Dissociation of morphine-induced potentiation of turning and striatal dopamine release by amphetamine in the nigrally-lesioned rat
Introduction
Presynaptic dopamine neurons are destroyed when rats are given a unilateral nigrostriatal lesion and postsynaptic dopamine receptor supersensitivity develops in the lesioned striatum (Robinson and Becker, 1983). Administration of the psychomotor stimulant amphetamine to nigrally lesioned rats produces ipsilateral turning (Lynch and Carey, 1989; Ungerstedt and Arbuthnott, 1970). Amphetamine preferentially releases newly synthesized dopamine from presynaptic cells (Arbuthnott et al., 1991; Kuczenski and Segal, 1989; Zetterström et al., 1986). In vivo microdialysis studies show that amphetamine increases extracellular dopamine levels in the striatum and nucleus accumbens of the rat (Di Chiara and Imperato, 1988a, Di Chiara and Imperato, 1988b; Kalivas and Stewart, 1991). This evidence suggests that amphetamine produces turning by increasing extracellular dopamine levels in the striatum.
Amphetamine-induced turning can be modified by μ-opioid receptor agonists. The μ-opioid receptor agonists levorphanol, meperidine, methadone, and morphine potentiated amphetamine-induced turning in the nigrally-lesioned rat (Kimmel and Holtzman, 1997). In addition, μ-opioid receptor agonists themselves can induce turning and dopamine release. For example, buprenorphine, levorphanol, and methadone produced turning greater than saline did in nigrally-lesioned rats (Kimmel and Holtzman, 1997). Fentanyl, methadone, and morphine also increased extracellular dopamine levels in the striatum and ventral tegmental area of rats (Di Chiara and Imperato, 1988a, Di Chiara and Imperato, 1988b; Kalivas and Stewart, 1991). Thus, opioid drugs can increase dopamine release as well as produce turning on their own and potentiate amphetamine-induced turning.
μ-Opioid receptors are localized upon inhibitory γ-aminobutryic (GABA) neurons that project from the striatum to the substantia nigra (Mansour et al., 1995). The stimulation of the μ-opioid receptors inhibits GABAergic activity, thus increasing dopamine release from nigrostriatal dopamine neurons (Kalivas and Stewart, 1991). This evidence suggests that stimulation of μ-opioid receptors by morphine increases dopamine release in the striatum, leading to an increase in dopamine-mediated behaviors.
The purpose of this study was to test the hypothesis that morphine potentiates turning induced by amphetamine by potentiating the amphetamine-induced release of dopamine in the intact striatum. To do this, we examined the effects of morphine (3.0 and 10 mg/kg) alone, amphetamine (1.0 mg/kg) alone, and the combination, on turning in nigrally-lesioned rats over a 4-h time period. In a second group of nigrally-lesioned rats, we placed a microdialysis probe into the intact striatum and measured extracellular dopamine levels after the administration of the same drugs that were tested in the first group. The doses of amphetamine and morphine selected for this study each increased dopamine release in the striatum of rats (Di Chiara and Imperato, 1988a, Di Chiara and Imperato, 1988b) and this dose of amphetamine and the lower dose of morphine had a synergistic effect on turning (Kimmel and Holtzman, 1997). Based on earlier microdialysis studies, we expected that morphine would potentiate amphetamine-induced dopamine release in the striatum and that this would correlate with turning.
Section snippets
Subjects
Male Sprague–Dawley rats (Sasco, Omaha, NE) weighing 240–260 g were used. All rats were group housed in polycarbonate cages and maintained in a temperature-controlled colony room with a 12L:12D light cycle. Rats had free access to food (Purina Rodent Chow, Purina Mills, St. Louis, MO) and water.
6-Hydroxydopamine lesions
The right nigrostriatal pathway of rats was lesioned by a single injection of 6-hydroxydopamine. Rats were anesthetized with 3.3 mg/kg Equithesin (i.p.) and placed into a stereotaxic frame. Stereotaxic
Results
Morphine (3.0 mg/kg) produced slight turning (F(7,15)=2.15, P=0.014), while 1.0 mg/kg amphetamine produced slightly more turning that peaked at 42 turns/15 min for the first 45 min after administration, then tapered off over 3 h (F(7,15)=9.01, P<0.0001) (Fig. 1A). The administration of 3.0 mg/kg morphine with 1.0 mg/kg amphetamine produced a large increase in turning, with a maximum of 108 turns/15 min, 75 min after administration. A two-way ANOVA with repeated measures on both factors revealed
Discussion
In this study, we found that while 3.0 mg/kg morphine alone and 1.0 mg/kg amphetamine alone produced low amounts of turning in nigrally-lesioned rats and that the combination produced large, significant amounts of turning that lasted for 4 h. These data agree with those found in earlier studies in this laboratory, in which 3.0 mg/kg morphine potentiated amphetamine-induced turning (Kimmel and Holtzman, 1997, Di Chiara and Imperato, 1988b). In contrast, 10 mg/kg morphine combined with 1.0 mg/kg
Acknowledgements
This research was supported by Grant DA00541, Research Scientist Award K05 DA00008, and NRSA Predoctoral Fellowship F31 DA05692-01, all from the National Institute on Drug Abuse, National Institutes of Health.
References (24)
- et al.
Comparison of the effects of prototypical behavioral stimulants on locomotor activity and rotational behavior in rats
Pharmacol. Biochem. Behav.
(1996) - et al.
Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats
Brain Res.
(1993) - et al.
δ-Opioid receptor antagonists attenuate motor activity induced by amphetamine but not cocaine
Eur. J. Pharmacol.
(1993) - et al.
Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity
Brain Res. Rev.
(1991) - et al.
Amphetamine-induced rotation reveals post 6-OHDA lesion neurochemical organization
Behav. Brain Res.
(1989) - et al.
Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications
Trends Neurosci.
(1995) - et al.
Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment
Brain Res.
(1991) - et al.
The rotating rodent: a two component system
Eur. J. Pharmacol.
(1978) - et al.
The rotational behavior model: asymmetry in the effects of unilateral 6-OHDA lesions of the substantia nigra in rats
Brain Res.
(1983) - et al.
Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine behaviour system
Brain Res.
(1970)