Effects of p-chlorophenylalanine (pCPA) on ethanol withdrawal syndrome in rats

Amaç: Sunulan çalışmada, serotonin depolarını boşaltan bir ajan olan p-klorfenilalaninin (pCPA) sıçanlarda etanol yoksunluk sendromu üzerine etkileri incelenmiştir. Böylece etanol yoksunluk sendromunun çeşitli belirtilerinesantralserotonerjik sistemin katkısı incelenmiş ve açıklığakavuşturulmuştur.Yöntem: Etanol (% 7.2 v/v) erişkin Wistar türü erkek sıçanlara sıvı diyet tekniği ile 21 gün süre ile verildi. pCPA (100 mg/kg) sıçanlara etanol yoksunluğunun test edilmesinden 24 saat önce intraperitoneal yoldan enjekte edildi. Etanol yoksunluğun 2, 4 ve 6. saatlerinde sıçanlarda 5’er dakika süre ile lokomotor hiperaktivite, ajitasyon, stereotipik davranışlar, ıslak köpek silkinmesi, tremor ve odiyojenik nöbetler gibi yoksunluk belirtileri değerlendirilerek bunların sıklık ve şiddeti kaydedildi veya skorlandı. pCPA (100 mg/kg) ayrıca etanole bağımlı olmayan kontrol sıçanlara da enjekte edilerek lokomotor aktivite üzerine etkileri değerlendirildi.Bulgular: pCPA uygulaması gözlem süreci boyunca hem etanole bağımlı hem de bağımlı olmayan sıçanların lokomotor aktivitelerinde anlamlı düzeyde artışlara neden oldu. pCPA etanol yoksunluğun 2. saatinde ajitasyonun şiddetinde, 6. saatinde ise ıslak köpek silkinmesi davranışının sıklığında anlamlı ölçüde artışlara neden oldu. Odiyojenik nöbetler hariç diğer yoksunluk belirtileri üzerine etkisizdi. pCPA verilmesi odiyojenik nöbetlerin sıklığını anlamlı ölçüde inhibe etti.Sonuç: Bulgularımız pCPA’nın etanole bağımlı sıçanlarda lokomotor hiperaktivite, ajitasyon ve ıslak köpek silkinmesi gibi yoksunluk belirtilerini daha da şiddetlendirirken, odiyojenik konvulsiyonların sıklığını azalttığına işaret etmektedir. Etanol yoksunluğunun bu belirtileri santral serotonerjik mekanizmalar ile ilişkili olabilir.

P-Klorfenilalaninin sıçanlarda etanol yoksunluk sendromu üzerine etkileri

Objective: In the present study, the effects of p- chlorophenylalanine (pCPA), a serotonin depleting agent, treatment on ethanol withdrawal syndrome have been investigated in rats. Thus, contributions of central serotonergic system to various signs of ethanol withdrawal syndrome have been examined and clarified.Methods: Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 21 days. pCPA (100 mg/kg) and saline were injected to rats intraperitoneally 24 h before ethanol withdrawal testing. After 2nd, 4th and 6th h of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs, including locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes, tremor and audiogenic seizures were recorded or rated. pCPA (100 mg/kg) were also administered to no ethanol-dependent control rats and locomotor activity was measured and evaluated like in ethanol-dependent group.Results: pCPA treatment produced some significant increases in locomotor activity of both control and ethanol- dependent rats during the observation period. pCPA caused some increases the severity of agitation and intensity of wet dog shakes at 2nd and 6th hrs of ethanol withdrawal, respectively. It was no effective on the other signs of ethanol withdrawal except audiogenic seizures. pCPA pretreatment inhibited significantly the incidence of audiogenic seizures.Conclusion: Our findings suggest that pCPA intensified locomotor hyperactivity, agitation and wet dog shakes but attenuated audiogenic seizures during ethanol withdrawal in ethanol-dependent rats. These signs of ethanol withdrawal may be related to serotonergic mechanisms in central nervous system.

PDF

___

1- Tollefson, G. Serotonin and alcohol: Interrelationships. Psychopathology 1989; 22 (Suppl. 1): 37-48.
2- McBride WJ, Murphy JM, Yoshimoto K, et al. Serotonin mechanisms in alcohol drinking behavior. Drug Dev Res 1993; 30: 170-177.
3- Wallis CJ, Rezazadeh M, Lal H. Role of serotonin in ethanol abuse. Drug Dev Res 1993; 30: 178-188.
4- De Witte P, Pinto E, Ansseau M, Verbanck P. Alcohol withdrawal: from animal research to clinical issues. Neurosci Biobehav Rev 2003; 27: 189-197.
5- Weiss, F., Parsons, L.H., Schulteis, G., et al. Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytriptamine releases in dependent rats. J. Neurosci 1996; 16: 3474-3485.
6- Uzbay IT, Usanmaz SE, Tapanyiğit EE, et al. Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs. Drug Alcohol Depend 1998; 53: 39-47.
7- Uzbay IT, Usanmaz SE, Akarsu ES. Effects of chronic ethanol administration on serotonin metabolism in the various regions of the rat brain. Neurochem Res 2000; 25: 257-262.
8- Uzbay İT, Saglam E, Kayir H, et al. Effects of fluoxetine on ethanol withdrawal syndrome in rats. J Psychiat Res 2004; 38: 445-450.
9- Koe BK, Weissman A. p-Chlorophenylalanine: a specific depletory of brain serotonin. J Pharmacol Exp Ther 1966;154: 499-516.
10- Blasig J, Papeschi R, Gramsch C, Herz A. Central serotonergic mechanisms and development of morphine dependence. Drug Alcohol Depend 1976; 1: 221-239.
11- Kruszewska A, Langwinski R. The role of central serotoninergic neurotransmission in the morphine abstinence syndrome in rats. Drug Alcohol Depend 1983; 12: 273-278.
12- Fuchs V, Coper H. The influence of p-chlorophenylalanine on different morphine effects. Drug Alcohol Depend 1980; 5: 367-377.
13- Suzuki T, Fukumori R, Yoshii T, et al. Effect of p-chlorophenylalanine on diazepam withdrawal signs in rats. Psychopharmacology 1980; 71: 91-93.
14- Goldstein DB. Alcohol withdrawal reactions in mice: Effects of drugs that modify neurotransmission. J Pharmacol Exp Ther 1973; 186: 1-9.
15- Collier HOJ, Hammond MD, Schneider C. Biogenic amines and head twitches in mice during ethanol withdrawal. Br J Pharmacol 1974; 51: 310-311.
16- Griffiths PJ, Littleton JM, Ortiz A. Effect of p-chlorophenylalanine on brain monoamines and behaviour during ethanol withdrawal in mice. Br J Pharmacol 1974; 51: 307-309.
17- Yamanaka Y. Effects of brain biogenic amines on ethanol withdrawal reactions and the development of ethanol dependence in mice. Japan J Pharmacol 1982; 32: 499-508.
18- Uzbay IT, Kayaalp SO. A modified liquid diet of chronic ethanol administration: Validation by ethanol withdrawal syndrome in rats. Pharmacol Res 1995; 31: 37-42.
19- Uzbay IT, Erden BF, Tapanyiğit EE, Kayaalp SO. Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats. Life Sci 1997; 61: 2197- 2029.
20- Alexander GJ, Kopeloff LM. Anticonvulsant effect p-chlorophenylalanine in mice on a low magnesium diet. Pharmacol Biocehem Behav 1978; 8: 291-293.
21- Uzbay IT, Akarsu ES, Kayaalp SO. Effects of bromocriptine and haloperidol on ethanol withdrawal syndrome in rats. Pharmacol Biochem Behav 1994; 49: 969-974.
22- Uzbay IT, Erden BF. Attenuation of ethanol withdrawal signs by high doses of L-arginine in rats. Alcohol Alcohol 2003; 38: 213-218.
23- Majchrowicz E. Induction of physical dependence upon ethanol and the associated behavioral changes in rats. Psychopharmacologia 1975; 43: 1993- 1996.
24- Dringenberg HC, Hargreaves EL, Baker GB, et al. p-chlorophenylalanine-induced depletion: reduction in exploratory locomotion but no obvious sensory-motor deficits. Behav Brain Res 1995; 68: 229-237.
25- Uzbay IT, Çinar M, Aytemir M, Tuglular I. Analgesic effect of tianeptine in mice. Life Sci 1999; 64: 1313-1319.
26- Valverde O, Mico JA, Maldonado R, Gibert-Rahola J. Participation of opioid and monoaminergic mechanisms on the antinociceptive effect induced by tricyclic antidepressants in two behavioural pain tests in mice. Prog Neuropsychopharmacol Biol Psychiat 1994; 18: 1073-1092.
27- Tura B, Tura S. The analgesic effect of tricyclic antidepressants. Brain Res 1990; 518: 19-22.