Modeling binge-like ethanol drinking by peri-adolescent and adult P rats

Alcohol binge-drinking, especially among adolescents and young adults, is a serious public health concern. The present study examined ethanol binge-like drinking by peri-adolescent [postnatal days (PNDs 30-72)] and adult (PNDs 90-132) alcohol-preferring (P) rats with a drinking-in-the-dark-multiple-scheduled-access (DID-MSA) procedure used by our laboratory. Male and female P rats were provided concurrent access to 15% and 30% ethanol for three 1-h sessions across the dark cycle 5 days/week. For the 1st week, adolescent and adult female P rats consumed 3.4 and 1.6 g/kg of ethanol, respectively, during the 1st hour of access, whereas for male rats the values were 3.5 and 1.1 g/kg of ethanol, respectively. Adult intakes increased to ~ 2.0 g/kg/h and adolescent intakes decreased to ~ 2.5 g/kg/h across the 6 weeks of ethanol access. The daily ethanol intake of adult DID-MSA rats approximated or modestly exceeded that seen in continuous access (CA) rats or the selection criterion for P rats (≥ 5 g/kg/day). However, in general, the daily ethanol intake of DID-MSA peri-adolescent rats significantly exceeded that of their CA counterparts. BELs were assessed at 15-min intervals across the 3rd hour of access during the 4th week. Ethanol intake was 1.7 g/kg vs. 2.7 g/kg and BELs were 57 mg% vs. 100 mg% at 15- and 60-min, respectively. Intoxication induced by DID-MSA in female P rats was assessed during the 1st vs. 4th week of ethanol access. Level of impairment did not differ between the 2 weeks (106 vs. 97 s latency to fall, 120 s criterion) and was significant (vs. naïve controls) only during the 4th week. Overall, these findings support the use of the DID-MSA procedure in rats, and underscore the presence of age- and sex-dependent effects mediating ethanol binge-like drinking in P rats.     

Daily patterns of ethanol drinking in adolescent and adult, male and female, high alcohol drinking (HAD) replicate lines of rats

The rationale for our study was to determine the pattern of ethanol drinking by the high alcohol-drinking (HAD) replicate lines of rats during adolescence and adulthood in both male and female rats. Rats were given 30 days of 24 h free-choice access to ethanol (15%, v/v) and water, with ad lib access to food, starting at the beginning of adolescence (PND 30) or adulthood (PND 90). Water and alcohol drinking patterns were monitored 22 h/day with a “lickometer” set-up. The results indicated that adolescent HAD-1 and HAD-2 males consumed the greatest levels of ethanol and had the most well defined ethanol licking binges among the age and sex groups with increasing levels of ethanol consumption throughout adolescence. In addition, following the first week of adolescence, male and female HAD-1 and HAD-2 rats differed in both ethanol consumption levels and ethanol licking behavior. Adult HAD-1 male and female rats did not differ from one another and their ethanol intake or licking behaviors did not change significantly over weeks. Adult HAD-2 male rats maintained a relatively constant level of ethanol consumption across weeks, whereas adult HAD-2 female rats increased ethanol consumption levels over weeks, peaking during the third week when they consumed more than their adult male counterparts. The results indicate that the HAD rat lines could be used as an effective animal model to examine the development of ethanol consumption and binge drinking in adolescent male and female rats providing information on the long-range consequences of adolescent alcohol drinking.     

Chronic ethanol tolerance through free-choice drinking in the P line of alcohol-preferring rats

The objective of this study was to determine if the selectively bred P line of alcohol-preferring rats would develop behavioral (neuronal) tolerance with free-choice drinking of ethanol. Adult, male P rats were divided into four groups. One group (FCE) received food, water and a 10% (v/v) ethanol solution ad lib, while the control group (C) had only food and water. The other two groups received either a liquid diet containing 5% (v/v) ethanol (LDE) or a control liquid diet (LDC). All groups were kept on their respective feeding regimens for 14 days. The mean (+/- SEM) ethanol intakes for the FCE and LDE groups were 6.8 +/- 0.5 and 9.9 +/- 0.4 g ethanol/kg body wt./day, respectively. A shock-motivated jumping task was used to test for tolerance. Each rat received an IP injection of 2.5 g ethanol/kg and was tested every 15 minutes for recovery to a criterion of 75% of the performance level achieved with training. All rats were tested twice, once on the day before beginning their feeding regimens (day 0) and again 14 days later. Tolerance was assessed from differences in time of recovery to criterion performance and in blood alcohol concentrations (BACs) at recovery on day 0 vs. day 14. The mean recovery times for the C, FCE, LDC, and LDE groups on day 0 were 177 +/- 6, 170 +/- 6, 143 +/- 10 and 153 +/- 13 minutes, respectively, and the BACs were 219 +/- 6, 222 +/- 5, 220 +/- 19 and 214 +/- 6 mg%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuropeptide Y administration into the amygdala suppresses ethanol drinking in alcohol-preferring (P) rats following multiple deprivations

The present experiment examines the effects of NPY administered into the amygdala on ethanol drinking by alcohol-preferring P rats following long-term continuous ethanol access, with and without multiple periods of imposed ethanol abstinence. P rats had access to 15% (v/v) ethanol and water for 11 weeks followed by 2 weeks of ethanol abstinence, re-exposure to ethanol for 2 weeks, 2 more weeks of ethanol abstinence, and a final ethanol re-exposure. Immediately prior to the second ethanol re-exposure, 4 groups of rats received bilateral infusions NPY (0.25, 0.5, 1.0 microg) or artificial cerebrospinal fluid (aCSF) into the amygdala. Two additional groups were given uninterrupted ethanol access and were infused with a single NPY dose (1.0 microg) or aCSF. The highest NPY dose (1.0 microg) suppressed ethanol intake for 24 h in rats with a history of ethanol abstinence (i.e. deprivation) periods, but had no effect in rats with a history of continuous ethanol access. Water and food intakes were not altered. These results suggest that the amygdala mediates the suppressive effects of centrally administered NPY on ethanol drinking, and that NPY may block relapse-like drinking by opposing the anxiogenic effects of ethanol abstinence.     

Induction of dependence on ethanol by free-choice drinking in alcohol-preferring rats

Studies were performed to examine whether chronic, voluntary consumption of ethanol by the selectively-bred, alcohol-preferring P-rats produces physical dependence. Body weight reduction, food restriction and flavoring the 10% ethanol solution increased ethanol consumption from 7 to 14 g ethanol/kg body weight/day when water was freely available. Under similar conditions, consumption by selectively-bred, alcohol-nonpreferring NP-rats increased from 1 to 12 g/kg/day. Removal of ethanol after eight weeks induced physical signs of withdrawal in both lines of animals. In two subsequent studies, P-rats were given food, water and unflavored 10% ethanol ad lib for 15 and 20 weeks; ethanol consumption was 7.2 and 5.6 g/kg/day, respectively. Upon removal of ethanol, manifestations of withdrawal, scored blind in one experiment, developed in 85% of the animals and persisted for 72 hours. Importantly, none in the control groups of P and NP rats given water only exhibited these signs. The ethanol withdrawn groups were hyperactive in both the open-field and the head-poke apparatus. These results indicate that sufficient ethanol was voluntarily consumed by the selectively-bred alcohol-preferring P-rats under free-feeding conditions to produce physical dependence.     

The development of metabolic tolerance in the alcohol-preferring P rats: Comparison of forced and free-choice drinking of ethanol

Experiments were performed to determine whether metabolic tolerance to alcohol develops in the alcohol-preferring P rats during free-choice drinking. In Experiment 1, alcohol elimination rates (AERs) in female Wistar and P rats were measured as a function of age from 26 to 180 days old. AERs calculated as mmol hr⁻¹ per kg body weight fell with age, whereas AERs expressed as mmol hr⁻¹ per rat increased to reach a constant value after 60 days of age. These data indicate that the chronic effects of ethanol on AER are most easily interpreted if experiments are performed in animals 60 days of age or older and AERs are calculated as mmol hr⁻¹ per rat. In Experiments 2 and 3, P female rats were exposed to alcohol for 6–7 weeks either by free-choice drinking or by forced feeding with liquid diets. With free-choice drinking of alcohol, solid food containig 31 percent of the calories as protein, 10 percent ethanol (v/v) and water were made available ad lib. The liquid diets used for forced ethanol feeding were the Bio-Serv-711 diet, a protein-supplemented Bio-Serv-711 diet and the AIN diet and they contained 18, 32 and 22 percent calories as protein, respectively. When compared with pair-fed or ad lib controls, all the P rats exposed to alcohol by either free-choice or forced-feeding exhibited increased AERs (i.e., metabolic tolerance) after 6–7 weeks. However, if AERs before and after alcohol exposure in the same animals were compared, a net increase in AER was evident only in the P rats on free-choice drinking or forced-fed diets which contained at least 22 percent protein. Alcohol consumption and blood alcohol concentrations of P rats exhibited diurnal variation during free-choice drinking or when they were forced-fed alcohol diets which contained at least 22 percent protein. The high BACs attained in the P rats given the ethanol-containing Bio-Serv-711 diet, presumably because of the lower AERs under this condition, disrupted the diurnal cycling of alcohol ingestion and blood alcohol concentrations. The studies demonstrate that the P rats on chroinic free-choice drinking of alcohol develop metabolic tolerance to much the same degree as animals forced fed ethanol contained in liquid diets. Additionally, they demonstrate that, in animals fed ethanol-containing liquid diets, a net increase in AER after alcohol exposure is evident only if dietary protein constitutes at least 22 percent of the total calories.     

Effects of intravenous ethanol and of 4-methylpyrazole on alcohol drinking in alcohol-preferring rats

Studies were undertaken to determine if elevated blood alcohol concentrations (BAC), produced by intravenous (IV) infusion of ethanol or by intraperitoneal (IP) administration of 4-methylpyrazole (4-MP), could reduce the free-choice oral alcohol consumption of adult male alcohol-preferring rats (P-rats). The IV infusion of ethanol either on a 24 or 12 (dark) hourly dose schedule reduced the amount of ethanol voluntarily ingested. There was a significant (p<0.05) inverse correlation between the amount of ethanol consumed orally and the amount of ethanol infused. Daily fluid and caloric intakes were not compromised. When the amount of ethanol infused was 85% or more of the control oral intake, there was a significant correlation between ethanol intake and tail-blood alcohol levels, taken at 5 min (r=0.98; p<0.05) and 55 min (r=0.93,p<0.05) after the last dark cycle infusion. Below the preinfusion level of 85%, the BAC were variable and did not correlate well with total ethanol intake. After a single IP injection of 4-MP, 90 mg/kg body wt, BAC increased from 10 mg% to 50–65 mg% for 2–3 days. Concomitant with the rise in BAC, these animals decreased their drinking of 10% ethanol and proportionately increased their water intake. The present studies suggest that pharmacological factors, distinct from orosensory cues, are important in regulating voluntary ethanol drinking behavior in the P-rats.     

Effects of repeated alcohol deprivations on operant ethanol self-administration by alcohol-preferring (P) rats.

We reported that repeated alcohol deprivations prolonged the expression of an alcohol-deprivation effect (ADE) under 24-h free-choice alcohol-drinking access and that the duration of the initial deprivation period had a positive effect of prolonging the duration of the ADE. In the present study, operant techniques (including progressive ratio measures) were used to examine the effects of initial deprivation length and number of deprivation cycles on the magnitude and duration of the ADE in alcohol-preferring (P) rats to test the hypothesis that repeated deprivations can increase the reinforcing effects of ethanol (ETOH). Adult male P rats were trained in two-lever operant chambers to self-administer 15% ETOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement in daily 1-h sessions. Following 6 weeks of daily 1-h sessions, the P rats were randomly assigned to one of four groups (n=10/group): nondeprived or deprived of alcohol for 2, 5, or 8 weeks. Following this initial period, the deprived groups were given 15% ETOH again in the operant chambers for a 2-week period, following which they were deprived again for 2 weeks (all three deprived groups). Following the fourth deprivation, the rats underwent a progressive ratio test to determine the breakpoints (FR values) for the nondeprived and the deprived groups. Repeated deprivations increased both the magnitude and duration of the ADE as indicated by increased responding on the ETOH lever. However, the length of the initial deprivation had little effect on expression of the ADE except following the first deprivation, where an ADE was not observed for the 8-week group. Breakpoint values for responding on the ETOH lever for all three deprived groups were two-fold higher than the value for the nondeprived group. The results suggest that repeated cycles of alcohol deprivation and alcohol access increased the reinforcing effects of ETOH in the P rats.     

Effects of systemic opioid receptor ligands on ethanol- and sucrose seeking and drinking in alcohol-preferring (P) and Long Evans rats

The endogenous opioid system has been implicated in mediating the reinforcing effects of ethanol (EtOH). Naltrexone (NTX), an opioid antagonist with concentration-dependent selectivity for the mu receptor, naltrindole (NTI), a selective delta receptor antagonist, and U50,488H, a selective kappa receptor agonist were examined in both alcohol-preferring (P) and nonselected (Long Evans (LE)) rats to determine whether they differentially affected the seeking and consumption of EtOH and sucrose. Using the sipper-tube model, rats reinforced with either 2 % sucrose or 10 % EtOH were injected with vehicle and either NTI (2.5, 5.0, or 10.0 mg/kg), U50 (2.5, 5.0, or 10.0 mg/kg), low-dose NTX (0.1, 0.3, or 1.0 mg/kg), or high-dose NTX (1.0, 3.0, or 10.0 mg/kg). Subsequent intakes (consummatory) or lever responses (seeking) were assessed. Overall, NTI, U50, and NTX attenuated intake and responding for sucrose and EtOH, with EtOH-reinforced P rats being the most sensitive to the effects of NTI on intake and seeking. U50 treatment decreased intake and seeking in both P and LE rats but did not selectively reduce EtOH intake or seeking in either line. P rats were more sensitive than LE rats to lower doses of NTX, and these doses more selectively attenuated responding for EtOH than sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results suggest that drugs selective for the opioid receptors may be good pharmacotherapeutic targets, particularly in those with an underlying genetic predisposition for greater EtOH preference/intake.     

Chronic ethanol tolerance as a result of free-choice drinking in alcohol-preferring rats of the WHP line

The development of tolerance to alcohol with chronic consumption is an important criterion for an animal model of alcoholism and may be an important component of the genetic predisposition to alcoholism. The aim of this study was to determine whether the selectively bred Warsaw High Preferring (WHP) line of alcohol-preferring rats would develop behavioral and metabolic tolerance during the free-choice drinking of ethanol. Chronic tolerance to ethanol-induced sedation was tested. The loss of righting reflex (LRR) paradigm was used to record sleep duration in WHP rats. Ethanol (EtOH)-naive WHP rats received a single intraperitoneal (i.p.) injection of 5.0 g ethanol/kg body weight (b.w.), and sleep duration was measured. Subsequently, rats had access to a 10% ethanol solution under a free-choice condition with water and food for 12 weeks. After 12 weeks of the free-choice intake of ethanol, the rats received another single i.p. injection of 5.0 g ethanol/kg b.w., and sleep duration was reassessed. The blood alcohol content (BAC) for each rat was determined after an i.p. injection of 5 g/kg of ethanol in naive rats and again after chronic alcohol drinking at the time of recovery of the righting reflex (RR). The results showed that the mean ethanol intake was 9.14 g/kg/24 h, and both sleep duration and BAC were decreased after chronic ethanol intake. In conclusion, WHP rats exposed to alcohol by free-choice drinking across 12 weeks exhibited increased alcohol elimination rates. Studies have demonstrated that WHP rats after chronic free-choice drinking (12 weeks) of alcohol develop metabolic tolerance. Behavioral tolerance to ethanol was demonstrated by reduced sleep duration, but this decrease in sleep duration was not significant.     

Effects of acute ethanol administration on monoamine and metabolite content in forebrain regions of ethanol-tolerant and -nontolerant alcohol-preferring (P) rats

The contents of dopamine (DA), serotonin (5-HT) and their metabolites in the frontal cortex, anterior striatum, nucleus accumbens and hypothalamus of alcohol-tolerant and -nontolerant rats of the alcohol-preferring P line were determined one hour after the IP administration of 2.5 g ethanol/kg body wt. Compared with saline-injected controls, nontolerant P-rats injected with ethanol had (a) 60% higher levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the frontal cortex; (b) 30-60% higher levels of DOPAC and HVA in the anterior striatum and nucleus accumbens; and (c) 20% higher levels of 5-HIAA in all three forebrain regions. In the tolerant group, the effects of IP ethanol on DOPAC and HVA were markedly attenuated or completely eliminated in these three forebrain regions. However, in the case of 5-HIAA, an attenuated response was observed only in the nucleus accumbens of the tolerant group. The IP administration of ethanol had little effect on the contents of DA or 5-HT in any of these three forebrain regions, with the exception that 5-HT levels were elevated in the anterior striatum of both the tolerant and nontolerant groups. In the hypothalamus, there were no significant differences for the contents of DA, 5-HT or their metabolites between the nontolerant or tolerant P rats after IP ethanol. The data indicate that both acute ethanol administration and chronic alcohol intake by the P line of rats alters certain DA and 5-HT systems that may be involved in the brain reward circuitry and in DA pathways involved in motor functions.     

Behavioral sensitization and voluntary ethanol drinking in alcohol-preferring AA rats exposed to different regimens of morphine treatment

The purpose of the study was to investigate the effects of three different regimens of morphine treatment on subsequent voluntary ethanol drinking in alcohol-preferring AA (Alko Alcohol) rats. The rats were given morphine subcutaneously either intermittently on alternating days (15 x 10 mg/kg or 5 x 5-20 mg/kg in escalating doses) or subchronically on four consecutive days (3-20 mg/kg/d). Horizontal locomotor activity was monitored after challenges with additional morphine injections (3 mg/kg) ten days and six weeks after termination of the pretreatment to test if behavioral sensitization was induced by repeated morphine administration. Both intermittent pretreatments induced sensitized locomotor response after the first challenge, whereas subchronic injections did not. After the challenge the rats were given a free choice between tap water and 10% (v/v) ethanol solution for four weeks. The rats pretreated and challenged with morphine did not differ significantly in the acquisition of ethanol drinking from the saline-treated controls. In contrast, ethanol drinking was impaired during the first week of ethanol access in the saline-treated rats given a single morphine injection. The second morphine challenge given after the ethanol-drinking phase did not reveal sensitization in any of the groups. The results suggest that pattern of morphine administration rather than the dose or number of exposures to the drug is the most important factor in induction of behavioral sensitization, and that exposure to ethanol may interfere with this process. They also support earlier findings showing that acute morphine may suppress voluntary ethanol drinking, but failed to provide clear evidence for behavioral sensitization to morphine contributing to predilection towards ethanol in AA rats.     

Pharmacological modulation of repeated ethanol withdrawal-induced anxiety-like behavior differs in alcohol-preferring P and Sprague-Dawley rats

Previous work with Sprague-Dawley (SD) rats indicated that subjecting these rats to multiple episodes of ethanol diet could provoke anxiety-like responses. Because alcohol-preferring P rats have been reported to have neurochemical alterations in many systems shown to modulate anxiety-like responses, P rats were compared to SD rats. Rats were subjected to one or three cycles of 5 days' exposure to 4.5% or 7% ethanol diet to assess anxiety-like behavior. The social interaction test was conducted 5 h after ethanol was removed. Other groups of P and SD rats were injected with flumazenil (5 mg/kg), a benzodiazepine (BZD) receptor antagonist, CP-154,526 (10 mg/kg), CRF1 receptor antagonist, SB243,213, a 5-HT2C receptor inverse agonist, or vehicle during the 1st and 2nd withdrawals but not the third. After a single 5-day cycle of ethanol exposure, SD rats did not exhibit a change in social interaction, but P rats exhibited a decrease after exposure to the 7% ethanol. Both strains of rats exhibited anxiety-like behavior following three cycles of exposure to ethanol and the concentration of ethanol in the diet did not influence the response. It was confirmed that flumazenil, CP-154,523, and SB243,213 had prophylactic effects on anxiety-like behavior in the SD rats. Neither flumazenil nor SB243,213 was as effective in the P rats, while the CRF1 receptor antagonist completely counteracted the reduced social interaction in repeatedly withdrawn P rats. A small study showed that buspirone, a 5-HT1A agonist, also had prophylactic effects in P rats. These findings show that alcohol-preferring P rats exhibit anxiety-like behavior more readily following exposure to ethanol-containing diets and that this behavior is counteracted more readily by pretreatment with a CRF1 receptor antagonist than with BZD or 5-HT2C receptor antagonists.     

The benzodiazepine inverse agonist RO19-4603 exerts prolonged and selective suppression of ethanol intake in alcohol-preferring (P) rats

The time course of the benzodiazepine (BDZ) inverse agonist RO19-4603 in antagonizing ethanol (EtOH) intake was investigated in alcohol-preferring (P) rats (n=7) maintained on 24-h continuous free-choice access to EtOH (10% v/v), water, and food. After fluid intakes had stabilized over several weeks, animals were injected with Tween-80 vehicle solution or RO19-4603 (0.075, 0.150, and 0.30 mg/kg). EtOH and water intakes were determined at 8- and 24-h intervals. RO19-4603 caused a marked attenuation of EtOH drinking with each of the doses tested. EtOH intake during the 8-h following 0.075, 0.150, and 0.30 mg/kg RO19-4603 was decreased by approximately 36, 74, and 57%, respectively. Intakes during the 24-h interval were similar to the vehicle control condition. However, 32 h post-drug administration, EtOH intakes were reduced to approximately 27, 31, and 29% following the 0.075, 0.150 and 0.30 mg/kg doses, respectively. To further confirm the reliability of the RO19-4603 dose-response effect, and its selectivity for EtOH, the highest dose condition (0.30 mg/kg) was tested twice. The second 0.30 mg/kg dose condition exerted a profile of effects similar to the initial treatment; 8 h following administration, intake was decreased to 60% of the control level, and 32 h post-drug administration intake was decreased to approximately 46% of the controls. These decreases were evidently selective in comparison with water, since water drinking showed compensatory increases which paralleled the decreased EtOH consumption. Dose-response comparisons indicated that 0.150 mg/kg approaches the maximum effective dose, since the 0.30 mg/kg dose of RO19-4603 did not produce an additional decrease in EtOH intake. Furthermore, unlike the lower doses, the 0.30 mg/kg dose failed to yield reliable compensatory increases in water drinking. The results demonstrated that a single acute administration of RO19-4603 produces prolonged and selective suppression of EtOH intake in P rats maintained on 24-h continuous free access to EtOH. While it is not clear at present what properties of the ligand might explain the observed effects on EtOH intake, these findings along with our previous work, clearly suggest that RO19-4603 may modify neuronal processes that promote EtOH self-administration. Neural transmission at the GABA_A-BDZ receptor complex may play an important role in mediating EtOH reinforcement.     

Acoustic startle and fear-potentiated startle in alcohol-preferring (P) and -nonpreferring (NP) lines of rats

The objective of the present study was to determine whether alcohol-preferring P and -nonpreferring NP rats differ in their acoustic startle response and in fear-potentiated startle. In Experiment 1, male P and NP rats were tested on the startle response to acoustic stimuli ranging from 90-115 dB. Experiments 2 and 3 examined fear-potentiated startle and extinction of the response. In Experiment 2, rats received two light foot shock training sessions separated by 3-4 h. Testing consisted of ten acoustic startle (115 dB) and fear-potentiated startle (light preceding the acoustic startle) presentations administered every 24 h for 9 consecutive days. To test potentiated startle learning under reduced training conditions, a single training session was administered in Experiment 3, and a single within-session extinction test of 50 startle and 50 potentiated startle trials occurred the following day. Results of Experiment 1 indicated that P and NP rats did not differ in startle at any of the acoustic intensities tested. Following fear-potentiated startle conditioning in Experiment 2, however, both acoustic startle and potentiated startle responding were consistently greater in P than NP rats over most of the first 6 test days with P rats having approximately a 100% greater acoustic startle and 50-100% greater potentiated startle response. Moreover, following a single training session in Experiment 3, only P rats showed significant fear-conditioned startle. Additionally, P rats exhibited a 50-100% elevated acoustic startle response over that observed in NP rats. Taken together, the data indicate that, although experimentally naive male P and NP rats show similar acoustic startle responses, P rats become more responsive to both startle-alone and potentiated startle stimuli following fear conditioning. The change in general startle reactivity of the P rat following aversive conditioning, along with facilitated light foot shock learning, suggests that stress exposure may be an important variable in examining associations between anxiety and alcohol drinking behavior.     

Effects of a stressor and corticotrophin releasing factor on ethanol deprivation-induced ethanol intake and anxiety-like behavior in alcohol-preferring P rats

Rationale  

Stress may elevate ethanol drinking and anxiety associated with ethanol drinking. Studies to identify relevant neurobiological substrates are needed.     

The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats

Rationale Recent research indicates that blockade of mGluR5 modifies the reinforcing properties of ethanol.Objectives The present studies examined the effects of mGluR5 receptor blockade in a genetic model of high ethanol intake, the alcohol-preferring (P) rat, on the maintenance of operant ethanol self-administration. In addition, we determined the effect of 2-methyl-6-(phenylethyl)-pyridine (MPEP) on the repeated alcohol deprivation effect.Methods Twelve male (P) rats were trained in experimental sessions to self-administer 10% w/v ethanol via a sucrose-fading procedure. After the establishment of operant ethanol self-administration, subjects were treated with various metabotropic glutamate receptor (mGluR) subtype antagonists immediately prior to experimental sessions: the mGluR5 antagonist MPEP (1, 3, and 10 mg/kg); the mGluR2–3 antagonist LY-341495 (1, 3, and 10 mg/kg); and the mGluR1 antagonist CPCCOEt (1, 3, and 10 mg/kg). After determining the role of mGluR5 in the maintenance of operant ethanol self-administration, we examined the role of this receptor in relapse following repeated periods of alcohol deprivation by depriving subjects of ethanol exposure for three 2-week deprivation periods.Results The mGluR5 antagonist MPEP dose-dependently decreased operant ethanol self-administration. In addition, rats that received saline immediately prior to repeated alcohol deprivation sessions self-administered ethanol at increasing levels that were above those achieved in the last operant-conditioning session prior to the initial 2-week deprivation period. This repeated alcohol deprivation effect was prevented in subjects pretreated with MPEP (10 mg/kg).Conclusions These findings suggest that mGluR5 receptors may modulate both the maintenance of operant ethanol self-administration and abstinence-induced increases in ethanol intake.     

Risperidone reduces limited access alcohol drinking in alcohol-preferring rats

An atypical antipsychotic drug risperidone reduced ethanol drinking of ethanol-preferring Alko, Alcohol (AA) rats in a limited access paradigm. Its effect was transient at a dose known to preferentially antagonize the 5-HT(2) receptors (0.1 mg/kg, s.c.), but long-lasting when the dose was increased to 1.0 mg/kg that also blocks dopamine D(2) receptors. Risperidone also reduced dose-dependently locomotor activity and limited access saccharin intake of the AA rats, indicating that its effect on ethanol drinking was not selective. Risperidone at 0.1 mg/kg given before four successive daily ethanol-drinking sessions significantly reduced the ethanol intake. These data from an animal model of high ethanol intake suggest that risperidone should be tested in various populations of alcoholics for reducing ethanol consumption.