Psychopharmacology (1992) 109:248-250
Psychopharmacology © Springer-Verlag 1992
Effects of chronic nicotine and haloperidol administration on muscarinic receptor-mediated phosphoinositide turnover in rat brain slices Rena Li 1, Lauren L. Wing ~, Darrell G. Kirch ~'2, Richard J. Wyatt 1, and D e - M a w Chuang 3
i Neuropsychiatry Branch, National Institute of Mental Health, Neuroscience Center at Saint Elizabeths, Washington, DC 20032, USA Division of Clinical Research, National Institute of Mental Health, Rockville, MD 20857, USA 3 Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA Received April 13, 1992 / Final version May 24, 1992
Abstract. Muscarinic receptor-mediated phosphoinositide (PI) turnover in rat brain slices was assessed after chronic administration o f nicotine (12 mg/kg/day) or haloperidol decanoate (1.5 mg/kg/day), either alone or in combination, for 6 weeks. Nicotine alone did not significantly alter carbachol-induced inositol monophosphate (IP1) accumulation in the frontal cortex, but did result in a significant increase in the hippocampus, and in a decrease in the striatum. Haloperidol alone attenuated carbachol-stimulated IP1 accumulation in all three brain regions. Chronic treatment with combined nicotine and haloperidol resulted in no significant change in carbachol-sensitive IP1 accumulation in either the frontal cortex or hippocampus but did result in a decrease in the striatum, The results suggest significant cross-talk between cholinergic and dopaminergic systems in affecting PI metabolism. Key words: N i c o t i n e - Haloperidot - Phosphoinositide turnover - Muscarinic receptor
consumption in the form of cigarette smoking is more common in schizophrenic patients (who are typically treated with neuroleptics), but also that smoking may be significantly more prevalent in those who have developed tardive dyskinesia (a side effect thought to be associated with neuroleptic treatment) than in those patients without tardive dyskinesia (Binder et al. 1987; Kirch et al. 1988). Recent animal studies and clinical evidence indicate that nicotine may potentiate haloperidol in the treatment of another neuropsychiatric disorder, Tourette syndrome (Sanberg et al. 1989). While it has been reported that nicotine stimulates the accumulation o f [3H]-IP1 in cultured adrenal chromaffin cells (Eberhard and Holz 1987), to our knowledge, no study has examined the in vivo effect of nicotine on PI turnover in the central nervous system. In the present study, we examined the effect o f nicotine alone and in combination with haloperidol on muscarinic receptormediated PI hydrolysis in the rat brain.
Materials and methods
There is increasing interest in the role of second messenger systems, including inositol phosphate (IP) in the clinical activity of neuropharmacologic agents (Chuang 1989; Fisher et al. 1992). Drugs which have differing receptor specificity may have common effects at the level o f second messengers. For example, there are preliminary indications that chronic administration of the neuroleptic, haloperidol, decreases carbachol-induced PI turnover in a fi~shion similar to that observed with lithium (Li et al. 1991). It has recently become apparent that there may be clinically significant neuropharmacologic associations between treatment with haloperidot and the use of nicotine. Several studies have shown not only that nicotine Correspondence to: R. Li
Dn~j administration. Male Sprague-Dawleyrats, weighing 325 ± 25 g, were housed in a temperature (23 ± t ° C) controlled environment with a 12 h tight-dark cycle and free access to food and water. Animals were treated for 6 weeks with (1) vehicle; (2) nicotine delivered via subcutaneously implanted Alzet 2ML4 osmotic pumps (12 mg/kg/day); (3) haloperidol decanoate (1.5 mg/kg/day, IM); or (4) nicotine and haloperidol combined in the same doses used individually (N= 5 in each group). Phosphoinositide hydrolysis assay. The brains were rapidly removed and dissected on ice. The hippocampus, striatum and frontal cortex were sliced into 350 × 350 ~tm cubes and transferred to buffer. The phosphoinositide hydrolysis assay was performed as previously described (Li et al. 1991). This method involves incubating the brain slices at 37° C with 0.3 ItCi myo-[2-3H]inositol followed by the addition of LiC1 (5 raM) and carbachol (1 raM). [3H]IP1 formation was determined by using a Dowex anion exchange resin (AG-1 × 8 formate form). To measure the incorporation of [aH]-inositol into the phospholipid, the lower organic phase was air-dried and the radioactivity counted after the addition of scintillation fluid.
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Psychopharmacology © Springer-Verlag 1992
Effects of chronic nicotine and haloperidol administration on muscarinic receptor-mediated phosphoinositide turnover in rat brain slices Rena Li 1, Lauren L. Wing ~, Darrell G. Kirch ~'2, Richard J. Wyatt 1, and D e - M a w Chuang 3
i Neuropsychiatry Branch, National Institute of Mental Health, Neuroscience Center at Saint Elizabeths, Washington, DC 20032, USA Division of Clinical Research, National Institute of Mental Health, Rockville, MD 20857, USA 3 Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA Received April 13, 1992 / Final version May 24, 1992
Abstract. Muscarinic receptor-mediated phosphoinositide (PI) turnover in rat brain slices was assessed after chronic administration o f nicotine (12 mg/kg/day) or haloperidol decanoate (1.5 mg/kg/day), either alone or in combination, for 6 weeks. Nicotine alone did not significantly alter carbachol-induced inositol monophosphate (IP1) accumulation in the frontal cortex, but did result in a significant increase in the hippocampus, and in a decrease in the striatum. Haloperidol alone attenuated carbachol-stimulated IP1 accumulation in all three brain regions. Chronic treatment with combined nicotine and haloperidol resulted in no significant change in carbachol-sensitive IP1 accumulation in either the frontal cortex or hippocampus but did result in a decrease in the striatum, The results suggest significant cross-talk between cholinergic and dopaminergic systems in affecting PI metabolism. Key words: N i c o t i n e - Haloperidot - Phosphoinositide turnover - Muscarinic receptor
consumption in the form of cigarette smoking is more common in schizophrenic patients (who are typically treated with neuroleptics), but also that smoking may be significantly more prevalent in those who have developed tardive dyskinesia (a side effect thought to be associated with neuroleptic treatment) than in those patients without tardive dyskinesia (Binder et al. 1987; Kirch et al. 1988). Recent animal studies and clinical evidence indicate that nicotine may potentiate haloperidol in the treatment of another neuropsychiatric disorder, Tourette syndrome (Sanberg et al. 1989). While it has been reported that nicotine stimulates the accumulation o f [3H]-IP1 in cultured adrenal chromaffin cells (Eberhard and Holz 1987), to our knowledge, no study has examined the in vivo effect of nicotine on PI turnover in the central nervous system. In the present study, we examined the effect o f nicotine alone and in combination with haloperidol on muscarinic receptormediated PI hydrolysis in the rat brain.
Materials and methods
There is increasing interest in the role of second messenger systems, including inositol phosphate (IP) in the clinical activity of neuropharmacologic agents (Chuang 1989; Fisher et al. 1992). Drugs which have differing receptor specificity may have common effects at the level o f second messengers. For example, there are preliminary indications that chronic administration of the neuroleptic, haloperidol, decreases carbachol-induced PI turnover in a fi~shion similar to that observed with lithium (Li et al. 1991). It has recently become apparent that there may be clinically significant neuropharmacologic associations between treatment with haloperidot and the use of nicotine. Several studies have shown not only that nicotine Correspondence to: R. Li
Dn~j administration. Male Sprague-Dawleyrats, weighing 325 ± 25 g, were housed in a temperature (23 ± t ° C) controlled environment with a 12 h tight-dark cycle and free access to food and water. Animals were treated for 6 weeks with (1) vehicle; (2) nicotine delivered via subcutaneously implanted Alzet 2ML4 osmotic pumps (12 mg/kg/day); (3) haloperidol decanoate (1.5 mg/kg/day, IM); or (4) nicotine and haloperidol combined in the same doses used individually (N= 5 in each group). Phosphoinositide hydrolysis assay. The brains were rapidly removed and dissected on ice. The hippocampus, striatum and frontal cortex were sliced into 350 × 350 ~tm cubes and transferred to buffer. The phosphoinositide hydrolysis assay was performed as previously described (Li et al. 1991). This method involves incubating the brain slices at 37° C with 0.3 ItCi myo-[2-3H]inositol followed by the addition of LiC1 (5 raM) and carbachol (1 raM). [3H]IP1 formation was determined by using a Dowex anion exchange resin (AG-1 × 8 formate form). To measure the incorporation of [aH]-inositol into the phospholipid, the lower organic phase was air-dried and the radioactivity counted after the addition of scintillation fluid.
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