavors and the CS+ was paired with 10% ethanol. Despite equal daily ethanol doses, the Sweet5 group strongly preferred the CS+ (89%) while the Plain10 group avoided it (31%). The two groups continued to show opposite CS+ preference profiles even when both were tested with sweet CS flavors and 10% ethanol infusions. Thus, sweet taste contributes to the development of ethanol-conditioned flavor preferences, and this effect is not explained by a simple enhancement of ethanol intake.     

Pharmacology of flavor preference conditioning in sham-feeding rats: effects of dopamine receptor antagonists

Opioid and dopamine systems are both implicated in the response to sweet solutions. Our laboratory previously reported that the opioid antagonist, naltrexone, reduced the intake of sweet solutions, yet had little or no effect on sucrose-conditioned flavor preferences in sham-feeding rats. The present study examined the role of dopamine D(1) and D(2) receptors in the expression of flavor preferences conditioned by the sweet taste of sucrose. All sessions were conducted under sham-feeding conditions to minimize postingestive influences. Training was accomplished by adding a novel flavor (CS+) to a 16% sucrose solution, a different flavor (CS-) to a less-preferred 0.2% saccharin solution in alternating, one-bottle sessions. Preferences were assessed in two-bottle tests with the CS+ and CS- flavors presented in mixed sucrose (8%)-saccharin (0.1%) solutions following systemic doses of 0, 50, 200, 400, or 800 nmol/kg of the D(2) antagonist, raclopride (Experiment 1) or the D(1) antagonist, SCH23390 (Experiment 2) under either food-restricted or unrestricted conditions. Rats significantly preferred the CS+ solutions in vehicle tests, and displayed equipotent and dose-dependent reductions in total intake and CS+ preference following either D(1) or D(2) receptor antagonism. Similar results were obtained with SCH23390 and raclopride in Experiment 3 conducted with water-restricted rats. These data indicate that dopaminergic D(1) and D(2) receptors play pivotal and functionally equivalent roles in the expression of flavor preferences conditioned by the sweet taste of sucrose.     

Role of systemic endocannabinoid CB-1 receptor antagonism in the acquisition and expression of fructose-conditioned flavor-flavor preferences in rats

Rats learn to prefer a flavor mixed into a fructose-saccharin solution over a different flavor mixed into a saccharin-only solution which is considered to be a form of flavor-flavor conditioning. Fructose-conditioned flavor preferences are impaired by systemic dopamine D1 and to a lesser degree, D2 receptor antagonism as well as by NMDA, but not opioid, receptor antagonism. Given the emerging role of the endocannabinoid system in mediating hedonically-driven food intake, the present study examined whether systemic administration of the inverse CB-1 receptor agonist, AM-251 would alter fructose-conditioned flavor preferences. In Experiment 1, food-restricted rats were trained over 10 sessions (30 min/day) to drink a fructose-saccharin solution mixed with one flavor (CS+/Fs) and a less-preferred saccharin-only solution mixed with another flavor (CS-/s). Subsequent two-bottle tests with the two flavors in saccharin (CS+/s, CS-/s) occurred 15 min following counterbalanced pairs of AM-251 doses of 0, 0.1, 1 or 3 mg/kg. Preference for CS+/s over CS-/s following vehicle treatment (74%) was significantly reduced by the 0.1 (67%) and 1 (65%) AM-251 doses, whereas CS+/s, but not CS-/s intake was significantly reduced by the 1 and 3 mg/kg AM-251 doses. In Experiment 2, rats received systemic injections of AM-251 (1 mg/kg) or vehicle prior to the 10 CS+/Fs and CS-/s training sessions. In subsequent two-bottle tests (drug-free) the AM-251 and control groups displayed similar preferences for the CS+ flavor (66% vs. 69%). Experiment 3 demonstrated that AM-251 significantly decreased chow intake (24 h), and 1-h intakes of fructose-saccharin and saccharin-only solutions in ad libitum-fed rats. These data indicate that functional CB-1 receptor antagonism significantly reduces the expression, but not the acquisition of fructose-conditioned flavor-flavor preferences. The endogenous endocannabinoid system is therefore implicated in the maintenance of this form of learned flavor preferences.     

Naltrexone does not prevent acquisition or expression of flavor preferences conditioned by fructose in rats

The effects of the general opioid antagonist, naltrexone, on the acquisition and expression of flavor preferences conditioned by the sweet taste of fructose were examined. Food-restricted rats were trained over eight daily alternating one-bottle sessions (2 h) to drink an 8% fructose solution containing one novel flavor (CS+/F) and a less preferred 0.2% saccharin solution containing a different flavor (CS-/S). Four groups of rats were treated daily with either saline (control group) or naltrexone doses of 0.1, 1.0, or 5.0 mg/kg during training. Preferences were assessed in two-bottle tests with the CS+/S and CS-/S flavors presented in 0.2% saccharin solutions following saline injections. Naltrexone dose-dependently reduced fructose and saccharin intakes during training, confirming the drug's well-known suppressive effect on the intake of sweet solutions. Despite their reduced training intakes, the naltrexone groups displayed preferences for the CS+/S over the CS-/S (72-86%) that were similar to that of the control group (78%). The effect of naltrexone on the expression of the CS+/S flavor preference was evaluated by treating control rats with naltrexone (0.1-5 mg/kg) prior to CS+/S vs. CS-/S choice tests. The drug doses produced a dose-dependent reduction in CS+/S intake but did not significantly attenuate the CS+/S preference. These data are consistent with the relative inability of naltrexone to reduce flavor-flavor conditioning by sucrose in sham-feeding rats and flavor-nutrient conditioning in rats receiving intragastric sucrose infusions. In contrast, dopamine antagonists reduce both sucrose- and fructose-conditioned flavor preferences, which indicates the sensitivity of these conditioning paradigms to neuropharmacological manipulations. These data indicate that the endogenous opioid system, unlike the dopamine system, does not play a major role in either the acquisition or expression of flavor preference learning as measured in two-bottle choice tests.     

Role of D(1) and D(2) dopamine receptors in the acquisition and expression of flavor-preference conditioning in sham-feeding rats

The present study examined the effects of D(1) and D(2) antagonists on flavor-preference conditioning by the sweet taste of sucrose. All sessions were conducted under sham-feeding conditions to minimize post-ingestive influences. The rats were trained in alternating, one-bottle sessions to sham-feed a 16% sucrose solution containing one novel flavor (CS+) and a less-preferred 0.2% saccharin solution containing a different flavor (CS-). Three groups of food-restricted rats were treated with either vehicle (control group), the D(1) antagonist, SCH23390 (200 nmol/kg), or the D(2) antagonist, raclopride (200 nmol/kg) during one-bottle training. A fourth group (yoked group) was vehicle-treated and its training intakes were matched to that of the D(1) and D(2) drug groups. Preferences were assessed in two-bottle tests with the CS+ and CS- flavors presented in mixed 8% sucrose+0.1% saccharin solutions following systemic doses of 0, 200, or 800 nmol/kg of either the D(1) or D(2) antagonists. All groups significantly preferred the CS+ flavor in vehicle tests, although the preferences were weaker in the D(1), D(2), and yoked groups compared to the control group. All groups selectively reduced their CS+ intakes when treated with either D(1) or D(2) antagonists during two-bottle testing, and the CS+ preference was blocked at the higher doses. These data show that D(1) and D(2) receptor antagonists block the expression of a sucrose-conditioned preference, but produces substantially lesser effects upon the acquisition of this form of flavor conditioning.     

Flavor preferences conditioned by intragastric infusion of ethanol in rats

Sprague-Dawley rats were trained 22 h/day to associate a flavored solution [conditioned stimulus (CS+)] with intragastric infusions of 6% ethanol and another flavored solution (CS-) with water infusions. The infusions were matched to the CS intakes so that the animals determined their timing and size. In Phase 1, chow and water were available ad libitum, and both CS flavors were initially sweetened with saccharin that was then faded out. The rats displayed a preference for the CS+ over the CS- under both reinforced and extinction conditions. When food-restricted in Phase 2, the rats displayed an increased preference for the CS+. In Phase 3, the rats were fed ad libitum chow and given preference tests with the CS+ paired with ethanol infusions of increasing concentration (6%, 12%, 18%, and 24%). Their preference for the CS+ over the CS- persisted, and self-administered ethanol dose increased with concentration to 5 g/kg/day. The ethanol-based conditioned flavor preference resembled those conditioned by carbohydrate and fat infusions, suggesting that at least some of reinforcing ability of ethanol may be related to its postingestive nutritive effects.     

D1 but not D2 dopamine receptor antagonism blocks the acquisition of a flavor preference conditioned by intragastric carbohydrate infusions

The effects of dopamine D1 (SCH23390) and D2 (raclopride) receptor antagonists on the acquisition and expressions of flavor preferences conditioned by the postingestive actions of sucrose were investigated. Food-restricted rats were trained in one-bottle sessions to associate one flavored saccharin solution (CS+) with intragastric (i.g.) infusions of 16% sucrose, and another flavored saccharin solution (CS-) with water infusions. Flavor preferences were then measured in two-bottle tests. In Experiment 1A, rats that received the D2 antagonist (raclopride, 200 nmol/kg; RAC group) throughout training consumed less CS+ and CS- than did saline-treated Control rats; a saline-treated Yoked group had its intake limited to that of the RAC group. All three groups displayed CS+ preferences during two-bottle tests when treated with saline or raclopride, except at doses that greatly suppressed intake. Experiment 1B obtained similar results with rats treated with 400 nmol/kg raclopride throughout training. In Experiment 2, rats that received the D1 antagonist (SCH23390, 200 nmol/kg; SCH group) throughout training consumed less CS+ and CS- than did saline-treated Control rats; a saline-treated Yoked group had its intake limited to that of the SCH group. Unlike the Control and Yoked groups, the SCH group failed to prefer the CS+ to the CS- in two bottle tests. SCH23390 treatment during two-bottle testing did not block CS+ preference in the Control or Yoked groups, except at doses that greatly suppressed intake. We conclude that D1, but not D2, dopamine receptors are critically involved in the acquisition of a sucrose-conditioned flavor preference, and both receptor subtypes have a more limited role in the expression of this preference.     

Pharmacology of flavor preference conditioning in sham-feeding rats: effects of naltrexone.

Relatively little is known about the neurochemical and pharmacological mechanisms involved in flavor preference learning. The present study examined the ability of the opioid antagonist, naltrexone to alter the acquisition and expression of flavor preferences conditioned by the sweet taste of sucrose. This was accomplished by adding a novel flavor (the CS+) to a sucrose solution, and a different flavor (the CS-) to a less-preferred saccharin solution. Rats were trained to drink these solutions with an open gastric fistula (sham-feeding), which minimized postingestive actions. Food-restricted (Experiments 1 and 2A) and ad lib-fed (Experiment 2B) rats were given either limited (Experiment 1) or unlimited (Experiment 2) access to the CS+ and CS- solutions during one-bottle training. Preferences were assessed in two-bottle tests (with the CS+ and CS- flavors presented in mixed sucrose-saccharin solutions) following vehicle or naltrexone (0.1-10 mg/kg, SC) treatment. The rats displayed significant CS+ preferences following vehicle, particularly after unlimited access training. In four of five experiments, naltrexone significantly reduced total intakes during the two-bottle, sham-feeding tests. Except for one instance, however, the drug failed to block the preference for the CS+ flavor over the CS- flavor. The effects of naltrexone (0.1 mg/kg) on the acquisition of flavor preferences were studied in sham-feeding rats under limited (Experiment 3A) and unlimited (Experiment 3B) training access conditions. Rats treated with naltrexone during training displayed similar CS+ preferences as did saline-treated rats, even though they consumed less CS+ during training. The naltrexone-trained rats also displayed smaller reductions in total or CS+ intakes than did saline-trained rats when all rats were treated with a 2.5 mg/kg dose of naltrexone during testing. As in previous studies, these results show that naltrexone significantly reduces the intake of sweet solutions, yet it has little or no effect on the acquisition or expression of flavor preferences conditioned by sucrose in sham-feeding rats.     

SB-334867-A, a selective orexin-1 receptor antagonist, enhances taste aversion learning and blocks taste preference learning in rats

Lateral hypothalamus (LH) has been proposed as a possible center for the anatomical convergence of gustatory and postingestive information relevant to taste aversion learning (TAL) and conditioned flavor preference (CFP). Orexin, a neuropeptide that mainly originates in neurons in lateral hypothalamic areas, was recently related to learning and memory processes. The present study was designed to analyze a possible relationship between the orexinergic system and taste learning. We studied the effect of intracerebroventricular administration of three doses (3, 6, and 12 μg/1 μl) of the selective orexin-1 receptor antagonist SB-334867-A on the acquisition of TAL induced by a single administration of LiCl. Infusion of SB-334867-A did not block this learning and appeared to enhance TAL in a two-bottle test. However, SB-334867-A (6 μg/1 μl) blocked taste preference learning when a flavor associated with saccharin (CS+) was offered on alternate days against a different flavor without saccharin (CS−), during three acquisition sessions. These results offer evidence of a relationship between the orexinergic system and taste learning; they tentatively suggest the possibility that endogenous orexin and gustatory and postingestive (visceral and oral) signals converge in brain areas relevant to the acquisition of taste learning.     

Flavor preference conditioning by oral self-administration of ethanol

 Oral self-administration and operant tasks have been used successfully to confirm ethanol′s positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS–). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol’s efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS– in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol’s rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol’s nutrient and pharmacological effects both contributed to the development of conditioned flavor preference. Received: 15 February 1997 / Final version: 11 June 1997     

伏隔核胆碱能神经元在线索诱导的海洛因复吸中的作用

目的 比较不同的二醋吗啡(海洛因)戒断时间对于环境线索(CC)或条件性线索(CS)诱导的大鼠复吸行为的影响,并探讨伏隔核胆碱能神经元可能的调节作用。方法 SD大鼠进行海洛因自身给药训练,每天4 h, 连续14 d,建立海洛因自身给药模型。随后置饲养笼自然戒断,随机分为第1天CC(d 1CC)组、d 14 CC组、d 1 CC+CS组和d 14 CC+CS组。测定有效鼻触次数,免疫组化双标法检测伏隔核(NAc)壳部和NAc核部胆碱乙酰转移酶(ChAT)与c-Fos共表达的水平。结果 海洛因自身给药大鼠随着戒断时间延长,CC诱导的海洛因觅药行为的恢复,即d 14 CC组与d 1 CC组比较,有效鼻触数明显增加(P<0.05);海洛因自身给药大鼠相同时间戒断后,不同线索诱导的海洛因觅药行为的恢复,即d 1 CC+CS组与d 1 CC组比较,以及d 14 CC+CS组与d 14 CC组比较,有效鼻触数均明显增加(P<0.05)。同时,在NAc壳部,与d 1 CC组比较,d 14 CC组大鼠的ChAT, c-Fos, ChAT+c-Fos免疫阳性细胞数分别为114±9,15±6,(13±5)个,ChAT+c-Fos占ChAT百分比为(11±4)%,明显增加(P<0.05);在NAc壳部和NAc核部,与d 1 CC组比较,d 1 CC+CS组大鼠的上述表达没有差异;在NAc壳部和NAc核部,与d 14 CC组比较,d 14 CC+CS组的ChAT, ChAT+c-Fos免疫阳性细胞数均明显减少(P<0.05)。结论 随着戒断时间的延长,CC诱导的海洛因觅药行为的增加,可能与NAc壳部胆碱能神经元的激活增多有关;而CS诱导的海洛因觅药行为的增加,可能与NAc壳部和核部胆碱能神经元的激活减少有关。     

Differential influence of morphine sensitization on accumbens shell and core dopamine responses to morphine- and food-conditioned stimuli

Rationale

Sensitization of the incentive and dopamine (DA) stimulant properties of drug-conditioned stimuli (CSs) by repeated exposure to drugs of abuse has been assigned an important role in the genesis of drug addiction.

Objective

To test in rats if morphine-induced sensitization potentiates incentive and DA-releasing properties in the nucleus accumbens (NAc) shell and core elicited by presentation of a morphine-conditioned stimulus(CS) and if this property generalizes to a non-drug-(palatable food, Fonzies)-CS.

Methods

Controls and rats previously sensitized by morphine were trained via three daily sessions consisting of a 10-min presentation of CS (Fonzies filled box, FB) followed by s.c. saline and morphine (1 mg/kg) or by standard food and Fonzies. Rats were implanted with microdialysis probes and the next-day incentive reactions and NAc shell and core DA were monitored during CS presentation and subsequent morphine (1 mg/kg) administration or Fonzies feeding.

Results

Morphine sensitization increased incentive and NAc shell and core DA responses to morphine-CS. Morphine conditioning per se increased incentive reactions and NAc shell but not core DA responses to FB presentation. Morphine sensitization potentiated incentive responses but did not affect NAc shell and core DA responses to Fonzies-CS. Fonzies conditioning increased incentive reactions and NAc core but not shell DA responses to FB presentation.

Conclusions

These observations confirm the prediction of the incentive sensitization theory in the case of drug-CS but not of non-drug-CS. NAc DA might be differentially involved in the expression of incentive sensitization of drug- and non-drug-CSs, thus providing a clue for the abnormal incentive properties of drug CSs.     

Addition of açaí (Euterpe oleracea) to cigarettes has a protective effect against emphysema in mice

Chronic inhalation of cigarette smoke (CS) induces emphysema by the damage contributed by oxidative stress during inhalation of CS. Ingestion of açai fruits (Euterpe oleracea) in animals has both antioxidant and anti-inflammatory effects. This study compared lung damage in mice induced by chronic (60-day) inhalation of regular CS and smoke from cigarettes containing 100 mg of hydroalcoholic extract of açai berry stone (CS + A). Sham smoke-exposed mice served as the control group. Mice were sacrificed on day 60, bronchoalveolar lavage was performed, and the lungs were removed for histological and biochemical analyses. Histopathological investigation showed enlargement of alveolar space in CS mice compared to CS + A and control mice. The increase in leukocytes in the CS group was higher than the increase observed in the CS + A group. Oxidative stress, as evaluated by antioxidant enzyme activities, mieloperoxidase, glutathione, and 4-hydroxynonenal, was reduced in mice exposed to CS + A versus CS. Macrophage and neutrophil elastase levels were reduced in mice exposed to CS + A versus CS. Thus, the presence of açai extract in cigarettes had a protective effect against emphysema in mice, probably by reducing oxidative and inflammatory reactions. These results raise the possibility that addition of açaí extract to normal cigarettes could reduce their harmful effects.     

Dopamine D1 and D2 antagonists reduce the acquisition and expression of flavor-preferences conditioned by fructose in rats

The effects of dopamine (DA) D(1) and D(2) receptor antagonists on the acquisition and expression of flavor-preferences conditioned by the sweet taste of fructose were examined. Food-restricted rats were trained over eight alternating one-bottle sessions to drink an 8% fructose solution containing one novel flavor (CS+) and a less preferred 0.2% saccharin solution containing a different flavor (CS-). Three groups of rats were treated daily with either vehicle (control group), SCH23390 (200 nmol/kg; D(1) group), or raclopride (200 nmol/kg; D(2) group) during training. Additional groups of vehicle-treated rats had their daily training intakes matched to that of the D(1) and D(2) groups. Preferences were assessed in two-bottle tests with the CS+ and CS- flavors presented in 0.2% saccharin solutions following doses of 0, 50, 200, 400, or 800 nmol/kg of either D(1) or D(2) antagonists. The D(1) and D(2) groups, unlike the control and yoked-control groups, failed to display a significant CS+ preference in the two-bottle tests following vehicle treatment. In addition, treatment with SCH23390 prior to the two-bottle tests blocked the expression of the CS+ preference in the control groups. Pretest raclopride treatment attenuated the CS+ preference at some dose levels. Raclopride also attenuated the preference for fructose in rats given two-bottle training with the CS+/fructose (CS+/F) and CS-/saccharin (CS-/S) solutions. These findings indicate that D(1) and D(2) antagonists block flavor-preference conditioning by sweet taste and that D(1), and to a lesser extent D(2), receptor antagonists attenuate the expression of a previously acquired preference.     

Key roles of the nucleus accumbens in sleep-wake regulation in rats

The nucleus accumbens(NAc) plays an important role in reward,pleasure,laughter,addiction,aggression,fear,and the placebo effect,however,its role in sleep-wake regulation remains unclear.Dopamine D1 and D2 receptor(R) and adenosine A1R and A2AR are densely localized in the core and shell of NAc,and have been reported to be critically involved in sleep-wake regulation,we hypothesized that NAc might also play an important role in the regulation of sleep-wake cycle.In the present study,we made cell body-specific lesions either in the core or shell of NAc by ibotenic acid,and observed the arousal effects of modafinil and caffeine,which have been reported to be mediated mainly by dopamine receptors and adenosine A2AR,respectively.Rats with NAc core lesions exhibited a 26.5% increase in wakefulness,a weaker response in terms of sleep rebound after a 6-h sleep deprivation,and less arousal effects of modafinil or caffeine,compared with control rats.Furthermore,these lesioned rats showed a strong response to an ip saline injection,as displayed by a striking 165% prolongation in the latency to sleep.Similarly,the rats with NAc shell lesions showed a 17.4% increase in wakefulness,but the arousal effects of modafinil and caffeine in these lesioned rats were the same as that in control rats.These results indicate that both core and shell of the NAc are essential in sleep-wake regulation,with the core being more important than the shell.     

Endogenous opioid blockade and impulsive responding in alcoholics and healthy controls.

The opioid receptor antagonist naltrexone (NTX) is one of few approved treatments for alcoholism, yet the mechanism by which it reduces drinking remains unclear. In rats, NTX reduces morphine-induced impulsive choice bias; however, nothing is known about the drug's effect on discrete aspects of impulsive behavior in humans, such as decision-making and inhibitory control. Here, we used a modified delay discounting procedure to investigate whether NTX improves decision-making or inhibitory control in humans. We measured the effect of acute NTX (50 mg) on choice between smaller sooner (SS) and larger later monetary rewards and on response errors (motor mismatch) in a high conflict condition in a group of abstinent alcoholics (AA) and healthy control subjects (CS). We previously reported that AA selected the SS option significantly more often than did CS in this paradigm. If the choice bias of AA is due to enhanced endogenous opioid signaling in response to potential reward, NTX should reduce such bias in the AA group. We found that NTX did not reliably reduce impulsive choice in the AA group; however, NTX's effect on choice bias across individuals was robustly predictable. NTX's effect on choice bias was significantly correlated with scores on Rotter's Locus of Control (LOC) scale; increasingly internal LOC scores predicted increasing likelihood of impulsive choices on NTX. In addition, we found that NTX significantly enhanced control of motor responses, particularly within the CS group. These results suggest that endogenous opioids may impair response selection during decision-making under conflict, and that NTX's effects on explicit decision-making are personality-dependent. Determining the biological basis of this dependence could have important implications for effective alcoholism treatment.