Ethanol-produced interoceptive stimuli are time dependent in selectively bred HAS and LAS rats.

Fourteenth generation high alcohol-sensitive (HAS) and low alcohol-sensitive (LAS) rats were trained to discriminate the effects of 600 mg/kg intraperitoneally administered ethanol from its vehicle at 6 and 30 min postadministration. Each of the earlier- and later-trained animals were given lower doses of ethanol and ED50 values at their trained postadministration interval were found to be nonsignificantly different. Thus, there was no difference between HAS and LAS animals as to their sensitivity to the discriminative effects of ethanol. Phase-generalization studies, where rats trained at 6 min postadministration were tested with the drug at 30 min postadministration were shown not to generalize, whereas the animals trained at 30 min postadministration and tested at 6 min postinjection were shown to readily discriminate the discriminative stimuli. This asymmetrical generalization lends evidence to the biphasic action of ethanol, and suggests that the earlier phase is quantitatively different than the latter phase. The similarity in sensitivity of the LAS and HAS animals, furthermore, suggests that the discrimination of ethanol is not based on its hypnotic effects.     

Ethanol discrimination in Fawn-Hooded rats is compromised when compared to other strains

The drug discrimination paradigm was used to evaluate the behavioral differences in response to ethanol between three strains of rats, viz., Sprague-Dawley, N/Nih and Fawn-Hooded. This latter group is thought to have a genetically-transmitted diminished central serotonin function. Each group of rats was trained to discriminate between the stimulus properties of 600 mg/kg ethanol and its vehicle in a two-lever, food-motivated operant task. Results indicate that the Fawn-Hooded rats required a significantly longer time and a higher ethanol dose to reach criterion discrimination performance. Furthermore, the ED50 value of the Fawn-Hooded rats, once trained, was higher than the Sprague-Dawley or N/Nih rats. The possibility that a reciprocal relationship exists between lowered central serotonin concentrations and higher alcohol consumption is suggested and the hypothesis that the diminished ability to recognize the interoceptive stimuli produced by ethanol may result in larger amounts of ethanol being consumed is offered.     

Interaction of ethanol and tetrahydro-beta-carboline (THBC) in a discriminative task

Rats (n = 10) were trained to discriminate between ethanol (600 mg/kg, IP) and its vehicle, or between THBC (20 mg/kg) and its vehicle in a two-lever food-motivated operant task. Once the discriminative training criterion was attained, rats in each group were administered different doses of both ethanol and THBC. The ED50 of ethanol in the ethanol-trained rats was 298.0 mg/kg and 15 mg/kg THBC produced ethanol-like responding. The ED50 of THBC in the THBC-trained rats was 3.63 mg/kg and 1200 mg/kg ethanol produced THBC-like responding. The cross-generalization between ethanol and THBC is, thus, indicated and relates to previous evidence in which both ethanol- and THBC-trained rats generalize to a common agent, TFMPP, a putatively specific 5HT1B receptor agonist. Taken together, these observations suggest that beta-carbolines may play a role in the discriminative stimulus properties of ethanol.     

The NMDA receptor antagonist MK-801 produces ethanol-like discrimination in the rat

Two groups of rats, one derived from N/Nih stock and the second from the (putatively) serotonin-compromised Fawn-Hooded line, were trained to discriminate ethanol from its vehicle in a drug discrimination paradigm. Once each of the two groups attained discrimination criterion, dose-response relationships with lower doses of ethanol indicated that the Fawn-Hooded rats were less sensitive (ED₅₀ value = 579.5 mg/kg) than the N/Nih rats (ED₅₀ = 371.4 mg/kg). Testing of various doses of the NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 produced complete generalization in each group of animals, with a similar difference in ED₅₀ values between N/Nih and Fawn-Hooded lines. These results extend previous ethanol-to-MK-801 generalization reported in pigeons, and are discussed in light of a possible NMDA-mediated contribution to the ethanol-induced discriminative stimulus cues.     

MDMA (ecstasy) substitutes for the ethanol discriminative cue in HAD but not LAD rats

Selectively bred high- and low-alcohol-drinking (HAD/LAD) rats were trained to discriminate the interoceptive stimuli produced by IP-administered 600 mg/kg ethanol (10% w/v) in a two-lever, food-motivated operant task. Once criterion discrimination was attained, animals were tested with 3.0, 1.5, 1.0, and 0.5 mg/kg MDMA. Although no differences in alcohol discrimination were observed between the HAD and LAD animals, the HAD line was significantly more sensitive than the LAD line to the effects of MDMA. These results provide additional information to the growing body of evidence suggesting serotonergic mediation of some of the behavioral effects of ethanol.     

Micro1-opioid antagonist naloxonazine alters ethanol discrimination and consumption.

The endogenous opioid system is implicated in excessive ethanol-drinking behavior. However, the role of individual opioid receptor subtypes in the mechanism underlying excessive ethanol-drinking behavior is not yet well understood. Therefore, we investigated the ability of a selective micro1-opioid antagonist, naloxonazine, to modulate ethanol-drinking behavior and ethanol discrimination in a rat model with the use of ethanol self-administration and drug discrimination paradigms. The effects of naloxonazine (0.001-10 mg/kg) on ethanol intake were examined in Sprague-Dawley rats under conditions of limited access to 10% (wt./vol.) ethanol and ad libitum access to food and water. Pretreatment with high doses of naloxonazine (1-10 mg/kg) significantly reduced ethanol consumption. When the effects of naloxonazine on food intake in free-feeding male rats were examined, naloxonazine (1.8-10 mg/kg) significantly suppressed 24-h food intake. Another group of rats was trained to discriminate ethanol (1.25 g/kg, i.p.) from saline on a fixed-ratio schedule (FR 10), and ethanol dose-response tests were conducted once rats had acquired ethanol-saline discrimination. Injections were given 15 min before ethanol dose-response tests were conducted, and after characterization of the ethanol dose-response curve, the effects of naloxonazine on ethanol discrimination were assessed by administering naloxonazine (0.001-10 mg/kg, i.p.) 15 min before ethanol administration. Treatment with naloxonazine (0.001-1.8 mg/kg, i.p.) before the ED(100) dose of ethanol partially antagonized the discriminative stimulus of ethanol without having any effect on the response rate. The results support the suggestion of involvement of micro1-opioid receptors in the discriminative effects of ethanol and ethanol-drinking behavior.     

Discriminative stimulus effects of ethanol: Lack of antagonism with N-methyl-d-aspartate and d-cycloserine

Several drug discrimination studies reported that both competitive and uncompetitive NMDA receptor antagonist substituted for ethanol stimulus in rats. In the present study we examined if compounds that act as agonists at the NMDA receptor complex, d-cycloserine (a partial agonist at the glycine positive modulatory site) and N-methyl-d-aspartate (an agonist at the glutamate binding site), could antagonize the discriminative stimulus effects of ethanol. Rats were trained to discriminate between IP administered 1.0 g/kg of ethanol (10% v/v) and saline under a sweetened milk-reinforced fixed ratio 10 (FR10) schedule of reinforcement. When the animals met the discriminative criteria, antagonism tests were conducted with d-cycloserine (0.3–10.0 mg/kg, IP) and N-methyl-d-aspartate (15.0–60.0 mg/kg, IP). Neither d-cycloserine nor N-methyl-d-aspartate antagonized the ethanol-mediated discriminative stimulus effects. In addition, d-cycloserine (3.0–300.0 mg/kg, IP) did not substitute for ethanol. These results indicate that at least certain agonists at the NMDA receptor complex do not attenuate the ethanol interoceptive cue in the rat.     

The effects of aminotriazole and acetaldehyde on an ethanol drug discrimination with a conditioned taste aversion procedure.

The present study was designed to investigate whether acetaldehyde shares stimulus properties with ethanol using the conditioned taste aversion (CTA) baseline of drug discrimination learning. Animals were trained to discriminate ethanol (0.8 g/kg, i.p.) from saline using 11 consecutive cycles consisting of a pairing day and three nonpairing days. On pairing days, all animals were injected with ethanol 30 min prior to a 20-min limited access to a saccharin solution (0.1% w/v) and then immediately injected with either LiCl (0.15 M, 1.8 meq) or distilled water. On the three following nonpairing days, animals were injected with saline and 30 min later presented with the same saccharin solution for 20 min. No injections followed on these nonpairing days. Results showed that animals acquired discriminative stimulus control for ethanol after seven pairings. Pretreatment with the catalase inhibitor did not alter the discriminative control for ethanol. Generalization tests revealed that acetaldehyde substituted for ethanol at a dose of 0.3 g/kg. The results of the present study suggest that catalase inhibition did not reverse or alter the discriminative stimulus effects of ethanol. However, generalization tests showed that acetaldehyde (0.3 g/kg) will substitute for ethanol suggesting that these two drugs share some similar properties.     

Study on the role of glycine,strychnine-insensitive receptors (glycineB sites) in the discriminative stimulus effects of ethanol in the rat

Several recent studies indicate that both competitive and noncompetitive NMDA receptor antagonists substitute for ethanol in a drug discrimination procedure. In the present study we examined compounds from another class of NMDA receptor antagonists—glycine, strychnine-insensitive, receptor (glycine_B site) antagonists in rats trained to discriminate between IP-administered 1.0 g/kg ethanol (10% v/v) and saline. When the animals met the discriminative criteria, substitution tests were conducted with the noncompetitive NMDA receptor antagonist, memantine (3.0–12.0 mg/kg, IP) and selective, glycine_B site antagonists—L-701,324 (0.3–3.0 mg/kg, IP) and MRZ 2/576 (0.1–10.0 mg/kg, IP). Memantine completely substituted for ethanol at the dose of 6.0 mg/kg, which significantly suppressed the rate of responding. L-701,324 substituted for ethanol at the dose of 3.0 mg/kg, which only tended to decrease the response rate. MRZ 2/576 produced maximal ethanol-appropriate responding (50%) at the dose of 5.0 mg/kg, which did not affect the rate of responding. Glycine (200–800 mg/kg, IP) did not antagonize the ethanol stimulus. These results indicate thatglycine, strychine-insensitive, site antagonists may induce some ethanol-like stimulus effects in the rat.     

Effects of calcium channel blockers on pentylenetetrazol drug discrimination in rats.

The effects of the dihydropyridine L-type calcium channel blockers nitrendipine and nimodipine on the pentylenetetrazol (PTZ) drug discrimination, an operant model of anxiety, were investigated. Male Long-Evans rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline. Both nitrendipine (5.0-25 mg/kg, i.p.) and nimodipine (5.0-25 mg/kg, i.p.) partially substituted for the PTZ discriminative stimulus. However, pretreatment with nitrendipine (25 mg/kg, i.p.) or nimodipine (25 mg/kg, i.p.) produced no change in the PTZ dose-effect function. Rats were given a nutritionally balanced liquid diet containing 6.5% ethanol for 10 days. Rats selected the PTZ drug lever during withdrawal. Subchronic coadministration of nitrendipine (1.25-5.0 mg/kg, i.p., b.i.d.) with ethanol failed to dose-dependently reduce PTZ-lever responding, but it did reverse withdrawal signs. Acute administration of nitrendipine (5, 10, and 20 mg/kg, i.p.) produced marked suppression of lever responding, but it failed to significantly reduce levels of PTZ-lever responding. Although calcium channel blockers reduce signs of ethanol withdrawal, they also markedly reduce rates of behavior and produce no clear effects on anxiety-like behaviors induced by ethanol withdrawal.     

Effects of 5,7-dihydroxytryptamine lesion of the dorsal raphe nucleus on ethanol discrimination in the rat.

It has been shown that ethanol produces a complex interoceptive cue in rodents with distinct GABAergic, glutamatergic, and serotonergic (5-hydroxytryptamine, 5-HT) components. The present study aimed to examine the contribution of the 5-HT system originating in the dorsal raphe nucleus (DRN) to the discriminative stimulus effects of ethanol in male Wistar rats. Therefore, selective lesions of 5-HT neurons in the DRN were induced by microinfusions of 5,7-dihydroxytryptamine. The DRN- and sham-lesioned rats were trained to discriminate ethanol (1.0 g/kg) from saline in a standard two-lever drug discrimination procedure. Acquisition of ethanol discrimination and discrimination performance after consumption of lower doses of ethanol did not differ between the groups. In substitution tests, diazepam (0.5-2.5 mg/kg), a nonselective benzodiazepine receptor agonist, partially generalized from the ethanol cue in both groups. In contrast, m-chlorophenylpiperazine (0.1-0.9 mg/kg), a mixed 5-HT(1B/2C) receptor agonist, did not mimic the ethanol cue. The drug decreased response rates in both groups, but this effect was more evident in the sham-lesioned group. A 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyloamino)-tetraline (0.05-0.4 mg/kg), did not produce significant increase in ethanol-appropriate responding in either group. These results may indicate that 5-HT neurons of the DRN are not critically involved in ethanol discrimination in the rat.     

Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (GABA(A)). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.     

HAD and LAD rats respond differently to stimulating effect but not discriminative effects of ethanol.

The drug discrimination paradigm (DD) was used to evaluate behavioral differences of rats selectively bred for differential ethanol drinking preferences. Seventh-generation high alcohol-drinking (HAD) and low alcohol-drinking (LAD) rats were trained to discriminate between ethanol (0.5 g/kg, IP) and saline vehicle, following a 2-min presession interval (PI), using an FR-10 schedule of reinforcement. The HAD line was more responsive than the LAD line to the stimulating effect of ethanol as measured by total response rates. ED50 values of 0.239 and 0.244 g/kg for the HAD and LAD lines, respectively, do not reflect any difference in the discriminative effects of ethanol. Response rates during DD indicated a dissociation of rate-increasing effects and discriminative performance following ethanol. In addition to differential drinking preference, these data suggest that selective breeding for the HAD and LAD animals also involves the stimulant action of ethanol but not on the discriminative effects.     

Salvia miltiorrhiza extract inhibits alcohol absorption, preference, and discrimination in sP rats.

Experiment 1 of the present study investigated the ability of a standardized extract of Salvia miltiorrhiza in reducing voluntary ethanol intake in ethanol-preferring rats of the sP line. Ethanol intake occurred under the two-bottle free-choice regimen between 10% (v/v) ethanol and water in daily 4-h scheduled access periods; water was present 24 h/day. Intragastric administration of 200 mg/kg Salvia miltiorrhiza extract resulted in approximately 40% reduction in ethanol intake and preference throughout the 4-day treatment. This effect of Salvia miltiorrhiza extract was likely due to its ability of altering ethanol absorption from the gastrointestinal tract. Indeed, Experiments 2 and 3 of this study demonstrated that 200 mg/kg Salvia miltiorrhiza extract reduced blood ethanol levels (BELs) up to 60% in comparison to control rats, when ethanol was given IG, whereas it failed to modify BELs when ethanol was injected IP. The reducing effect of Salvia miltiorrhiza extract on ethanol absorption may have therefore resulted in an attenuated perception of the psychoactive effects of ethanol sought by ethanol-drinking rats. Consistently, the results of Experiment 4 of the present study demonstrated that a combination of 200 mg/kg Salvia miltiorrhiza extract IG and 1 or 2 g/kg ethanol IG resulted in a partial blockade of the discriminative stimulus effects of ethanol in sP rats trained to discriminate these doses of ethanol from water in a drug discrimination procedure. Collectively, the results are discussed as being suggestive that drugs curbing ethanol absorption from the gastrointestinal tract may constitute a novel strategy for controlling excessive alcohol consumption in human alcoholics.     

Effects of ethanol on an acetaldehyde drug discrimination with a conditioned taste aversion procedure.

The current study was designed to investigate whether ethanol shares stimulus properties with acetaldehyde with the use of a discriminative taste aversion procedure. Animals were trained to discriminate a dose of acetaldehyde (0.2 or 0.3 g/kg, i.p.) from saline in eight consecutive cycles consisting of a pairing day (PD) and three nonpairing days (NPDs). On PDs, all animals were injected with a particular dose of acetaldehyde 30 min before a 20-min limited access to a saccharin solution [0.1% (wt./vol.)] and then injected immediately with either LiCl (0.15 M, 1.8 mEq) or saline. On the three following NPDs, animals were injected with saline and 30 min later were presented with the same saccharin solution for 20 min. All animals in each acetaldehyde training dose group acquired discriminative stimulus control before generalization tests were conducted. Results of generalization tests (ethanol doses of 0.8, 1.2, 1.6, and 2.0 g/kg) revealed that ethanol substituted for acetaldehyde at doses of 1.2 and 1.6 g/kg for both training doses of acetaldehyde. The findings for this study indicate that acetaldehyde and ethanol may share some stimulus properties.     

Substitution profiles of N-methyl-D-aspartate antagonists in ethanol-discriminating inbred mice.

C57BL/6J (B6) and DBA/2J (D2) inbred mice show pronounced differences in ethanol-induced behaviors, such as loss of righting reflex and locomotor activation, among others. They also differ in measures of conditioned place preference and oral self-administration of ethanol. In the current study, I examined whether B6 and D2 mice differed in their expression of the N-methyl-D-aspartate (NMDA) receptor-mediated component of the discriminative stimulus effects of ethanol. B6 and D2 mice were trained to discriminate ethanol (1.5 g/kg, i.p.) from saline in a two-choice, milk-reinforced operant procedure. After training was completed, substitution and response rate dose-effect curves were generated for ethanol; the uncompetitive NMDA antagonists phencyclidine and ketamine; and the competitive NMDA antagonist D-CPPene. Dose-effect curves were also generated for midazolam, cocaine, m-chlorophenylpiperazine (mCPP), morphine, and gamma-hydroxybutyric acid (GHB). B6 and D2 mice learned the ethanol-versus-saline discrimination. Phencyclidine produced near full substitution for ethanol in both strains, whereas ketamine fully substituted for ethanol only in B6 mice. D-CPPene partially substituted for ethanol in both strains. Moderate doses of phencyclidine produced greater response rate-increasing effects in B6 mice than in D2 mice, and high doses of phencyclidine were more potent for suppressing response rates in D2 mice. In contrast, D-CPPene had similar response rate-increasing effects in both strains, but high doses produced more potent response rate-decreasing effects in B6 mice. Among the other drugs tested, only midazolam produced substantial substitution for ethanol. Taken together, these findings seem to indicate that the behavioral effects of NMDA antagonists differ between strains, but that the NMDA-mediated component of the discriminative stimulus effects of ethanol is similar in B6 and D2 mice.     

Effects of N-methyl-D-aspartate receptor antagonists on reinforced and nonreinforced responding for ethanol in rats.

Results of several recent studies indicate that the discriminative stimulus effects of ethanol are related, at least partially, to ethanol-induced decrease in the N-Methyl-D-aspartate (NMDA) receptor function. The role of NMDA receptors in ethanol reinforcement remains still unclear. The aim of the present study was to evaluate the effects of two novel NMDA receptor antagonists in rats lever pressing for 8% ethanol in the oral self-administration procedure. In addition, the effects of the drugs on intensity of nonreinforced responding for ethanol (i.e., "experimental craving") were examined in the extinction procedure. To assess selectivity of the drugs' actions the same range of doses was tested in rats lever pressing for water (control experiments). A low-affinity, uncompetitive NMDA receptor antagonist, MRZ 2/579 (2.5-7.5 mg/kg) selectively and dose-dependently decreased ethanol self-administration. This compound exerted also selective effects on nonreinforced responding for ethanol with lower dose (2.5 mg/kg) increasing and higher dose (5 mg/kg) suppressing operant behavior in the extinction procedure. MRZ 2/579 (5 mg/kg) did not alter open field activity when given in combination with either saline or ethanol (0.5-1 g/kg). In contrast, a glycineB site antagonist, MRZ 2/576 (2.5-7.5 mg/kg) did not produce any selective effects on either reinforced or nonreinforced lever pressing for ethanol. The present results suggest that MRZ 2/579 may selectively suppress both ethanol self-administration and experimental ethanol craving.     

Abecarnil and alprazolam reverse anxiety-like behaviors induced by ethanol withdrawal.

This study investigated the effects of a benzodiazepine partial agonist, abecarnil, and a full agonist, alprazolam, on ethanol withdrawal-induced anxiety-like behaviors in rats. Anxiety was assessed in two models: elevated plus maze and pentylenetetrazol (GABA(A) antagonist) discrimination assay. Male rats received an ethanol-containing (4.5%) liquid diet for 7 to 10 days and were tested for withdrawal symptoms 12 h after termination of the diet. In the elevated plus maze, ethanol-withdrawn rats displayed less open arm activity and total arm entries than pair-fed rats. Abecarnil (0.08-0.32 mg/kg, IP) and alprazolam (0.08-1.25 mg/kg, IP) each produced a dose-dependent, full reversal of ethanol withdrawal-induced reduction of open arm activity, but only alprazolam increased the total arm entries. In the pentylenetetrazol assay, ethanol-withdrawn rats selected the pentylenetetrazol lever (100%) over the salin-lever. Abecarnil (0.04-0.32 mg/kg, IP) and alprazolam (0.08-0.32 mg/kg, IP) dose dependently reduced pentylenetetrazol-lever responding to control levels (10-20%). Alprazolam was more potent than abecarnil in reversing ethanol withdrawal-induced decrease in open arm activities, but showed comparable potency and efficacy to abecarnil in blocking the pentylenetetrazol-like ethanol withdrawal stimulus. These results suggest that abecarnil and alprazolam may have therapeutic potential for treatment of ethanol withdrawal-induced anxiety-like symptoms.     

Persistence of tolerance in the P line of alcohol-preferring rats does not require performance while intoxicated

Persistence of tolerance was measured seven days after a single ethanol injection (2.5 g/kg b. wt.) in the alcohol-preferring P line of rats with and without testing in a shock-motivated jump task during the initial ethanol exposure. P rats were trained to jump 50 cm to avoid shock and were assigned to one of three groups. On day 0, group E/J (n = 8) was injected with ethanol and tested on the jump task until recovery to criterion (37.5 cm), while group S/J (n = 21) was injected with saline and was tested yoked to an E/J rat. Rats in the E/NJ group (n = 19) received ethanol but were not tested on day 0. Seven days later, all rats received 2.5 g ethanol/kg and were tested to criterion. Recovery times on day 7 were significantly longer (p less than 0.05) for rats in the S/J group (169 +/- 7 min) than for the E/J (141 +/- 11 min) and E/NJ (145 +/- 6 min) rats. Blood ethanol concentrations at recovery for the E/NJ group were higher than the S/J group on day 7 and higher than the E/J group on day 0 (p less than 0.05). The results indicate that the persistence of tolerance manifested by the P rats is an inherited behavioral trait that requires only ethanol exposure.     

The neuropeptide-Y Y5 receptor antagonist L-152,804 decreases alcohol self-administration in inbred alcohol-preferring (iP) rats.

Neuropeptide-Y (NPY) is the most abundant and widely distributed peptide in the mammalian central nervous system and increases feeding behavior through actions at the Y5 receptor subtype. Recent pharmacological evidence indicates that NPY activity at this receptor subtype can modulate ethanol reinforcement. The purpose of this study was to determine if NPY Y5 receptor antagonism reduces ethanol self-administration and reinforcement in a rodent genetic animal model of alcoholism. Selectively inbred alcohol-preferring (iP) rats were trained to voluntarily consume ethanol (10% vol/vol) versus H2O in a 24-h two-bottle choice test. An additional group of iP rats was trained in operant ethanol self-administration to lever press on a fixed-ratio 1 schedule for ethanol (10% vol/vol) reinforcement. Following establishment of baseline intake or ethanol-reinforced responding, iP rats were injected with L-152,804 (0-20 mg/kg) prior to two-bottle or operant ethanol self-administration sessions. In the two-bottle choice test, L-152,804 (3 and 10 mg/kg, ip) significantly reduced ethanol intake (g/kg) at 4- and 6-h postinjection and had no effect on food intake. In the operant procedure, L-152,804 (10 and 20 mg/kg, ip) significantly reduced both the dosage of self-administered ethanol (g/kg/1-h) and the total number of ethanol-reinforced responses. No effect was observed on latency to the first response or the number of inactive lever presses. These results indicate that blockade of NPY Y5 receptor activity decreases both voluntary ethanol drinking and ethanol reinforcement in a rodent genetic animal model of alcoholism. For this reason, NPY Y5 receptor antagonists may be useful in medical management of alcohol abuse and alcoholism in the human population.