Biphasic dose-related effects of morphine on dopamine release

Biphasic dose-related effects of morphine on dopamine release

Drug and Alcohol Dependence 65 (2001) 55 – 63 www.elsevier.com/locate/drugalcdep Biphasic dose-related effects of morphine on dopamine release Isabel...

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Drug and Alcohol Dependence 65 (2001) 55 – 63 www.elsevier.com/locate/drugalcdep

Biphasic dose-related effects of morphine on dopamine release Isabelle M. Maisonneuve *, Laurie M. Warner, Stanley D. Glick Center for Neuropharmacology and Neuroscience, MC-136, Albany Medical College, 47 New Scotland A6e, Albany, NY 12208 USA Received 1 December 2000; received in revised form 8 March 2001; accepted 11 March 2001

Abstract The effects of morphine on extracellular dopamine levels in brain have never been studied over a wide range of doses within a single study. This has made it difficult to make definitive interpretations of drug interactions with morphine. An inhibition of morphine-induced increases in dopamine could be interpreted as either antagonism or potentiation depending the shape of the morphine dose–response curve. Accordingly, the aim of the present study was to determine the effects of a wide range of morphine doses (0, 5, 10, 20 and 30 mg/kg, i.p.) on extracellular dopamine, DOPAC and HVA levels in the nucleus accumbens and striatum of awake and freely moving female Sprague– Dawley rats. The results show that, in both brain regions, the dose–response curve for morphine-induced increases in dopamine is non-monotonic while the dose– response curve for morphine-induced increases in DOPAC and HVA is monotonic in the nucleus accumbens. The results of this study are discussed in terms of their implications for interpreting drug interactions with morphine and with relationship to morphine’s mode of action at mu and kappa opioid receptors. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Dopamine; Microdialysis; Morphine; Nucleus accumbens; Striatum

1. Introduction Opioid agents such as morphine and heroin are readily self-administered by many species, including humans. Heroin abuse is currently an alarming problem in the US; according to the Drug Abuse Warning Network the number of heroin-related emergency room episodes has almost quadrupled since the early 1990s. This crisis may be related to the increase in purity of heroin observed during this same period (Drug Enforcement Administration Domestic Monitor Program), allowing heroin to be smoked instead of being injected and therefore eliminating the specter of HIV infection. Injected or smoked, heroin produces a ‘rush’ within seconds or minutes. This pleasurable effect is caused by the interaction of heroin’s metabolites, 6monoacetyl morphine and morphine, with opioid receptors, leading to immediate and specific changes in * Correspondence author. Tel.: + 1-518-2624991; fax: + 1-5182625799. E-mail addresses: [email protected] (I.M. Maisonneuve), [email protected] (L.M. Warner), [email protected] (S.D. Glick).

neurotransmission. Dopaminergic as well as non-dopaminergic systems have been postulated to underlie the rewarding effect of morphine. The dopaminergic mesolimbic system, which originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens, appears to be importantly involved. Laboratory animals will self-administer morphine into the VTA (Bozarth and Wise, 1981), and morphine infusions into the VTA lower brain stimulation reward thresholds (Broekkamp and Phillips, 1979). Morphine, like other drugs that have abuse liability, increases extracellular dopamine level in the nucleus accumbens when administered systemically (Di Chiara and Imperato, 1988) or infused directly into the VTA (Leone et al., 1991). Morphine activation of mu opioid receptors located on GABAergic neurons in the VTA has been shown to attenuate the negative control that these neurons exert on the firing of dopamine neurons and subsequently increase dopamine release in the nucleus accumbens (Kalivas et al., 1990). Numerous pharmacological and anatomical lesion studies have attempted to validate the essential role of the dopaminergic mesolimbic system in the rewarding effect of morphine. The results have been inconsistent (Pettit et al., 1984; Singer and Wallace,

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1984; Dworkin et al., 1988; Gerrits and Van Ree, 1996; but see Smith et al., 1985; Bozarth and Wise, 1986). Recently, the role of a dopaminergic mechanism in opioid reward has been reemphasized with the use of knockout mice. A deficit of dopamine D2 receptors leads to a marked decrease in the rewarding effect of opioids (Maldonado et al., 1997). Therefore, at the present time, it is possible to conclude that the dopaminergic system plays a critical, although not sole, role in the rewarding effect of morphine. Therapy for opioid addiction is mainly based on substitution therapy, replacing a short acting opioid drug with a long acting one. The success rate varies but usually oscillates around 30% (Johnson et al., 2000). New therapeutic approaches involve drugs that interact with systems that modulate the dopaminergic system. The reasoning is that if an agent can decrease basal dopamine release, it may also prevent the increase in dopamine levels induced by opioid agents, thereby reducing their rewarding appeal. Some examples are gamma-vinyl GABA (vigabatrin), ibogaine and its related congener, 18-methoxycoronaridine, as well as kappa agonists; all reduce dopaminergic transmission in the nucleus accumbens although by different mechanisms (Maisonneuve et al., 1991; Spanagel et al., 1992; Glick et al., 1996; Gerasimov et al., 1999). As hypothesized, they all reduce the dopaminergic effects of opioid agents (Maisonneuve et al., 1991; Xi et al., 1998; Gerasimov et al., 1999; Maisonneuve and Glick, 1999). One drawback in all these studies is that only one or two doses of the opioid agents have been examined making it difficult to understand how these potential therapies are really interacting with the opioid. The usual conclusion made in the various papers cited is that the treatment antagonizes the opioid; however, such a statement cannot be made with confidence without knowing the shape of the opioid dose– response curve. This is true for any drug interaction study. If the dose –response curve is monotonic, then an inhibition such as observed in the above mentioned studies can be accurately labelled an antagonism; but, if the dose– response curve is non-monotonic, this inhibition could result from either an antagonism or a potentiation. Such knowledge could have significant implications for our understanding of mechanisms mediating putative anti-addictive effects of new medications. The effects of morphine on extracellular dopamine levels in the brain have never been studied over a wide range of doses within a single study. In fact most studies have reported the effects of one to three dosages at most (e.g., studies done in the nucleus accumbens: Di Chiara and Imperato, 1988; Pothos et al., 1991; Rada et al., 1991; Maisonneuve et al., 1991; Pontieri et al., 1995; Borg and Taylor, 1997; Giorgi et al., 1997; Willins and Meltzer, 1998; Barrot et al., 1999; Di Giannuario et al., 1999). Because of our recent work with 18-methoxy-

coronaridine (Maisonneuve and Glick, 1999), a potentially novel anti-addictive medication, and because of our concern regarding morphine’s interactions with other such putative treatments, the present study was undertaken to determine the dose– response curve of morphine’s effects on extracellular levels of dopamine in the nucleus accumbens and striatum.

2. Materials and methods

2.1. Chemicals Morphine sulfate, purchased from Research Biochemicals International (Natick, MA), was dissolved in saline at the concentration (5–30 mg/ml) required for each experiment.

2.2. Animals The animals were female Sprague–Dawley derived rats (Taconic, Germantown, NY), weighing 250–275 g. They were maintained on a normal 12 h light cycle (lights on at 07:00 h; lights off at 19:00 h) with food and water ad libitum. For all animal experiments the ‘Principles of laboratory animal care’ (NIH publication No. 85-23, revised 1985) were followed.

2.3. In 6i6o microdialysis procedure Under pentobarbital anesthesia [50 mg/kg, intraperitoneally (i.p.)], the rats were implanted stereotaxically with two microdialysis guide cannulae (CMA: 8309010; Acton, MA) over the nucleus accumbens and the striatum. The coordinates were chosen such that, when inserted, the tips of the dialysis probes were located either in the medial portion of the shell area of the nucleus accumbens (AP,+1.6 mm and L, 9 0.8 mm from bregma; V, −8.6 mm from the surface of the skull) or in the striatum (AP,+ 0.5 mm; L, 9 3.0 mm; V, − 7.0 mm) (Paxinos and Watson, 1986). Animals were monitored for proper recovery but otherwise left undisturbed for 4 days after surgery. The afternoon prior to the in vivo microdialysis experiment the rats were placed in a cubical microdialysis chamber with free access to food and water. With the rats briefly anesthetized with Brevital (45 mg/kg, i.p.), dialysis probes (CMA 8309502 for the nucleus accumbens and CMA 8309503 for the striatum) were inserted through the guide cannulas. Artificial cerebrospinal fluid containing 146 mM NaCl, 2.7 mM KCl, 1.2 mM CaCl2 and 1.0 mM MgCl2 was delivered continuously by a Harvard syringe pump at a flow rate of 1 ml/min. Collection of perfusates began the next day. Twentyminute fractions were collected in vials containing 2.0 ml of 0.95 M perchloric acid solution (containing 500

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mg/l EDTA and 500 mg/l sodium metabisulfite). After 2 h of baseline collections, the rats received a dose of morphine (5, 10, 20 or 30 mg/kg, i.p.) or saline. The collection of dialysate samples was then continued for 3 h. Upon completion of an experiment, rats were killed by an overdose of pentobarbital. Each brain was removed, frozen and sliced (50 mm coronal sections) in a cryostat. The tracks left by the probes were identified and their exact positions determined by reference to the Paxinos and Watson atlas (1986). Only the dialysates of animals whose tracks were within 0.5 mm of the correct placement were analyzed.

2.4. Catecholamine assay Dialysate samples were assayed for dopamine, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) by high pressure liquid chromatography (HPLC) with electrochemical detection. The HPLC system consisted of a ESA 540 autosampler, an ESA 580 solvent delivery system, an ESA C18 column (MD-150) and an ESA Coulochem II electrochemical detector with a working electrode set at a potential of 0.25 V. The mobile phase was purchased from ESA (MD-TM) and consisted of 0.075 mM sodium dihydrogen phosphate, monohydrate, 0.0017 mM octane sulfonic acid and 25 mM EDTA in 10% HPLC grade acetonitrile, adjusted to pH 3.0 with phosphoric acid. The flow rate was set at 0.53 ml/min. Chromatograms were integrated using Hewlett Parkard ChemStation software.

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2.5. Statistical analysis The data, expressed as pmoles/10 ml or percent of baseline, were analyzed using analysis of variance (with repeated measures for time) followed by Duncan tests for post-hoc comparisons when appropriate.

3. Results

3.1. Extracellular basal le6els In both regions the basal levels of extracellular dopamine, DOPAC and HVA were not significantly different among the various group doses (two-way ANOVA with repeated measures, no main effect of Dose). For all dose groups pooled, the basal levels (mean of six 20-min sampling periods9 SEM), expressed as picomoles/10 ml, were the following: nucleus accumbens dopamine 0.0199 0.004, DOPAC 6.899 0.69, HVA 2.849 0.30 and striatum dopamine 0.0289 0.004, DOPAC 21.6491.24, HVA 13.509 0.63.

3.2. Effect of morphine on dopamine le6els An overall analysis of variance demonstrated an interaction between dose and time [F(56,812)= 5.49; PB .00001], but did not reveal any regional difference [main effect of region F(1,58)= 1.84; PB 0.1801]. In the nucleus accumbens (Fig. 1) the analysis of variance showed that the time courses induced by the various

Fig. 1. Extracellular dopamine levels in the nucleus accumbens, expressed as percent of baseline, prior to and following morphine (0 – 30 mg/kg, i.p.) administered at time 0. Insert: Average of the dopamine increases over 3 h induced by morphine (0 – 30 mg/kg, i.p.), expressed as percent of baseline; *P B0.05: morphine doses significantly different from control; cP B 0.05 morphine doses significantly different from 20 mg/kg morphine.

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Fig. 2. Extracellular dopamine levels in the striatum, expressed as percent of baseline, prior to and following morphine (0 – 30 mg/kg, i.p.) administered at time 0. Insert: Average of the dopamine increases over 3 h induced by morphine (0 – 30 mg/kg, i.p.), expressed as percent of baseline; *P B 0.05: morphine doses significantly different from control.

morphine doses were different [interaction between doses and time F(56,378) =3.38; P B 0.00001 and main effect of dose F(4,27)= 6.58; P B0.0008]. To decompose the above-mentioned interaction post-morphine values were compared to pre-morphine values at each dose. Five mg/kg morphine (n =6) increased dopamine levels significantly from 40 to 160 min following drug administration [main effect of time, F(14,70) = 5.14; P B .00001]; 10 mg/kg (n = 7) increased dopamine from 60 to the end of the experiment [main effect of time, F(14,84)=5.40; PB0.00001]; 20 mg/kg (n = 5) increased dopamine from 40 to the end of the experiment [main effect of time, F(14,56) = 7.78; P B 0.00001]; and 30 mg/kg (n=6) did not increase dopamine [main effect of time, F(14,70)= 1.44; P B0.1579]. To assess the shape of the dose – response, the percent increases observed after morphine administration were averaged across time (3 h). The curve was biphasic with the 5, 10 and 20 mg/kg doses inducing significant dopamine increases as compared to the saline group. The curve peaked at 20 mg/kg; 5 and 30 mg/kg doses were significantly different from 20mg/kg (Fig. 1, insert). In the striatum (Fig. 2), as in the nucleus accumbens, the analysis showed an interaction between dose and time [F(56,434)= 2.29; P B0.00001] and a main effect of dose [F(4,31)= 4.10; P B0.0088]. The analysis of each dose effect revealed that 5 mg/kg (n = 8) morphine increased dopamine levels significantly from 40 min following drug administration to the end of the experiment [main effect of time, F(14,98) = 9.28; PB 0.00001]; 10 mg/kg (n = 7) increased dopamine from 40 min following drug administration to the end of the experiment [main effect of time, F(14,84) = 4.85; PB

0.00001]; 20 mg/kg (n= 7) increased dopamine from 20 to 40 min after drug administration and from 80 min to the end of the experiment [main effect of time, F(14,84)= 7.58; PB 0.00001]; and 30 mg/kg (n=7) increase dopamine during the last sampling period [main effect of time, F(14,84)= 2.62; PB 0.0034]. In the striatum the shape of the dose response curve (average percent increase over 3 h) was also biphasic with the 10 and 20 mg/kg doses being significantly different from the saline group (Fig. 2, insert).

3.3. Effect of morphine on dopamine metabolite le6els 3.3.1. DOPAC An overall ANOVA of extracellular DOPAC levels expressed as percent of their respective baselines showed a three way interaction [F(56,812)= 3.26; PB 0.00001] with a significant effect of dose [F(4,58)= 6.78; PB 0.0002] and region [F(1,58)=54.1; PB0.00001]. All doses of morphine produced greater increases in DOPAC in the nucleus accumbens than in the striatum. In the nucleus accumbens (Fig. 3, left panel) the analysis of variance showed an interaction between dose and time [F(56,378)= 5.15; PB 0.00001] and a main effect of dose [F(4,27)=5.88; PB 0.0015]. The analysis of each dose revealed that 5 [main effect of time F(14,70)= 23.99; PB 0.00001] and 30 mg/kg [main effect of time F(14,70)= 21.87; PB 0.00001] morphine increased DOPAC levels from 20 min following drug administration to the end of the experiment while 10 [main effect of time F(14,84)= 13.94; PB 0.00001] and 20 mg/kg [main effect of time F(14,56)=

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10.08; PB0.00001] morphine increased DOPAC levels from 40 min following drug administration to the end of the experiment. The shape of the dose– response curve (average percent increase over 3 h) was monotonic. All the doses of morphine were significantly different from saline, but not from each other. In the striatum (Fig. 4, left panel) the analysis of variance showed an interaction between dose and time [F(56,434)= 1.74; PB 0.0013]. The analysis of each dose revealed that 5 mg/kg morphine increased DOPAC levels from 40 to 140 min following drug administration [main effect of time F(14,98) =7.9; P B0.00001]; 10 mg/kg increased DOPAC from 40 to 160 min following drug administration [main effect of time F(14,84)=6.92; P B.00001]; 20 mg/kg increased DOPAC from 100 min following drug administration to the end of the experiment [main effect of time F(14,84)=4.63; PB 0.00001] and 30 mg/kg increased DOPAC from 80 min following drug administration to the end of the experiment [main effect of time F(14,84)= 3.66; P B 0.0001]. The increases in the striatum were so small that when averaged across time (3 h) no main effect of doses was observed [main effect of dose F(4,31)=1.38; P B0.2626].

3.3.2. HVA An overall ANOVA of extracellular HVA levels expressed as percent of their respective baselines showed a three way interaction [F(56,812) =4.31; PB 0.00001] with a significant effect of dose [F(4,58) = 13.39; PB 0.00001] and region [F(1,58) =88.29; P B 0.00001]. All doses of morphine produced greater increases in HVA in the nucleus accumbens than in the striatum. In the nucleus accumbens (Fig. 3, right panel) the analysis of variance showed an interaction between dose and time [F(56,378) =9.52; P B0.00001] and a main effect of dose [F(4,27) = 9.72; P B 0.0001]. The analysis of each dose revealed that 5 [main effect of

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time F(14,70)= 25.45; PB 0.00001], 10 [main effect of time F(14,84)= 43.66; P B 0.00001], 20 [main effect of time F(14,56)= 27.83; PB 0.00001], and 30 mg/kg [main effect of time F(14,70)= 27.49; PB 0.00001] morphine increased HVA levels from 40 min following drug administration to the end of the experiment. The shape of the dose–response curve (average percent increase over 3 h) was monotonic. All the doses of morphine were significantly different from saline, but not from each other. In the striatum (Fig. 4, right panel) the analysis of variance showed an interaction between dose and time [F(56,434)= 3.85; PB 0.00001] and a main effect of dose [F(4,31)=4.70; PB 0.0044]. The analysis of each dose revealed that 5 [main effect of time F(14,98)= 24.18; PB 0.00001] and 10 mg/kg [main effect of time F(14,84)= 10.14; PB 0.00001] morphine increased HVA levels from 60 min following drug administration to the end of the experiment while 20 [main effect of time F(14,84)= 13.70; PB 0.00001] and 30 mg/kg [main effect of time F(14,84)= 12.03; PB 0.00001] morphine increased HVA from 80 min following drug administration to the end of the experiment. When averaged across time (3 h) all the doses of morphine were significantly different from saline and the curve peaked at 10 mg/kg; this dose was significantly different from control, 5 mg/kg and 30 mg/kg (PB 0.05).

4. Discussion This study demonstrates that the dose– response curve for morphine’s effect on extracellular dopamine levels in the nucleus accumbens and striatum has a curvilinear shape while the dose–response curve for morphine’s effects on extracellular dopamine metabolites is a monotonic curve, except for extracellular HVA in the striatum. The data agree with previous reports

Fig. 3. Average of the DOPAC (left panel) and HVA (right panel) increases over 3 h induced by morphine (0 – 30 mg/kg, i.p.) in the nucleus accumbens, expressed as percent of baseline; *PB 0.05: morphine doses significantly different from control.

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Fig. 4. Average of the DOPAC (left panel) and HVA (right panel) increases over 3 h induced by morphine (0 – 30 mg/kg, i.p.) in the striatum, expressed as percent of baseline; *PB 0.05: morphine doses significantly different from control.

from this and other laboratories (Maisonneuve et al., 1991; Pothos et al., 1991; Rada et al., 1991; Johnson and Glick, 1994; Shoaib et al., 1995; Di Giannuario et al., 1999) using single dosages of morphine on the ascending or descending limb of the dose– response curve. Opioid mu receptors are located both in the terminal areas and in the cell body regions of the mesolimbic and nigrostriatal dopamine pathways (Mansour et al., 1995). Stimulation of mu opioid receptors can produce a wide array of cellular responses that begin with the activation of an inhibitory G protein of the Gi or Go type. In the ventral tegmental area and substantia nigra, morphine inhibits GABAergic neurons and subsequently reduces their inhibition of dopaminergic neurons (Gysling and Wang, 1983; Lacey et al., 1989; Johnson and North, 1992). Administration of mu opioid receptor agonists in the VTA increases dopamine release in the VTA (Klitenick et al., 1992) and in the nucleus accumbens (Spanagel et al., 1992). Morphine also increases dopamine metabolism (Piepponen et al., 1999a). In the terminal regions direct infusion of morphine may cause a decrease in extracellular dopamine levels without affecting dopamine metabolites (Piepponen et al., 1999b); this action may also involve the mu opioid receptor. The net result of systemic mu opioid receptor agonist administration is an increase of dopamine, DOPAC and HVA release (Di Chiara and Imperato, 1988). Morphine is also a weak kappa opioid receptor agonist (Meng et al., 1993; Kristensen et al., 1995; Mignat et al., 1995). In the nigrostriatal and mesolimbic systems kappa opioid receptors are synthesized in the dopamine cell bodies and transported to the terminal regions (Mansour et al., 1996). In addition, in the nucleus accumbens, kappa opioid receptors are also located on non-dopaminergic neurons, possibly glutamatergic terminals (Mansour et al., 1996; Meshul and

McGinty, 2000). Dopamine release is under glutamate control in the nucleus accumbens (Segovia et al., 1999). Local and systemic administration of a kappa opioid agonist in terminal regions decreases dopamine output (Di Chiara and Imperato, 1988; Spanagel et al., 1992), either by stimulating kappa opioid receptors located on dopaminergic terminals (Smith et al., 1992) or by inhibition of glutamate release (Hill and Brotchie, 1999). Systemic kappa opioid receptor agonist administration has little effect on extracellular dopamine metabolite levels even at high doses (Di Chiara and Imperato, 1988). Therefore, the lack of significant increases in dopamine levels that we observed with a high dose (e.g. 30 mg/kg) of morphine can be explained by an opposing action of morphine on kappa opioid receptors. Findings published by Xi and colleagues in 1998, showing that kappa agonists (dynorphin A and U50,488) attenuate dopamine increases induced by heroin, and that a kappa antagonist (nor-binaltorphimine) enhances heroin’s effects, are consistent with our explanation. An interesting finding of the present study is the marked regional difference in the increases in dopamine metabolites induced by morphine. While morphine causes robust DOPAC and HVA increases in the nucleus accumbens, the increases in the striatum are minimal. This finding is in agreement with other laboratories’ findings. This difference may be due to a regional difference in the density of mu opioid receptors or in the number of dopamine autoreceptors. The densities of mu opioid receptors have been found to be fairly similar in the substantia nigra and ventral tegmental areas (Mansour et al., 1995). Dopamine synthesis is controlled by autoreceptors located in the terminal regions (Kehr et al., 1972). Several reports suggest that D3 receptors could serve this function (Aretha et al., 1995; Nissbrandt et al., 1995), and it has been shown that the distribution of D3 receptors differs markedly in the nucleus accumbens and striatum (Meador-

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Woodruff, 1994). Since extracellular DOPAC is closely related to the amount of newly synthesized dopamine, the regional disparity in DOPAC levels may be explained by a regional difference in the control of dopamine synthesis. While we observed a marked regional difference in dopamine metabolite changes, there was no statistical difference between the regional increases in extracellular dopamine levels induced by morphine. This is at odds with results published by the Di Chiara laboratory (Di Chiara and Imperato, 1988; Cadoni and Di Chiara, 1999) in which morphine caused a greater increase in dopamine in the nucleus accumbens than in the striatum. This discrepancy may be due to a technical difference. In the present studies, the dialysis experiment was not conducted until 4– 5 days after surgical implantation of guide cannulae. However, in both of the previous studies, the dialysis experiment occurred within 24 h of the implantation of dialysis probes, and the stress due to surgery may not yet have dissipated. It is therefore possible that an abnormal baseline may have altered the response to morphine. Indeed, stress has been shown to differentially alter dopamine levels in the nucleus accumbens and striatum (Abercrombie et al., 1989). Knowing the effects of morphine over a wide range of dosages should allow one to make more definitive conclusions regarding treatments that attenuate the dopamine increases induced by a certain dose of morphine. Our laboratory encountered such a situation while studying the interactions of 18-methoxycoronaridine, a putative anti-addictive agent, and morphine. In that study (Maisonneuve and Glick, 1999) 18-methoxycoronaridine pretreatment attenuated, in the nucleus accumbens, the increases in extracellular dopamine levels induced by morphine (5 mg/kg) while enhancing the increases in extracellular metabolite levels. The latter enhancement of dopamine metabolites along with the dose – response effects shown in this study suggest that the effect of 18-methoxycoronaridine pretreatment is to potentiate the acute dopamine response to morphine. In contrast, the same 18-methoxycoronaridine pretreatment has recently been shown to antagonize the sensitized dopamine response to chronic morphine (Szumlinski et al., 2000), consistent with 18-methoxycoronaridine’s effects on morphine self-administration (Maisonneuve and Glick, 1999). 18-Methoxycoronaridine has affinity for a variety of receptors (e.g. opioid, 5HT3, nicotinic, Glick et al., 1999). The results of this study suggest that different actions of 18-methoxycoronaridine may be responsible for its differential interaction with acute and chronic morphine treatment. This study demonstrates that, although the dose–response curve for morphine’s effects on extracellular dopamine metabolites in the nucleus accumbens is monotonic, the dose– response curve for morphine’s

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effect on extracellular dopamine levels has a curvilinear shape. Failure to consider the latter may lead to misinterpretations of drug interactions involving morphine’s effects on dopamine release. Although it is difficult to relate the present findings with bolus doses of morphine to situations in which animals repeatedly self-administer small doses of morphine, our understanding of morphine’s mechanism of action is largely based on similarly conducted studies with bolus doses. Moreover, human addicts typically administer bolus doses of opioids rather than intermittent small doses. Hence, the present results may be more relevant to mechanisms of addiction than would be immediately apparent.

Acknowledgements This research was supported by NIDA grant DA 03817.

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