LAD rats learn a three-key drug discrimination more rapidly and achieve a higher level of performance than HAD rats.

High-alcohol drinking (HAD1) and low-alcohol drinking (LAD1) rats were trained to discriminate among 0.75 g/kg ethanol, 1.5 g/kg ethanol and saline under a fixed-ratio 10 schedule. LAD rats learned the discrimination more rapidly than HAD rats, and asymptotic performance by LAD rats was better than that of HAD rats. The 0.75 g/kg dose of ethanol failed to control the responding of HAD rats, both when baseline responding stabilized and during the determination of an ethanol dose-response curve. These differences between LAD and HAD rats in ethanol discrimination were not observed in previous experiments using a two-choice procedure. The three-choice procedure may be useful for establishing strain differences in ethanol discrimination. These and previous experiments with alcohol-preferring rats suggest that the learning of an ethanol discrimination may be dissociable from voluntary ethanol consumption in rat strains bred selectively to consume ethanol.     

Differences between alcohol-preferring and alcohol-nonpreferring rats in ethanol generalization.

Alcohol-preferring (P rats) and alcohol-nonpreferring rats (NP rats) were trained to discriminate intraperitoneal injections of 0.5 g/kg ethanol, or subcutaneous injections of 0.6 mg/kg nicotine from saline. P rats learned the ethanol discrimination more rapidly and made a higher percentage (88%) of their responses on the ethanol lever after ethanol and a lower percentage (7%) after saline than NP rats (78 and 15%, respectively). In substitution tests, increasing doses of ethanol produced increases in the percentage of responses on the ethanol lever with similar ED50s (0.43 and 0.44 g/kg) in P and NP rats. P rats trained to discriminate ethanol from saline made more responses on the ethanol lever after nicotine (80%) and d-amphetamine (63%) than NP rats (33 and 40%). The ethanol stimulus did not generalize to morphine in either P or NP rats. NP rats trained to discriminate ethanol from saline responded more on the ethanol lever after bupropion (77%) than P rats (49%). In rats trained to discriminate nicotine from saline, the nicotine discriminative stimulus did not generalize to ethanol in either P or NP rats, suggesting that the genetic difference in the stimulus generalization of ethanol was not symmetrical.     

Dopamine and serotonin content in select brain regions of weanling and adult alcohol drinking rat lines

The objective of the present study was to examine innate differences in the tissue content of dopamine (DA), serotonin (5-HT) and their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in five brain regions of weanling and adult alcohol-preferring (P), alcohol-nonpreferring (NP), high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) selected rat lines. Adult male and weanling (postnatal day 25) male rats were killed by decapitation and brains were rapidly dissected for the following regions: olfactory tubercles (OTU), nucleus accumbens (ACB), septum (SEP), anterior cerebral cortex (ACTX) and amygdala (AMYG). Tissue extracts were assayed by HPLC with electrochemical detection. Due to significantly higher content levels in the adults, adult and weanling animals were analyzed separately. Significant differences were found in the ACB and OTU between the adult lines in both DA and 5-HT content, with P and HAD rats having lower levels than NP and LAD rats, respectively. Significant differences in DA content between the weanling lines were also found in the OTU, with P and HAD rats having lower DA levels than NP and LAD rats, respectively. These results confirm previous findings of an association between innate low DA content in select limbic regions and high alcohol drinking behavior.     

Moderate doses of ethanol partially reverse avoidance learning deficits in high-alcohol-drinking rats

We previously reported that ethanol-naive high-alcohol-drinking (HAD1 and HAD2) rats exhibited selective deficits in active avoidance learning, as compared to low-alcohol-drinking (LAD1 and LAD2) rats, in a signaled bar-pressing task [Alcohol. Clin. Exp. Res. 24 (2000) 1778]. In the current study, we used appetitive and aversive learning tasks to assess whether administration of ethanol influences approach and avoidance learning in HAD and LAD rats. Rats were administered 0.0, 0.5, 1.0, or 1.5 g ethanol/kg body weight during appetitive and aversive conditioning sessions. We found that ethanol impaired acquisition of the appetitive conditioned response in a dose-dependent manner in both HAD and LAD rats, with 1.5 g/kg ethanol producing the greatest deficits. Notably, moderate doses of ethanol (0.5 and 1.0 g/kg) partially reversed avoidance learning deficits in HAD rats, but only when appetitive conditioning preceded aversive conditioning. The highest dose (1.5 g/kg EtOH) abolished avoidance responding altogether in HAD rats. Avoidance responding in LAD rats was not affected by any dose of ethanol. These results are consistent with previous studies suggesting that alcohol preference may be associated with increased fear or anxiety, but the conditions under which ethanol produces a reduction of fear and anxiety in HAD rats appear to be relatively complex.     

Behavioral and Biochemical Correlates of Alcohol Drinking Preference: Studies on the Selectively Bred P and NP Rats

Abstract: The alcohol-preferring P and alcohol-nonpreferring NP lines of rates have been selectively bred and used to study the behavioral and biochemical correlates of alcohol-seeking behavior. The P rats satisfy all the perceived criteria for an animal model of alcoholism. Specifically, free-fed P rats voluntarily drink alcoholic solutions (10 to 30% v/v) to intoxication; they bar-press to obtain alcohol and self-administer ethanol intragastrically when food and water are available; and they acquire metabolic and neuronal tolerance and develop physical dependence when they drink alcohol chronically in a free-choice situation. The spontaneous motor activity in the P rats, but not in the NP rats, is stimulated acutely by low doses of alcohol. With a single hypnotic dose of ethanol, acute tolerance develops faster and to a greater degree and persists many days longer in the P than in the NP rats. These differences in response to ethanol may explain the disparate alcohol drinking behaviors of the P and NP rats. Biochemically, the P rats exhibit decreased serotonin levels in several brain regions including the nucleus accumbens. Serotonin uptake inhibitors curtail the alcohol drinking of the P rats suggesting a role of serotonin in mediating alcohol preference.     

High-alcohol-drinking rats exhibit persistent freezing responses to discrete cues following Pavlovian fear conditioning

We previously reported that high-alcohol-drinking (HAD) rats exhibited selective deficits in active avoidance learning and that those deficits were partially reversed by moderate doses of ethanol under certain training conditions [Pharmacol. Biochem. Behav. 75 (2003) 89]. In that study, we hypothesized that HAD deficits resulted from exaggerated fear in the conditioning context and that the anxiolytic properties of ethanol, along with prior exposure to the conditioning apparatus, were responsible for the facilitated avoidance learning that was observed in HAD rats following moderate doses of ethanol. The current study was designed to test whether HAD rats exhibit behaviors consistent with increased fear in aversive learning contexts. We used a standard Pavlovian fear conditioning paradigm to assess behavioral freezing in HAD (HAD-1 and HAD-2) and low-alcohol-drinking (LAD; LAD-1 and LAD-2) rats. No significant differences were observed between HAD-1 and HAD-2 or between LAD-1 and LAD-2 rats, indicating that the replicate lines performed similarly in this study. Both HAD and LAD rats exhibited robust fear conditioning during training. Although no differences were observed between HAD and LAD rats during fear training, HAD rats failed to extinguish freezing behavior in response to the discrete tone conditional stimulus during subsequent fear retention tests. Thus, HAD rats demonstrated prolonged cue-elicited fear that was resistant to extinction.     

An assessment of novelty-seeking behavior in alcohol-preferring and nonpreferring rats

This study examined novelty-seeking behavior in rat populations selectively bred for high and low alcohol-drinking behavior. In Experiment 1, and "odor-enhanced" novel environment produced greater behavioral activation in P compared to NP rats. In Experiment 2, the activity of high alcohol-drinking P and HAD rats was enhanced to a greater extent following the presentation of novel odors in a familiar arena, compared to the NP and LAD rats. The results suggest that, when measuring locomotor activity, alcohol-preferring rats are more reactive to novelty than their nonpreferring counterparts. Experiments 3 and 4, however, did not support the hypothesis that novelty seeking is associated with genetic vulnerability to high alcohol-drinking behavior. When measuring nose-poking behavior in response to novel odors and preference for a novel vs. a familiar chamber, behavior of the preferring lines did not differ from that of the nonpreferring lines, although P rats were more active in the place-preference paradigm. The overall results indicate that the relationship between novelty and alcohol drinking is only modestly associated, and is observed under specific conditions. Moreover, this study underscores the importance of using multiple measures when assessing complex behaviors such as novelty seeking.     

Initial sensitivity and acute tolerance to ethanol in the P and NP lines of rats

We recently reported that selectively bred, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ in sensitivity to a single sedative-hypnotic dose of ethanol, as measured by performance in the jump test. The present study examines the contributions of initial sensitivity and acute tolerance development to this difference. Initial sensitivity, assessed by brain alcohol content upon loss of the aerial righting reflex, was not significantly different between P and NP groups given 3 g ethanol/kg body weight intraperitoneally. Acute tolerance was indexed from blood alcohol concentrations (BAC) upon recovery of jumping performance following two successive ethanol doses. Practiced P and NP rats were required to jump 35 cm to a descending platform following the IP injection of 2.0 g ethanol/kg. The NP group took signiificantly longer (74 min) than the P (33 min) group whereupon BAC₁ of NP rats (234 mg%) was significantly lower than that of P rats (250 mg%). A second injection (1.0 g/kg) was given immediately after the animals reached the 35 cm criterion. Again, NP rats took significantly longer (124 min) than P rats (52 min) to jump 35 cm and BAC₂ of NP animals was lower (295 mg%) than that of P rats (343 mg%). The difference between BAC₂ and BAC₁, the measure of tolerance development, was significantly larger for P rats (90 mg%) than for NP rats (61 mg%). No significant differences in blood ethanol elimination weree observed between the groups. The data indicate no difference in initial sensitivity between P and NP animals but that P rats develop acute tolerance more rapidly and/or to a greater degree than do NP rats. The results are consistent with a relationship in these selectively bred lines of rats between alcohol preference and the development of acute tolerance.     

Genetic propensities to increase ethanol intake in response to stress: studies with selectively bred swim test susceptible (SUS), alcohol-preferring (P), and non-preferring (NP) lines of rats

Rationale

Swim test susceptible (SUS) rats selectively bred for reduced struggling in the forced swim test (FST) following stress show high voluntary ethanol intake like alcohol-preferring (P) rats selectively bred for ethanol preference. It is unknown whether stress enhances drinking in SUS rats or FST behavior in P and non-preferring (NP) rats.

Objectives

The aim of this study was to assess the response to stress in male SUS, Sprague-Dawley (SD), P, and NP rats on 10% ethanol drinking and FST behavior.

Methods

In experiment 1, SUS and SD rats had limited access to ethanol and water following white noise, rehousing, and forced swim stress. In experiment 2, P and NP rats received footshock, white noise, restraint, or no stress prior to the FST. Rats then had continuous access to ethanol and water, and the effects of weekly exposures to stress were measured.

Results

SUS rats drank more ethanol (M?=?2.98?g/kg) than SD rats (M?=?1.26?g/kg) at baseline. Stress produced sustained increases (~33% of baseline) in ethanol intake in SUS rats. NP rats spent twice as much time immobile as P rats in the FST. Stress did not alter FST behavior in P or NP rats. Only footshock produced an increase (~29%) in ethanol intake in P rats.

Conclusions

Selection for stress-induced depressive-like behavior in SUS rats is associated with enhanced stress-induced ethanol drinking. However, the selection for alcohol preference is not associated with stress-induced depressive-like behavior but is associated with footshock stress-induced ethanol drinking. In these experiments, relationships among stress, depressive-like behavior, and alcohol preference were not symmetrical.     

Urocortin 1 expression in five pairs of rat lines selectively bred for differences in alcohol drinking

Rationale There is accumulating evidence that the neuropeptide urocortin 1 (Ucn1) is involved in alcohol consumption. Thus far, however, most studies have been performed in mice. Objectives The purpose of the present study was to characterize Ucn1 expression in rats selectively bred for either high or low alcohol intake. Methods Brains from naive male rats of five pairs of independently selected lines (iP/iNP, AA/ANA, HARF/LARF, HAD1/LAD1, and HAD2/LAD2) were analyzed by immunohistochemistry. Results Significant differences were found between iP/iNP, HARF/LARF, and HAD2/LAD2 in number of Ucn1-containing cells in the Edinger–Westphal (EW) nucleus (the main source of Ucn1 in the brain), whereas no significant differences were found between HAD1/LAD1 and AA/ANA. Similarly, significant differences in the optical density of Ucn1 immunoreactivity in EW were found between iP/iNP, HARF/LARF, and HAD2/LAD2, whereas no differences on this measure were found between HAD1/LAD1 and AA/ANA. In the lateral septum (LS, the main projection area of Ucn1-containing neurons in the rat), significant differences were found only between AA/ANA and HAD2/LAD2; however, a meta-analysis indicated that across all five lines, preferring animals had a significantly greater number of Ucn1-positive fibers than nonpreferring animals. Conclusions These results provide evidence that, in rats, Ucn1 may be involved in regulation of alcohol intake, and that this regulation may occur through the Ucn1 projections to LS.     

The neurobiology of alcoholism in genetically selected rat models

Rats selectively bred for their tendency to drink large or small quantities of alcohol are a useful model for investigators examining the possible neurobiological processes underlying alcoholism. Studies with the alcohol-preferring (P) and alcohol-nonpreferring (NP) and the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) pairs of rat lines developed at Indiana University have illustrated differences in several behavioral and neurobiological characteristics associated with alcohol consumption. Specifically, compared with alcohol-avoiding rats, rats with an affinity for alcohol have a greater sensitivity to the stimulatory effects of low to moderate doses and a reduced sensitivity to the negative effects of high doses. Rats that voluntarily drink large quantities of alcohol also acquire tolerance to alcohol's aversive effects. In addition, these rats differ from their alcohol-avoiding counterparts in the levels of several chemical mediators (i.e., neurotransmitters) found in the brain, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and the endogenous opioids.     

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.     

Interactions between depressants (alcohol-type) and stimulants (amphetamine-type)

The rotarod disruption in rats by 1.5 g/kg of ethanol was prolonged by combining the depressant with 2 or 8 mg/kg d-amphetamine, but not after combinations with 4 or 6 mg/kg of the stimulant. The combination with 8 mg/kg d-amphetamine also induced a prolonged coma and lethality. Cocaine or methylphenidate in combination form with ethanol also showed prolonged disruption of rotarod performance, but severe depression and lethality were not observed at any dose combination. d-Amphetamine in combination with pentobarbital or diazepam also increased the duration of rotarod impairment. Amphetamine plus methaqualone did not prolong rotarod disruption, but rather showed a trend toward antagonism. These combinations of 8 mg/kg d-amphetamine with depressants other than alcohol did not cause prolonged coma and lethality. Lower doses of ethanol (0.25 and 0.5 g/kg) plus 8 mg/kg d-amphetamine induced a delayed impairment of rotarod performance in rats as well as a comatose state and lethality. Mice showed a similar trend for these interactions between alcohol and d-amphetamine but the influence was much less predictable. Analysis of alcohol levels in rat serum and brain indicated little effect of d-amphetamine on the rate of elimination of ethanol. On the other hand, 1.5 g/kg of ethanol prolonged the d-amphetamine decay from brain and serum. This latter interaction was not observed in rats treated with 8 mg/kg d-amphetamine plus 0.5 g/kg ethanol. Mice treated with 8 mg/kg d-amphetamine plus 2.25 g/kg alcohol showed little trend for changes in rate of elimination of either drug. The behavioral effects of the combination of d-amphetamine and ethanol cannot be explained adequately on the basis of altered pharmacokinetics of either drug.     

Differential effects of ethanol in the nucleus accumbens shell of alcohol-preferring (P), alcohol-non-preferring (NP) and Wistar rats: A proteomics study

The objective of this study was to determine the effects of ethanol injections on protein expression in the nucleus accumbens shell (ACB-sh) of alcohol-preferring (P), alcohol-non-preferring (NP) and Wistar (W) rats. Rats were injected for 5 consecutive days with either saline or 1 g/kg ethanol; 24 h after the last injection, rats were killed and brains obtained. Micro-punch samples of the ACB-sh were homogenized; extracted proteins were subjected to trypsin digestion and analyzed with a liquid chromatography-mass spectrometer procedure. Ethanol changed expression levels (1.15-fold or higher) of 128 proteins in NP rats, 22 proteins in P, and 28 proteins in W rats. Few of the changes observed with ethanol treatment for NP rats were observed for P and W rats. Many of the changes occurred in calcium-calmodulin signaling systems, G-protein signaling systems, synaptic structure and histones. Approximately half the changes observed in the ACB-sh of P rats were also observed for W rats. Overall, the results indicate a unique response to ethanol of the ACB-sh of NP rats compared to P and W rats; this unique response may reflect changes in neuronal function in the ACB-sh that could contribute to the low alcohol drinking behavior of the NP line.     

Effects of Ro 15-4513, fluoxetine and desipramine on the intake of ethanol, water and food by the alcohol-preferring (P) and -nonpreferring (NP) lines of rats

The effects of the IP administration of RO 15-4513 (1,2 and 4 mg/kg), fluoxetine (5 and 10 mg/kg) and desipramine (5 and 10 mg/kg) on the intake of 10% ethanol, H₂O and food were determined in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats with daily access to fluids being limited to single 2-hour sessions. The imidazobenzodiazepine Ro 15-4513 (a partial inverse benzodiazepine agonist) significantly reduced the intake of 10% ethanol by the P rats to 50–60% of control levels in the first 30 minutes without altering food or H₂O intake. The attenuating actions of 2 mg/kg Ro 15-4513 on ethanol intake could be completely blocked by the central benzodiazepine receptor antagonist Ro 15-1788 (10 mg/kg). Ro 15-1788, by itself, produced no effects on alcohol and H₂O consumption. The 5 mg/kg dose of fluoxetine significantly reduced 10% ethanol intake by the P rats to 20% of control values without altering either H₂O or food consumption. The 10 mg/kg dose of fluoxetine further reduced ethanol intake by the P rats, but this dose also reduced daily food intake to approximately 70% of normal. Desipramine at both doses significantly (p<0.05) reduced both ethanol and food uptake by the P rats and had a tendency to reduce H₂O consumption as well. In general, the three drugs had effects in the NP rats similar to those observed for the P group, although the effects on 10% ethanol intake were difficult to compare because of the low, variable intake of alcohol by the NP group. The data are consistent with the involvement of serotonin and the GABA-benzodiazepine receptor complex in alcohol drinking behavior.     

Calcitonin gene-related peptide (CGRP) levels and alcohol

Calcitonin gene-related peptide (CGRP) when administered into the brain exerts stress-like effects such as increased pain sensitivity, anorexia, and potentiation of fear-related behaviours. Since alcohol consumption may be related to alcohol's anxiolytic properties, the present study sought to determine if brain CGRP levels were correlated with genetic differences in preference for drinking alcohol and/or affected by alcohol exposure/withdrawal. CGRP-like immunoreactivity (CGRP-LI) was measured by radioimmunoassay (RIA) in amygdala, hippocampus, frontal cortex, hypothalamus, and caudate. In the first experiment, CGRP-LI was compared in alcohol-naive rats [preferring (P) and non-preferring (NP)], lower concentrations were found in the hippocampus (U = 153.5; d.f. = 1,28; p < 0.014) and frontal cortex (U = 183.0; d.f. = 1,28; p < 0.0001) of the P rats. In a second experiment, a group of outbred Wistar rats were exposed to alcohol in vapour chambers, or control conditions. At 7 wk of alcohol exposure there were no differences in exposed rats as compared to controls. However, at 4 wk following ethanol withdrawal, higher concentrations of CGRP-LI were found in the hippocampus (U = 26.5; d.f. = 1,20 p < 0.05), hypothalamus (U = 17.5; d.f. = 1,20; p < 0.009), and caudate-putamen (U = 17.0; d.f. = 1,20; p < 0.009) of the previously exposed animals. These studies suggest that CGRP may modulate alcohol preference and additionally, that exposure/withdrawal from ethanol produces long-lasting effects on CGRP-LI.     

Calcium-dependent mechanisms of the reinstatement of nicotine-conditioned place preference by drug priming in rats

Reinstatement of drug-seeking behaviour in animals is relevant to relapse to drug taking in humans. We used the conditioned place preference version of the reinstatement model to investigate the establishment, extinction, reinstatement and cross-reinstatement of nicotine-induced place conditioning in rats. Nicotine produced a place preference to the compartment paired with its injections during conditioning (0.5 mg/kg, i.p., three drug sessions). Once established, nicotine place preference was extinguished by repeated training. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.5 mg/kg, i.p.), a cannabinoid receptor agonist WIN55,212-2 (0.5 mg/kg, i.p.), ethanol (0.5 g/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). The priming injections of nicotine, WIN55,212-2 and ethanol, but not of d-amphetamine renewed a preference for the compartment previously paired with nicotine. Finally, we examined the influence of the calcium channel antagonists, nimodipine (5 and 10 mg/kg, i.p.) and flunarizine (5 and 10 mg/kg, i.p.), on the reinstatement of nicotine place conditioning induced by WIN55,212-2 and ethanol. It was shown that the calcium channel blockers attenuated the reinstatement of nicotine-conditioned response induced by both drugs. As reinstatement of drug-seeking is a factor for the development of dependence, the L-type calcium channel antagonists may be useful in the relapse-prevention phase of addiction treatment, including cannabinoid, ethanol, and/or nicotine dependence.     

Electrophysiological response to neuropeptide Y (NPY): in alcohol-naive preferring and non-preferring rats.

Electroencephalograms (EEGs) and event-related potentials (ERPs) to auditory stimuli were recorded following intracerebroventricular administration of neuropeptide Y (saline, NPY: 1.0, 3.0 nmol) in two lines of rats that have been genetically selected for alcohol preferring (P) or non-preferring (NP) behaviors. Previous studies have demonstrated that NPY has a distinct electrophysiological profile that is similar to that of ethanol. In outbred Wistar rats, both NPY and ethanol produced highly significant decreases in the amplitude and increases in the latency of the N1 component of the ERP to all three auditory stimuli. Because the N1 has been associated with attention, these data suggest that both NPY and alcohol may diminish attentional processes. In the present study, NPY-induced decreases in N1 amplitude were also found, but only to the frequently presented tone. This suggests that both P and NP rats may have attenuated responses to NPY's effects on attention/arousal. Like outbred Wistars, P and NP rats were also found to have significant NPY-induced increases in N1 latency in the cortex and hippocampus. However, in the amygdala, while P rats evidenced increases in N1 latency and decreases in N1 amplitudes, NP rats displayed the opposite effects. Spectral analysis revealed that NPY also produced differential EEG responses in P and NP rats. In previous studies in outbred Wistar rats NPY has been found to produce slowing of delta (1-2 Hz) frequencies at the 1-nmol dose and reductions in power, particularly in the higher frequencies in the amygdala, at the 3-nmol dose. This electrophysiological profile is not unlike what is seen following alcohol and benzodiazepines and is associated with anxiolysis. P rats were found to have this general pattern of EEG responses to NPY but attenuated suggesting that they may have reduced responses to electrophysiological measures of the anxiolytic effects of NPY. In contrast, NP rats had NPY-induced EEG effects in amygdala and frontal cortex that were opposite to those seen in P rats. These opposing responses to NPY tended to produce a "normalization" of the power differences that existed between the two rat lines at baseline. Taken together with previous findings that P rats have decreased NPY concentrations in limbic and frontal cortical sites, these data suggest that differences in the regulation of NPY neurons may contribute to the expression of behavioral preference for ethanol consumption in these rat lines.     

Modulation of ethanol drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice

Rationale  Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed “drinking in the dark” (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in binge-like ethanol consumption is unknown. Objectives  To determine if nAChRs are involved in binge drinking as measured by the DID assay in C57Bl/6J mice. Materials and methods  Adult male C57Bl/6J mice were injected i.p. with nicotinic receptor antagonists including mecamylamine, hexamethonium, dihydro-β-erythroidine, and methyllycaconitine. Immediately following injection, mice were presented with 20% ethanol for 2 h in the DID assay to measure ethanol consumption. Nicotinic agonists including cytisine and nicotine were also evaluated. The effects of mecamylamine and nicotine on ethanol-induced dopaminergic neuronal activation in the VTA were evaluated via immunohistochemistry. Results  Mecamylamine dose dependently reduced ethanol consumption; whereas, the peripheral antagonist hexamethonium had no significant effect. Nicotinic agonists, cytisine and nicotine, reduced ethanol consumption. None of the effective nicotinic receptor drugs reduced sucrose drinking. Mecamylamine blocked ethanol activation of dopaminergic neurons while nicotine alone activated them without additional activation by ethanol. Conclusions  Neuronal nAChRs are involved in ethanol consumption in the DID paradigm. The effects of mecamylamine, nicotine, and cytisine on ethanol intake appear to be specific because they do not reduce sucrose drinking. Mecamylamine reduces alcohol consumption by blocking activation of dopaminergic neurons; whereas, nicotinic agonists may activate the same reward pathway as alcohol.