- Email: [email protected]
Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats
Neuroscience Letters 230 (1997) 140–142
Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats Dean E. Dluzen*, Linda I. Anderson Department of Anatomy, Northeastern Ohio Universities, College of Medicine, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272-0095, USA Received 2 June 1997; received in revised form 25 June 1997; accepted 25 June 1997
Abstract In the present experiment we examined the effects of an in vitro infusion of nicotine (10 mM) upon dopamine release from superfused striatum of castrated male and female rats treated or not treated with estrogen. Estrogen exerted bidirectional effects on nicotine-evoked dopamine release as a function of the sex of the animal. Nicotine-evoked dopamine release was increased in estrogen treated females and decreased in estrogen treated males. Peak nicotine-evoked dopamine output from estrogen treated females was significantly greater than that of estrogen treated males. These results may be related to the gender differences in response to nicotine and smoking behavior. 1997 Elsevier Science Ireland Ltd. Keywords: Sex differences; Gonadal steroids; Nigrostriatal; Dopamine release; Dopamine transporter; Smoking
There are marked differences in the effects of nicotine (NIC) between males and females. For example, activity related energy expenditures following NIC are significantly greater in males [12] and the magnitude of smoking suppression from NIC is substantially lower in females [13]. Sex differences in response to NIC are also observed in laboratory rats. Long term NIC exposure produces a marked reduction in serum prolactin in females and an increase in luteinizing hormone in males [6] and intermittent exposure to cigarette smoke increases corticosterone secretion in the male rat [2], but not in diestrous females [1]. Finally, female rats receiving subcutaneous injections of NIC attain higher concentrations of NIC within the brain as compared with males [14]. The nigrostriatal dopaminergic (NSDA) system represents one important central nervous system site for the actions of NIC. At this site NIC has been shown to alter dopamine (DA) metabolism [16], uptake [5] and release [15,18]. Interestingly, similar modulatory effects upon NSDA function have also been observed in response to gonadal steroid hormones, in particular, estrogen [17] and clear sex differences in a number of NSDA functions have * Corresponding author. Tel.: +1 330 3252511, ext. 285; fax: +1 330 3251076; e-mail: [email protected]
been reported in response to estrogen [3,8,9]. Since the NSDA system is responsive to both NIC and estrogen and these two agents appear to exert differential effects in males and females, in the present experiment we evaluated the interactive effects of NIC and estrogen in male and female rats upon NSDA function. To accomplish this goal the in vitro NIC-evoked dopamine release from superfused striatal tissue fragments of castrated male and female rats treated or not treated with estrogen in vivo was examined. Adult male and female Sprague–Dawley rats were castrated and at 14 days post-castration approximately half the animals of each sex were implanted with an estrogen pellet (0.1 mg Estradiol; Innovative Research of America Inc.) while the remaining animals were subjected to a sham implant procedure. All animals were housed individually in a temperature (22°C) and light controlled (12:12 light/dark cycle, lights on at 0600 h) colony room. Food and water were available ad libitum. All treatments adhered to the NIH Guide for the Care and Treatment of Laboratory Animals and were approved by the Animal Care Committee at NEOUCOM. At 7–10 days post estrogen/sham implant, rats were sacrificed by rapid decapitation, the corpus striatum (CS) was removed, dissected into small tissue fragments and placed into individual superfusion chambers. Following a
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940 (97 )0 0487-4
D.E. Dluzen, L.I. Anderson / Neuroscience Letters 230 (1997) 140–142
35–45 min equilibration period during which no samples were collected, effluent samples were collected at 10 min intervals for the duration of the nine collection interval experiment. The modified Kreb’s Ringer phosphate (KRP) superfusion medium was delivered through the bottom of the superfusion chamber at a flow rate of approximately 25 ml/min. After a three interval basal collection period, NIC (10 mM), diluted in the KRP superfusion medium was infused for a 20 min period during collection intervals 4– 5. The normal KRP medium was resumed with the start of collection interval 6 and continued until the termination of the superfusion at collection interval 9. At the end of the superfusion, tissue fragments were removed and weighed. Assays for DA release were performed with HPLC-EC using a Biophase C-18, 5 mm sphere column to separate biogenic amines. Standards for DA were diluted in the KRP superfusion medium and doses of 12.5, 25, 50, 100, 200 and 400 pg/20 ml were used to construct a standard curve. The sensitivity of this assay, as defined by a response reliably detectable over baseline noise, was ≤12.5 pg/20 ml. In order to analyze DA responses resulting from the infusion of NIC into the superfusion chamber, the peak DA release rate value obtained during or immediately following NIC infusion was used for comparisons among the four treatment groups. This value was chosen since it was believed to best represent the evoked DA response to NIC. These data were entered into a 2 (Sex: Male vs. Female) ×2 (Treatment: Estrogen vs. No Estrogen) twoway ANOVA. Post-hoc comparisons were performed using the Fisher’s LSD test and P ≤ 0.05 was required for results to be considered statistically significant. The DA release rate profiles from castrated male and female rats treated with estrogen, along with a summary of the peak NIC-evoked DA responses of these two groups are contained within Fig. 1A. The analogous data from the non-estrogen treated castrated rats are contained within Fig. 1B. The overall analysis revealed a statistically significant interaction term (F1,25 = 4.24, P = 0.05). Subsequent post-hoc comparisons showed that peak NICevoked DA release of castrated females treated with estrogen was significantly greater than that of castrated males treated with estrogen (Fig. 1A). No statistically significant differences were obtained between castrated, non-estrogen treated male and female rats (Fig. 1B). The presence of the statistically significant interaction term along with an inspection of Fig. 1 illustrates the bases for the differential responses between castrated males and females as responsiveness of females tends to increase while that of males decreases in response to estrogen. The present results demonstrate that estrogen exerts bidirectional effects upon NIC-evoked DA release depending upon whether male or female striatal tissue is utilized. Under the present experimental conditions, maximal levels of NIC-evoked DA release were obtained in castrated estrogen treated females and minimal levels in castrated estrogen treated males. Castrated female rats and mice treated with
141
estrogen show augmented levels of spontaneous CS DA output as compared with non-treated castrated females [7,9]. By contrast, in the male rat spontaneous striatal DA output is enhanced in the castrated condition and reduced following testosterone propionate treatment [4]. In this way, the presence of gonadal steroid hormones has the effect of increasing basal CS DA output from castrated females, but decreasing output from castrated males. These dissimilarities in hormonal modulation of basal DA output may, in part, serve as one important indicator for the basis of the sex differences in response to NIC. The estrogen-dependent increase in basal CS DA output in the female can result from two potential sources. First, chronic treatment of castrated female rats, analogous to that of the present experiment, has been reported to increase the density of DA uptake sites within the CS [11]. Such an increase in DA uptake density
Fig. 1. Mean ± SEM in vitro dopamine (DA) release rates (pg/mg per min) from superfused corpus striatal (CS) tissue fragments (line graphs) and accompanying summary of the peak nicotine (NIC)-evoked DA responses obtained from each condition (bar graphs). Following a three interval basal collection period, NIC (10 mM) was directly infused into the superfusion chambers for a two collection interval (20 min) period. The resultant peak NIC-evoked DA responses were then used in the analysis. (A) Data from castrated male (n = 8) and female (n = 8) rats treated with estrogen. (B) Data from castrated male (n = 6) and female (n = 7) rats not receiving estrogen. Treatment with estrogen tends to reduce NIC-evoked DA release in castrated males and increase DA release in castrated females. The peak NIC-evoked DA responses obtained from castrated females receiving estrogen were significantly greater than that of castrated males treated with estrogen (*). No statistically significant differences in peak NICevoked DA responses were obtained between castrated, non-estrogen, treated male and female rats (NS).
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D.E. Dluzen, L.I. Anderson / Neuroscience Letters 230 (1997) 140–142
would necessitate an increase in basal striatal dopaminergic activity to compensate for the enhanced clearance. One consequence of augmented dopaminergic activity may be an increase in spontaneous DA output. Alternatively, increased basal DA output can result from the capacity for estrogen to block DA uptake [7]. The combination of NIC’s ability to both evoke DA release [15,18] and inhibit uptake [5] within the CS under conditions where basal responsiveness is increased, as achieved with the castrated estrogen treated female, could then result in the maximal levels of NICevoked DA efflux observed. Since gonadal steroid hormones appear to exert an opposite effect upon CS DA activity within the castrated male, a significantly attenuated NICevoked DA responses in the castrated estrogen treated males results. In the absence of estrogen these modulatory effects are lost with the outcome that levels of NIC-evoked DA release from castrated males and females were not significantly different and intermediate as compared to the extreme bidirectional NIC-evoked DA outputs obtained in their respective estrogen treated cohorts. These results may have important implications for the sex differences in NIC responsiveness that have been observed in both laboratory animals [1,2,6,14] and man [12,13]. It has been suggested that the reinforcing features of smoking are in part due to the capacity of NIC to evoke DA release. That being the case the augmented DA responses in estrogen treated females would imply a greater potential for reinforcement or dependency. It has been reported that the magnitude of smoking suppression from NIC is substantially lower in females [13]. Moreover, the rate of decline in smoking has been slower and the prevalence of cigarette smoking has actually increased from 25.6% in 1990 to 26.9% in 1992 in women [10]. While a number of social/ psychological factors undoubtedly contribute to these gender differences (e.g. concerns with weight gain, handling of stress related to parenting small children, minimizing health risks), the present results indicate a potentially important neurochemical basis for the interactive effects among NIC, gender and estrogen which may serve to enhance the effects of NIC in the female.
[3] [4]
[5]
[6]
[7]
[8]
[9]
[10] [11]
[12]
[13]
[14]
[15]
[16] [1] Anderson, K., Eneroth, P., Fuxe, K. and Harfstrand, A., Effect of acute intermittent exposure to cigarette smoke on hypothalamic and preoptic catecholamine nerve terminal systems and on neuroendocrine function in the diestrous rat, Arch. Pharmacol., 337 (1988) 131–139. [2] Anderson, K., Fuxe, K., Eneroth, P., Mascagni, F. and Agnati, L.F.,
[17] [18]
Effect of acute intermittent exposure to cigarette smoke on catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as well as on the secretion of adenohypohyseal hormones and corticosterone, Acta Physiol. Scand., 124 (1985) 277–285. Becker, J.B., Direct effect of 17B-estradiol on striatum: sex differences in dopamine release, Synapse, 5 (1990) 157–164. Dluzen, D.E. and Ramirez, V.D., Effects of orchidectomy on nigrostriatal dopaminergic function: behavioral and physiological evidence, J. Neuroendocrinol., 1 (1989) 285–290. Izenwasser, S., Jacocks, H.M., Rosenberger, J.G. and Cox, B.M., Nicotine directly inhibits [3H]dopamine uptake at concentrations that do not directly promote [3H]dopamine release in rat striatum, J. Neurochem., 56 (1991) 603–610. Jansson, A., Anderson, K., Fuxe, K., Bjelke, B. and Eneroth, P., Effects of combined pre- and postnatal treatment with nicotine on hypothalamic catecholamine nerve terminal systems and neuroendocrine function in the four week old and adult male and female diestrous rat, J. Neuroendocrinol., 1 (1989) 455–464. McDermott, J.L., Effects of estrogen upon dopamine release from the corpus striatum of young and aged female rats, Brain Res., 606 (1993) 118–125. McDermott, J.L., Kreutzberg, J.D., Liu, B. and Dluzen, D.E., Effects of estrogen treatment on sensorimotor task performance and brain dopamine concentrations in gonadectomized male and female CD-1 mice, Horm. Behav., 28 (1994) 16–28. McDermott, J.L., Liu, B. and Dluzen, D.E., Sex differences and effects of estrogen on dopamine and DOPAC release from the striatum of male and female CD-1 mice, Exp. Neurol., 125 (1994) 306– 311. McGann, K.P. and Spangler, J.G., Alcohol, tobacco, and illicit drug use among women, Prim. Care, 24 (1997) 113–122. Morissette, M. and Di Paolo, T., Effect of chronic estradiol and progesterone treatments of ovariectomized rats on brain dopamine uptake sites, J. Neurochem., 60 (1993) 1876–1883. Perkins, K.A., Grobe, J.E., Stiller, R.L., Fonte, C. and Goettler, J.E., Nasal spray nicotine replacement suppresses cigarette smoking desire and behavior, Clin. Pharmacol. Ther., 52 (1992) 627–634. Perkins, K.A., Sexton, J.E., Epstein, L.H., DiMarco, A., Fonte, C., Stiller, R.L., Scierka, A. and Jacobs, R.G., Acute thermogenic effects of nicotine combined with caffeine during light physical activity in male and female smokers, Am. J. Clin. Nutr., 60 (1994) 312–319. Rosecrans, J.A., Effects of nicotine on brain area 5-hydroxytryptamine function in male and female rats separated for differences in activity, Eur. J. Pharmacol., 16 (1971) 123–127. Rowell, R.P., Nanomolar concentrations of nicotine increase the release of [3H]dopamine from striatal synaptosomes, Neurosci. Lett., 189 (1995) 171–175. Tsai, M.J. and Lee, E.H.Y., Nicotine enhances brain biopterin concentrations in rats, Neurochem. Int., 27 (1995) 213–217. Van Hartesveldt, C. and Joyce, J.N., Effects of estrogen on the basal ganglia, Neurosci. Biobehav. Rev., 10 (1986) 1–14. Wonnacott, S., Soliakov, L., Wilkie, G., Redfern, P. and Marshall, D., Presynaptic nicotine acetylcholine receptors in the brain, Drug Dev. Res., 38 (1996) 149–159.
Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats Dean E. Dluzen*, Linda I. Anderson Department of Anatomy, Northeastern Ohio Universities, College of Medicine, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272-0095, USA Received 2 June 1997; received in revised form 25 June 1997; accepted 25 June 1997
Abstract In the present experiment we examined the effects of an in vitro infusion of nicotine (10 mM) upon dopamine release from superfused striatum of castrated male and female rats treated or not treated with estrogen. Estrogen exerted bidirectional effects on nicotine-evoked dopamine release as a function of the sex of the animal. Nicotine-evoked dopamine release was increased in estrogen treated females and decreased in estrogen treated males. Peak nicotine-evoked dopamine output from estrogen treated females was significantly greater than that of estrogen treated males. These results may be related to the gender differences in response to nicotine and smoking behavior. 1997 Elsevier Science Ireland Ltd. Keywords: Sex differences; Gonadal steroids; Nigrostriatal; Dopamine release; Dopamine transporter; Smoking
There are marked differences in the effects of nicotine (NIC) between males and females. For example, activity related energy expenditures following NIC are significantly greater in males [12] and the magnitude of smoking suppression from NIC is substantially lower in females [13]. Sex differences in response to NIC are also observed in laboratory rats. Long term NIC exposure produces a marked reduction in serum prolactin in females and an increase in luteinizing hormone in males [6] and intermittent exposure to cigarette smoke increases corticosterone secretion in the male rat [2], but not in diestrous females [1]. Finally, female rats receiving subcutaneous injections of NIC attain higher concentrations of NIC within the brain as compared with males [14]. The nigrostriatal dopaminergic (NSDA) system represents one important central nervous system site for the actions of NIC. At this site NIC has been shown to alter dopamine (DA) metabolism [16], uptake [5] and release [15,18]. Interestingly, similar modulatory effects upon NSDA function have also been observed in response to gonadal steroid hormones, in particular, estrogen [17] and clear sex differences in a number of NSDA functions have * Corresponding author. Tel.: +1 330 3252511, ext. 285; fax: +1 330 3251076; e-mail: [email protected]
been reported in response to estrogen [3,8,9]. Since the NSDA system is responsive to both NIC and estrogen and these two agents appear to exert differential effects in males and females, in the present experiment we evaluated the interactive effects of NIC and estrogen in male and female rats upon NSDA function. To accomplish this goal the in vitro NIC-evoked dopamine release from superfused striatal tissue fragments of castrated male and female rats treated or not treated with estrogen in vivo was examined. Adult male and female Sprague–Dawley rats were castrated and at 14 days post-castration approximately half the animals of each sex were implanted with an estrogen pellet (0.1 mg Estradiol; Innovative Research of America Inc.) while the remaining animals were subjected to a sham implant procedure. All animals were housed individually in a temperature (22°C) and light controlled (12:12 light/dark cycle, lights on at 0600 h) colony room. Food and water were available ad libitum. All treatments adhered to the NIH Guide for the Care and Treatment of Laboratory Animals and were approved by the Animal Care Committee at NEOUCOM. At 7–10 days post estrogen/sham implant, rats were sacrificed by rapid decapitation, the corpus striatum (CS) was removed, dissected into small tissue fragments and placed into individual superfusion chambers. Following a
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940 (97 )0 0487-4
D.E. Dluzen, L.I. Anderson / Neuroscience Letters 230 (1997) 140–142
35–45 min equilibration period during which no samples were collected, effluent samples were collected at 10 min intervals for the duration of the nine collection interval experiment. The modified Kreb’s Ringer phosphate (KRP) superfusion medium was delivered through the bottom of the superfusion chamber at a flow rate of approximately 25 ml/min. After a three interval basal collection period, NIC (10 mM), diluted in the KRP superfusion medium was infused for a 20 min period during collection intervals 4– 5. The normal KRP medium was resumed with the start of collection interval 6 and continued until the termination of the superfusion at collection interval 9. At the end of the superfusion, tissue fragments were removed and weighed. Assays for DA release were performed with HPLC-EC using a Biophase C-18, 5 mm sphere column to separate biogenic amines. Standards for DA were diluted in the KRP superfusion medium and doses of 12.5, 25, 50, 100, 200 and 400 pg/20 ml were used to construct a standard curve. The sensitivity of this assay, as defined by a response reliably detectable over baseline noise, was ≤12.5 pg/20 ml. In order to analyze DA responses resulting from the infusion of NIC into the superfusion chamber, the peak DA release rate value obtained during or immediately following NIC infusion was used for comparisons among the four treatment groups. This value was chosen since it was believed to best represent the evoked DA response to NIC. These data were entered into a 2 (Sex: Male vs. Female) ×2 (Treatment: Estrogen vs. No Estrogen) twoway ANOVA. Post-hoc comparisons were performed using the Fisher’s LSD test and P ≤ 0.05 was required for results to be considered statistically significant. The DA release rate profiles from castrated male and female rats treated with estrogen, along with a summary of the peak NIC-evoked DA responses of these two groups are contained within Fig. 1A. The analogous data from the non-estrogen treated castrated rats are contained within Fig. 1B. The overall analysis revealed a statistically significant interaction term (F1,25 = 4.24, P = 0.05). Subsequent post-hoc comparisons showed that peak NICevoked DA release of castrated females treated with estrogen was significantly greater than that of castrated males treated with estrogen (Fig. 1A). No statistically significant differences were obtained between castrated, non-estrogen treated male and female rats (Fig. 1B). The presence of the statistically significant interaction term along with an inspection of Fig. 1 illustrates the bases for the differential responses between castrated males and females as responsiveness of females tends to increase while that of males decreases in response to estrogen. The present results demonstrate that estrogen exerts bidirectional effects upon NIC-evoked DA release depending upon whether male or female striatal tissue is utilized. Under the present experimental conditions, maximal levels of NIC-evoked DA release were obtained in castrated estrogen treated females and minimal levels in castrated estrogen treated males. Castrated female rats and mice treated with
141
estrogen show augmented levels of spontaneous CS DA output as compared with non-treated castrated females [7,9]. By contrast, in the male rat spontaneous striatal DA output is enhanced in the castrated condition and reduced following testosterone propionate treatment [4]. In this way, the presence of gonadal steroid hormones has the effect of increasing basal CS DA output from castrated females, but decreasing output from castrated males. These dissimilarities in hormonal modulation of basal DA output may, in part, serve as one important indicator for the basis of the sex differences in response to NIC. The estrogen-dependent increase in basal CS DA output in the female can result from two potential sources. First, chronic treatment of castrated female rats, analogous to that of the present experiment, has been reported to increase the density of DA uptake sites within the CS [11]. Such an increase in DA uptake density
Fig. 1. Mean ± SEM in vitro dopamine (DA) release rates (pg/mg per min) from superfused corpus striatal (CS) tissue fragments (line graphs) and accompanying summary of the peak nicotine (NIC)-evoked DA responses obtained from each condition (bar graphs). Following a three interval basal collection period, NIC (10 mM) was directly infused into the superfusion chambers for a two collection interval (20 min) period. The resultant peak NIC-evoked DA responses were then used in the analysis. (A) Data from castrated male (n = 8) and female (n = 8) rats treated with estrogen. (B) Data from castrated male (n = 6) and female (n = 7) rats not receiving estrogen. Treatment with estrogen tends to reduce NIC-evoked DA release in castrated males and increase DA release in castrated females. The peak NIC-evoked DA responses obtained from castrated females receiving estrogen were significantly greater than that of castrated males treated with estrogen (*). No statistically significant differences in peak NICevoked DA responses were obtained between castrated, non-estrogen, treated male and female rats (NS).
142
D.E. Dluzen, L.I. Anderson / Neuroscience Letters 230 (1997) 140–142
would necessitate an increase in basal striatal dopaminergic activity to compensate for the enhanced clearance. One consequence of augmented dopaminergic activity may be an increase in spontaneous DA output. Alternatively, increased basal DA output can result from the capacity for estrogen to block DA uptake [7]. The combination of NIC’s ability to both evoke DA release [15,18] and inhibit uptake [5] within the CS under conditions where basal responsiveness is increased, as achieved with the castrated estrogen treated female, could then result in the maximal levels of NICevoked DA efflux observed. Since gonadal steroid hormones appear to exert an opposite effect upon CS DA activity within the castrated male, a significantly attenuated NICevoked DA responses in the castrated estrogen treated males results. In the absence of estrogen these modulatory effects are lost with the outcome that levels of NIC-evoked DA release from castrated males and females were not significantly different and intermediate as compared to the extreme bidirectional NIC-evoked DA outputs obtained in their respective estrogen treated cohorts. These results may have important implications for the sex differences in NIC responsiveness that have been observed in both laboratory animals [1,2,6,14] and man [12,13]. It has been suggested that the reinforcing features of smoking are in part due to the capacity of NIC to evoke DA release. That being the case the augmented DA responses in estrogen treated females would imply a greater potential for reinforcement or dependency. It has been reported that the magnitude of smoking suppression from NIC is substantially lower in females [13]. Moreover, the rate of decline in smoking has been slower and the prevalence of cigarette smoking has actually increased from 25.6% in 1990 to 26.9% in 1992 in women [10]. While a number of social/ psychological factors undoubtedly contribute to these gender differences (e.g. concerns with weight gain, handling of stress related to parenting small children, minimizing health risks), the present results indicate a potentially important neurochemical basis for the interactive effects among NIC, gender and estrogen which may serve to enhance the effects of NIC in the female.
[3] [4]
[5]
[6]
[7]
[8]
[9]
[10] [11]
[12]
[13]
[14]
[15]
[16] [1] Anderson, K., Eneroth, P., Fuxe, K. and Harfstrand, A., Effect of acute intermittent exposure to cigarette smoke on hypothalamic and preoptic catecholamine nerve terminal systems and on neuroendocrine function in the diestrous rat, Arch. Pharmacol., 337 (1988) 131–139. [2] Anderson, K., Fuxe, K., Eneroth, P., Mascagni, F. and Agnati, L.F.,
[17] [18]
Effect of acute intermittent exposure to cigarette smoke on catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as well as on the secretion of adenohypohyseal hormones and corticosterone, Acta Physiol. Scand., 124 (1985) 277–285. Becker, J.B., Direct effect of 17B-estradiol on striatum: sex differences in dopamine release, Synapse, 5 (1990) 157–164. Dluzen, D.E. and Ramirez, V.D., Effects of orchidectomy on nigrostriatal dopaminergic function: behavioral and physiological evidence, J. Neuroendocrinol., 1 (1989) 285–290. Izenwasser, S., Jacocks, H.M., Rosenberger, J.G. and Cox, B.M., Nicotine directly inhibits [3H]dopamine uptake at concentrations that do not directly promote [3H]dopamine release in rat striatum, J. Neurochem., 56 (1991) 603–610. Jansson, A., Anderson, K., Fuxe, K., Bjelke, B. and Eneroth, P., Effects of combined pre- and postnatal treatment with nicotine on hypothalamic catecholamine nerve terminal systems and neuroendocrine function in the four week old and adult male and female diestrous rat, J. Neuroendocrinol., 1 (1989) 455–464. McDermott, J.L., Effects of estrogen upon dopamine release from the corpus striatum of young and aged female rats, Brain Res., 606 (1993) 118–125. McDermott, J.L., Kreutzberg, J.D., Liu, B. and Dluzen, D.E., Effects of estrogen treatment on sensorimotor task performance and brain dopamine concentrations in gonadectomized male and female CD-1 mice, Horm. Behav., 28 (1994) 16–28. McDermott, J.L., Liu, B. and Dluzen, D.E., Sex differences and effects of estrogen on dopamine and DOPAC release from the striatum of male and female CD-1 mice, Exp. Neurol., 125 (1994) 306– 311. McGann, K.P. and Spangler, J.G., Alcohol, tobacco, and illicit drug use among women, Prim. Care, 24 (1997) 113–122. Morissette, M. and Di Paolo, T., Effect of chronic estradiol and progesterone treatments of ovariectomized rats on brain dopamine uptake sites, J. Neurochem., 60 (1993) 1876–1883. Perkins, K.A., Grobe, J.E., Stiller, R.L., Fonte, C. and Goettler, J.E., Nasal spray nicotine replacement suppresses cigarette smoking desire and behavior, Clin. Pharmacol. Ther., 52 (1992) 627–634. Perkins, K.A., Sexton, J.E., Epstein, L.H., DiMarco, A., Fonte, C., Stiller, R.L., Scierka, A. and Jacobs, R.G., Acute thermogenic effects of nicotine combined with caffeine during light physical activity in male and female smokers, Am. J. Clin. Nutr., 60 (1994) 312–319. Rosecrans, J.A., Effects of nicotine on brain area 5-hydroxytryptamine function in male and female rats separated for differences in activity, Eur. J. Pharmacol., 16 (1971) 123–127. Rowell, R.P., Nanomolar concentrations of nicotine increase the release of [3H]dopamine from striatal synaptosomes, Neurosci. Lett., 189 (1995) 171–175. Tsai, M.J. and Lee, E.H.Y., Nicotine enhances brain biopterin concentrations in rats, Neurochem. Int., 27 (1995) 213–217. Van Hartesveldt, C. and Joyce, J.N., Effects of estrogen on the basal ganglia, Neurosci. Biobehav. Rev., 10 (1986) 1–14. Wonnacott, S., Soliakov, L., Wilkie, G., Redfern, P. and Marshall, D., Presynaptic nicotine acetylcholine receptors in the brain, Drug Dev. Res., 38 (1996) 149–159.