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Fluid consumption in water-deprived rats after administration of naloxone or quaternary naloxone
Prqf. Neum&ychophmocol 6 Bid. Psychiat 1983. Vol. 7.pp.835-838 Rin&dinGreetBrMn.AUrightsreserved.
027s5848183so.00 + .50 Copyright0 1083PergamonRess Ltd.
FLUID CONSUMPTION IN WATER-DEPRIVED RATS AFTER ADMINISTRATION OF NALOXONE OR QUATERNARY NALOXONE SUZANNE TURKISH and STEVEN J. COOPER Department
of Psychology, University Birmingham, U.K.
of Birmingham
(Final form, July 1983) Abstract
Turkish,Suzanne and Cooper, Steven J.: Fluid consumption in water-deprived rats after administration of naloxone or quaternary naloxone. Prog. Neuropsychopharmacol.& Biol. Psychiat. 1983, 1(4-6) :835-839. 1. Water-deprived male rats were given access to water , or to a 0.005M sodium saccharin solution, or to a 0.9% sodium chloride solution, during a 30 min test period. 2. Naloxone (0.01-10.0mg/kg) produced dose-dependent reductions in the consumption of each fluid. Saccharin-drinkingwas significantlyreduced by 0.01 mg/kg naloxone, and water- and saline-drinkingby 0.1 mg/kg naloxone. Quaternary naloxone (0.01-10.0mg/kg) had no effect on drinking under any condition. 3. Access to the saline solution resulted in hyperdipsia, due to a prolongation of the initial bout of avid drinking in the thirsty rats. Naloxone, in small doses, completely abolished this hyperdipsia. Since the quaternary compound had no effect, it was concluded that opiate antagonist suppression of saline-inducedhyperdipsia was probably mediated at central opiate receptors. Keywords: drinking, naloxone, opiate receptors, quaternary naloxone, saccharin, saline, taste, water-deprivation.
Introduction There is good evidence that endogenous opiard peptides are drrectlp knvolved in the regulation of thirst in several marmnalianspecies. In recent years, a large body of data has been rapidly accumulated which shows that opiate receptor antagonists (naloxone,naltrexone, diprenorphine) consistently attenuate water consumptfon in animals maintained on ad libitum food and water and in animals challenged with a variety of thirst stimuli (review by Sanger, 1983). Analysis of the temporal pattern of drfnkrng following a period of water deprivation has yielded important information concerning the antkdfpsogenfceffect of opiate antagonists. Water-deprived rats typically show an initfasuninterruptedbout of avid drinking, followed by a satiety pattern of shortening bouts of drinking terminated by cessation of the drinking response. Opiate receptor antagonists, in small doses, do not appear to affect the initial drinking phase. Instead the typical temporal pattern of thirst satiety seems to occur sooner in animals treated with the antagonists (Cooper and Holtzman, 1983). It is unlikely, therefore, that opiate antagonists interfere with theinitiation of drinking, or the drinking response per se. This conclusion is borne out by the failure of opiate antagonists to affect schedule-inducedpolydipsia, where considerable drinking can be engendered without evidence of satiation (Brown and Holtzman, 1981b; Cooper and Holtzman, 1983). Opiate peptides and receptors are found in high concentrationsnot only in numerous regions of the brain, but also in several peripheral tissues, including the pituitary, pancreas, adrenal medulla and gastrointestinaltract (Pasternakand Chflders, 1983). Selective antagonism of peripheral opiate receptors can in principle be achieved usrng systemic admfnistration of quaternary analogues of opiate receptor antagonists, provided that these do not readily cross the blood-brain barrier. Investigatorshave compared the effects of naloxone and naltrexone with those of the quaternary analogues in a number of different test systems (e.g. Bianchi et., 1982; Manara et., 1982; Schulz et., 1979; Valentino at., 1981). Adopting this approach, Brown and Holtzman (1981a) recently demonstrated that quaternary naloxone and naltrexone failed to affect water consumption in water-deprived rats, 835
836
S. Turkish and S.J. Cooper
whereas the tertiary compounds produced dose-dependent (0.1 - 10.0 mg/kg) reductions in drinking. Sanger (1983) also found no significant effects of quaternary naloxone (0.3, 3.0 and 30.0 mg/kg) on the food and water intake of food-deprived rats, although substantial reductions in food and water intake occurred after 0.3 mg/kg naloxone. These data suggest that peripheral opiate receptor blockade may not be the major factor in the suppressant effect of opiate antagonists affecting ingestive responses. Since taste factors can exert major modulatory effects on drinking in water-deprived and non-deprived rats (Cooper, 1982; Ernits and Corbit, 1973; Hall and Blass, 19751, we investigated the effects of naloxone and methylnaloxone on drinking responses to water, saccharin solution and saline in the water-deprived rat. The aim was to determine if the effects of naloxone on taste-induced modulation of drinking could be attributed to either central or peripheral opiate receptor blockade.
Methods The subjects were 60 male hooded rats of the General strain (weight range 250 - 35Og) bred in our laboratory. They were housed in individual stainless steel cages, with food peglets (modifiedDiet 41B) and tap water available. Room temperature was maintained at 21 C+l, and a 12hr light - 12hr dark cycle was in operation. All animals were accustomed to handling and injection procedures, and were adapted to a deprivation schedule of 22hr without water, on alternate days. The rats were allocated to three equal groups, according to the type of fluid which was available during the drinking tests. For the first30 min after each deprivation period, food was removed, and the test fluid was available in a calibrated cylinder, which was clipped to the front of the cage. The groups were given access to water, 0.005 M sodium saccharin solution, and 0.9% sodium chloride solution, respectively. On irterveningnon-deprivationdays, food and water were available ad lib. Within each taste condition, the animals were subdivided into two groups, one receiving naloxone hydrochloride or isotonic saline vehicle, the other receiving methylnaloxone hydrochloride, or vehicle. Within each drug group, each animal was tested on 5 occasions, following subcutaneous administration of 0.01, 0.1, 1.0 or 10.0 mg/kg, or vehicle, respectively. Order of injection was randomised within each animal, and at least 48 hrs intervened between successive injections. Drug doses refer to the base , and injections were given 15-20 min before the drinking test. During the 30 min test (carried out in the light phase), fluid consumption (ml) was determined at 6 min intervals. The data were analysed using 3-way analysis 0f variance @NOVA) with repeated measures on two factors, separately for naloxone and its quaternary analogue. The factors were drug dose, fluid condition, and time-course of drinking. The Dunnett test (one tailed) was used for comparisons between individual groups and the corresponding control group, and the t-statistic was employed for planned comparisons between fluid conditions.
Results Naloxone. In the naloxone-treatedgroups, there were significant differences between the 30 min consumption of the three available fluids, F (2,271 = 13.60, ~~0.001. After injection of either vehicle or 0.01 mg/kg naloxone, the totaiconsumption of saline was significantly greater than either water or the saccharin solution ~~0.01, in each case. The maximum saline intake recorded was 35m4wmparedwithZtmland 24ml for water and saccharin solution respectively. There were no significant differences between water and saccharin consumption. Naloxone produced a highly-significantdose-related suppression of intake in each of the three taste conditions, E (4,108) = 11.90, p
Fluid consumption after naloxone in rats
WATER
25
SACCHARIN
F
I
837
SALINE
Y
II v 0.01 04 IO 10 v 0.01 0.11.010 "E5i-&%+O NALOXONE mg.kg-'
Fig. 1. Suppression of water, saccharin solution or saline consumption hy naloxcne (0.01 10 mg/kg) in water-deprived rats.
VEHKLE
Is
NALOXONE
lo0 0~9%SALlNE
3 E 8-
0 WATER
Y u %6cl 5 2 42-
0TIME COURSE -SIX MINUTE INTERVALS
Saline-drinking WBS sfgn%fiCWtb gWeatW2than water-drinkfng du&g t&e second 6 ain interval of the drinking test (A). Naloxone il.0 w/kg2 completely aboltshea the hyperdipsia associated with saline-drinking (B).
Fig 2.
838
S. Turkish and S.J. Cooper
Analysis of the time-course data provided additional information which clarified drug and taste effects on consumption. Under control injection conditions, saline, saccharin and water consumptions were statistically indistinguishableduring the first 6 min period, when the rate of fluid consumption was maximal. During the second 6 min period, water and sac&&n intakes showed rapid satiation, while saline intake was significantlypotentiated through the second 6 min period, before showing satiation (Fig. 2A). As Fig. 2B shows, naloxone (l.Omp/kqf completely abolished the hyperdipsia associated with the saline condition. Very similarresults were seen with naloxone in doses of 0.1 and 10.0 mg/kq. Quaternary naloxone. whilst there were significant differences in fluid intake due to taste condition, as in the naloxone-treatedanimals, analysis of variance revealed no significant overall main effect of guaternary naloxone, or interaction with taste condition or time-course.
Discussion Although naloxone produced dose-related reductions in fluid intake in each of the three taste conditions, its quaternary analogue did not. Evidence indicates that, in viva, quaternary naloxone may be lo-30 less potent than the tertiary compound Manara et al., 1982; Schulz Sal., 1979). Therefore potency relationships must first be considered before conclusions are drawn about the relative distributions of naloxone and its quaternary analogue. In the case of saccharin drinking, drinking was reduced by 0.01 mg/kg naloxone, but not by 10 mq/kq methylnaloxone (a 1000-fold dose difference). Differences in potency of lo-30 times cannot account for the results, and thenaforecnshasto conclude that guaternary naloxone was largely excluded from central opiate receptors involved in the control of drinking. Similar arguments could be advanced in the case of water drinking and saline drinking. We have found in an additional study that methylnaloxone (30 mq/kq) produced a significant reduction in water consumption in water-deprived rats. Hall and Blass (1975) described the increased drinking displayed by water-deprivedratsqiven 0.9% saline to drink. The results of the present experiment are in agreement with their findings, showing that animals having access to palatable saline extend the initial period of avid drinking, thus delaying the onset of satiety_ It has been suggested that ta.&efactors may be particularly sensitive to the action of opiate antagonists (LevineI'&al., 1982). In the present study, naloxone treatment completely abolished the extra drink~tributable to the salty solution. Naloxone may act therefore not only to depress fluid consumption but also to suppress the hyperdipsia due to taste factors_ Since quaternary naloxone was without effect on saline drinking, we suggest that the suppression of the saline-inducedhyperdipsta may have been mediated at central opiate receptors_ At present, however, we do not have information on the location of the central receptors which appear to be involved in the additional drinking induced by the saline.
Acknowledgements We thank Endo Laboratories for the gift of naloxone, and P'rancopia(Paris) for the gift of methylnaloxone hydrochloride. S.T. is a recipient of a postgraduate studentship from the Medical Research Council (U.K.)
References BIANCRI, G., FIOCCHI, R., TAVANI, A_ and MANARA, L. (1982) Quaternary narcotic antageniste' relative ability to prevent antinociceptionand gastrointestinaltransit inhibition in morphine-treatedrats as an index of peripheral selectivity. Life Sci., 30: 18751883. BROWN, D.R. and HOLTZMAN, S.G. (1981a) Opiate antagonists: central sites of action in 221: 432-436. suppressing water intake of the rat. Brain Res., BROWN, D.R. and HOLT!ZMAN,S.G. (1981bl Suppression of drinking by nalexone in the rat: a 69: 331-340. further characterization. Rurop. 3. Pharmacel., -
Fluid consumption after naloxone in rats
839
COOPER, S.J. (1982) Palatability-induceddrinking after administration of morphine,naltrexons and diazepam in the non-deprived rat. Substance Alcohol Actions/Misuse, 3: 259-265. COOPER, S.J. and HOLTZMAN, S.G. (1983) Patterns of drinking in the rat following the administrationof opiate antagonists. Pharmacol. Biochem. Behav., (in press). ERNITS, T. and CORBIT, J.D. (1973) Taste as a dipsogenic stimulus. J. Comp.Physiol.Psychol~: 27-31. HALL, W.G. and BLASS, E.M. (1975) Orogastric, hydrational, and behavioral ContrOlS of drinking following water deprivation in rats. J. Comp. Physiol. Psychol., 89: 939-954. LEVINE, A.S., MURRAY, S.S., KNEIP, J. GRACE, M. and MORLEY, J.E. (1982) Flavor enhances 28: 23-25. the antidipsogenic effect of naloxone. Physiol. Behav., -. MANARA, L., BIANCHI, G., FIOCCHI, R., NOTARNICOLA, A., PERACCHIA, F. and TAVANI, A. (1982) Inhibition of gastrointestinaltransit by morphine and FK 33-824 in the rat and comparative narcotic antagonist properties of naloxone and its N-methyl quaternary analog. Life Sci., -31: 1271-1274. PASTBRNAK, G.W. and CAILDERS, S.R. (1983) The actions of opiates and opioid peptides. In: Recent Advances in Clinical Pharmacology, 3, P. Turner and D. G. Shand (eds.) pp. 252-279, Churchill Livingstone, Edinburgh. SANGER, D. J. (1983) Opiates and ingestive behaviour. In: Theory in Psychopharmacology,Vol. 2, S. J. Cooper (ed.) Academic Press, London (in press). SCHULZ, R., WlJSTBR,M.andHERZ, (1979) Centrally and peripherally mediated inhibition A. of intestinal motility by opioids. Naunyn-Schmiedeberg'sArch. Pharmacol., 308: 255-260. VAIENTINO, R.J., HBRLING, S., WOODS, J.H., MEDZIHRADSKY, F. and MBRZ, H. (1981) Quaternary naltrexone: evidence for the central mediation of discriminative stimulus effects of narcotic agonists and antagonists. J. Pharmac. Exp. Ther., 217: 652-659.
Inquiries and reprint requests should be addressed to: Dr. Steven J. Cooper Department of Psychology University of Birmingham Birmingham, B15 2TT lbited Kingdom
027s5848183so.00 + .50 Copyright0 1083PergamonRess Ltd.
FLUID CONSUMPTION IN WATER-DEPRIVED RATS AFTER ADMINISTRATION OF NALOXONE OR QUATERNARY NALOXONE SUZANNE TURKISH and STEVEN J. COOPER Department
of Psychology, University Birmingham, U.K.
of Birmingham
(Final form, July 1983) Abstract
Turkish,Suzanne and Cooper, Steven J.: Fluid consumption in water-deprived rats after administration of naloxone or quaternary naloxone. Prog. Neuropsychopharmacol.& Biol. Psychiat. 1983, 1(4-6) :835-839. 1. Water-deprived male rats were given access to water , or to a 0.005M sodium saccharin solution, or to a 0.9% sodium chloride solution, during a 30 min test period. 2. Naloxone (0.01-10.0mg/kg) produced dose-dependent reductions in the consumption of each fluid. Saccharin-drinkingwas significantlyreduced by 0.01 mg/kg naloxone, and water- and saline-drinkingby 0.1 mg/kg naloxone. Quaternary naloxone (0.01-10.0mg/kg) had no effect on drinking under any condition. 3. Access to the saline solution resulted in hyperdipsia, due to a prolongation of the initial bout of avid drinking in the thirsty rats. Naloxone, in small doses, completely abolished this hyperdipsia. Since the quaternary compound had no effect, it was concluded that opiate antagonist suppression of saline-inducedhyperdipsia was probably mediated at central opiate receptors. Keywords: drinking, naloxone, opiate receptors, quaternary naloxone, saccharin, saline, taste, water-deprivation.
Introduction There is good evidence that endogenous opiard peptides are drrectlp knvolved in the regulation of thirst in several marmnalianspecies. In recent years, a large body of data has been rapidly accumulated which shows that opiate receptor antagonists (naloxone,naltrexone, diprenorphine) consistently attenuate water consumptfon in animals maintained on ad libitum food and water and in animals challenged with a variety of thirst stimuli (review by Sanger, 1983). Analysis of the temporal pattern of drfnkrng following a period of water deprivation has yielded important information concerning the antkdfpsogenfceffect of opiate antagonists. Water-deprived rats typically show an initfasuninterruptedbout of avid drinking, followed by a satiety pattern of shortening bouts of drinking terminated by cessation of the drinking response. Opiate receptor antagonists, in small doses, do not appear to affect the initial drinking phase. Instead the typical temporal pattern of thirst satiety seems to occur sooner in animals treated with the antagonists (Cooper and Holtzman, 1983). It is unlikely, therefore, that opiate antagonists interfere with theinitiation of drinking, or the drinking response per se. This conclusion is borne out by the failure of opiate antagonists to affect schedule-inducedpolydipsia, where considerable drinking can be engendered without evidence of satiation (Brown and Holtzman, 1981b; Cooper and Holtzman, 1983). Opiate peptides and receptors are found in high concentrationsnot only in numerous regions of the brain, but also in several peripheral tissues, including the pituitary, pancreas, adrenal medulla and gastrointestinaltract (Pasternakand Chflders, 1983). Selective antagonism of peripheral opiate receptors can in principle be achieved usrng systemic admfnistration of quaternary analogues of opiate receptor antagonists, provided that these do not readily cross the blood-brain barrier. Investigatorshave compared the effects of naloxone and naltrexone with those of the quaternary analogues in a number of different test systems (e.g. Bianchi et., 1982; Manara et., 1982; Schulz et., 1979; Valentino at., 1981). Adopting this approach, Brown and Holtzman (1981a) recently demonstrated that quaternary naloxone and naltrexone failed to affect water consumption in water-deprived rats, 835
836
S. Turkish and S.J. Cooper
whereas the tertiary compounds produced dose-dependent (0.1 - 10.0 mg/kg) reductions in drinking. Sanger (1983) also found no significant effects of quaternary naloxone (0.3, 3.0 and 30.0 mg/kg) on the food and water intake of food-deprived rats, although substantial reductions in food and water intake occurred after 0.3 mg/kg naloxone. These data suggest that peripheral opiate receptor blockade may not be the major factor in the suppressant effect of opiate antagonists affecting ingestive responses. Since taste factors can exert major modulatory effects on drinking in water-deprived and non-deprived rats (Cooper, 1982; Ernits and Corbit, 1973; Hall and Blass, 19751, we investigated the effects of naloxone and methylnaloxone on drinking responses to water, saccharin solution and saline in the water-deprived rat. The aim was to determine if the effects of naloxone on taste-induced modulation of drinking could be attributed to either central or peripheral opiate receptor blockade.
Methods The subjects were 60 male hooded rats of the General strain (weight range 250 - 35Og) bred in our laboratory. They were housed in individual stainless steel cages, with food peglets (modifiedDiet 41B) and tap water available. Room temperature was maintained at 21 C+l, and a 12hr light - 12hr dark cycle was in operation. All animals were accustomed to handling and injection procedures, and were adapted to a deprivation schedule of 22hr without water, on alternate days. The rats were allocated to three equal groups, according to the type of fluid which was available during the drinking tests. For the first30 min after each deprivation period, food was removed, and the test fluid was available in a calibrated cylinder, which was clipped to the front of the cage. The groups were given access to water, 0.005 M sodium saccharin solution, and 0.9% sodium chloride solution, respectively. On irterveningnon-deprivationdays, food and water were available ad lib. Within each taste condition, the animals were subdivided into two groups, one receiving naloxone hydrochloride or isotonic saline vehicle, the other receiving methylnaloxone hydrochloride, or vehicle. Within each drug group, each animal was tested on 5 occasions, following subcutaneous administration of 0.01, 0.1, 1.0 or 10.0 mg/kg, or vehicle, respectively. Order of injection was randomised within each animal, and at least 48 hrs intervened between successive injections. Drug doses refer to the base , and injections were given 15-20 min before the drinking test. During the 30 min test (carried out in the light phase), fluid consumption (ml) was determined at 6 min intervals. The data were analysed using 3-way analysis 0f variance @NOVA) with repeated measures on two factors, separately for naloxone and its quaternary analogue. The factors were drug dose, fluid condition, and time-course of drinking. The Dunnett test (one tailed) was used for comparisons between individual groups and the corresponding control group, and the t-statistic was employed for planned comparisons between fluid conditions.
Results Naloxone. In the naloxone-treatedgroups, there were significant differences between the 30 min consumption of the three available fluids, F (2,271 = 13.60, ~~0.001. After injection of either vehicle or 0.01 mg/kg naloxone, the totaiconsumption of saline was significantly greater than either water or the saccharin solution ~~0.01, in each case. The maximum saline intake recorded was 35m4wmparedwithZtmland 24ml for water and saccharin solution respectively. There were no significant differences between water and saccharin consumption. Naloxone produced a highly-significantdose-related suppression of intake in each of the three taste conditions, E (4,108) = 11.90, p
Fluid consumption after naloxone in rats
WATER
25
SACCHARIN
F
I
837
SALINE
Y
II v 0.01 04 IO 10 v 0.01 0.11.010 "E5i-&%+O NALOXONE mg.kg-'
Fig. 1. Suppression of water, saccharin solution or saline consumption hy naloxcne (0.01 10 mg/kg) in water-deprived rats.
VEHKLE
Is
NALOXONE
lo0 0~9%SALlNE
3 E 8-
0 WATER
Y u %6cl 5 2 42-
0TIME COURSE -SIX MINUTE INTERVALS
Saline-drinking WBS sfgn%fiCWtb gWeatW2than water-drinkfng du&g t&e second 6 ain interval of the drinking test (A). Naloxone il.0 w/kg2 completely aboltshea the hyperdipsia associated with saline-drinking (B).
Fig 2.
838
S. Turkish and S.J. Cooper
Analysis of the time-course data provided additional information which clarified drug and taste effects on consumption. Under control injection conditions, saline, saccharin and water consumptions were statistically indistinguishableduring the first 6 min period, when the rate of fluid consumption was maximal. During the second 6 min period, water and sac&&n intakes showed rapid satiation, while saline intake was significantlypotentiated through the second 6 min period, before showing satiation (Fig. 2A). As Fig. 2B shows, naloxone (l.Omp/kqf completely abolished the hyperdipsia associated with the saline condition. Very similarresults were seen with naloxone in doses of 0.1 and 10.0 mg/kq. Quaternary naloxone. whilst there were significant differences in fluid intake due to taste condition, as in the naloxone-treatedanimals, analysis of variance revealed no significant overall main effect of guaternary naloxone, or interaction with taste condition or time-course.
Discussion Although naloxone produced dose-related reductions in fluid intake in each of the three taste conditions, its quaternary analogue did not. Evidence indicates that, in viva, quaternary naloxone may be lo-30 less potent than the tertiary compound Manara et al., 1982; Schulz Sal., 1979). Therefore potency relationships must first be considered before conclusions are drawn about the relative distributions of naloxone and its quaternary analogue. In the case of saccharin drinking, drinking was reduced by 0.01 mg/kg naloxone, but not by 10 mq/kq methylnaloxone (a 1000-fold dose difference). Differences in potency of lo-30 times cannot account for the results, and thenaforecnshasto conclude that guaternary naloxone was largely excluded from central opiate receptors involved in the control of drinking. Similar arguments could be advanced in the case of water drinking and saline drinking. We have found in an additional study that methylnaloxone (30 mq/kq) produced a significant reduction in water consumption in water-deprived rats. Hall and Blass (1975) described the increased drinking displayed by water-deprivedratsqiven 0.9% saline to drink. The results of the present experiment are in agreement with their findings, showing that animals having access to palatable saline extend the initial period of avid drinking, thus delaying the onset of satiety_ It has been suggested that ta.&efactors may be particularly sensitive to the action of opiate antagonists (LevineI'&al., 1982). In the present study, naloxone treatment completely abolished the extra drink~tributable to the salty solution. Naloxone may act therefore not only to depress fluid consumption but also to suppress the hyperdipsia due to taste factors_ Since quaternary naloxone was without effect on saline drinking, we suggest that the suppression of the saline-inducedhyperdipsta may have been mediated at central opiate receptors_ At present, however, we do not have information on the location of the central receptors which appear to be involved in the additional drinking induced by the saline.
Acknowledgements We thank Endo Laboratories for the gift of naloxone, and P'rancopia(Paris) for the gift of methylnaloxone hydrochloride. S.T. is a recipient of a postgraduate studentship from the Medical Research Council (U.K.)
References BIANCRI, G., FIOCCHI, R., TAVANI, A_ and MANARA, L. (1982) Quaternary narcotic antageniste' relative ability to prevent antinociceptionand gastrointestinaltransit inhibition in morphine-treatedrats as an index of peripheral selectivity. Life Sci., 30: 18751883. BROWN, D.R. and HOLTZMAN, S.G. (1981a) Opiate antagonists: central sites of action in 221: 432-436. suppressing water intake of the rat. Brain Res., BROWN, D.R. and HOLT!ZMAN,S.G. (1981bl Suppression of drinking by nalexone in the rat: a 69: 331-340. further characterization. Rurop. 3. Pharmacel., -
Fluid consumption after naloxone in rats
839
COOPER, S.J. (1982) Palatability-induceddrinking after administration of morphine,naltrexons and diazepam in the non-deprived rat. Substance Alcohol Actions/Misuse, 3: 259-265. COOPER, S.J. and HOLTZMAN, S.G. (1983) Patterns of drinking in the rat following the administrationof opiate antagonists. Pharmacol. Biochem. Behav., (in press). ERNITS, T. and CORBIT, J.D. (1973) Taste as a dipsogenic stimulus. J. Comp.Physiol.Psychol~: 27-31. HALL, W.G. and BLASS, E.M. (1975) Orogastric, hydrational, and behavioral ContrOlS of drinking following water deprivation in rats. J. Comp. Physiol. Psychol., 89: 939-954. LEVINE, A.S., MURRAY, S.S., KNEIP, J. GRACE, M. and MORLEY, J.E. (1982) Flavor enhances 28: 23-25. the antidipsogenic effect of naloxone. Physiol. Behav., -. MANARA, L., BIANCHI, G., FIOCCHI, R., NOTARNICOLA, A., PERACCHIA, F. and TAVANI, A. (1982) Inhibition of gastrointestinaltransit by morphine and FK 33-824 in the rat and comparative narcotic antagonist properties of naloxone and its N-methyl quaternary analog. Life Sci., -31: 1271-1274. PASTBRNAK, G.W. and CAILDERS, S.R. (1983) The actions of opiates and opioid peptides. In: Recent Advances in Clinical Pharmacology, 3, P. Turner and D. G. Shand (eds.) pp. 252-279, Churchill Livingstone, Edinburgh. SANGER, D. J. (1983) Opiates and ingestive behaviour. In: Theory in Psychopharmacology,Vol. 2, S. J. Cooper (ed.) Academic Press, London (in press). SCHULZ, R., WlJSTBR,M.andHERZ, (1979) Centrally and peripherally mediated inhibition A. of intestinal motility by opioids. Naunyn-Schmiedeberg'sArch. Pharmacol., 308: 255-260. VAIENTINO, R.J., HBRLING, S., WOODS, J.H., MEDZIHRADSKY, F. and MBRZ, H. (1981) Quaternary naltrexone: evidence for the central mediation of discriminative stimulus effects of narcotic agonists and antagonists. J. Pharmac. Exp. Ther., 217: 652-659.
Inquiries and reprint requests should be addressed to: Dr. Steven J. Cooper Department of Psychology University of Birmingham Birmingham, B15 2TT lbited Kingdom