From Bozarth, M.A., & Wise, R.A. (1986). Involvement of the ventral tegmental dopamine system in opioid and psychomotor stimulant reinforcement. In L.S. Harris (Ed.), Problems of drug dependence, 1985 (National Institute on Drug Abuse Research Monograph 67, pp. 190-196). Washington, DC: U.S. Government Printing Office.
Involvement of the Ventral Tegmental
Dopamine System in Opioid and Psychomotor
Michael A. Bozarth and Roy A. Wise
Center for Studies in Behavioral Neurobiology
Montréal, P.Q. H3G 1M8 CANADA
We have previously reported evidence that opioid reinforcement is dependent on an action in the ventral tegmental area. Rats will self-administer morphine directly into the ventral tegmental area (Bozarth & Wise, 1981a), and the approximate anatomical boundaries of these reward-relevant opiate receptors correspond to the location of the dopamine-containing cell bodies in the ventral tegmentum (Bozarth, 1982; Bozarth & Wise, 1982). This reinforcing action of morphine is anatomically dissociable from physical dependence mechanisms (Bozarth & Wise, 1983a, 1984), and reward from systemically administered heroin is blocked by the administration of dopamine-receptor blockers (Bozarth & Wise, 1981b; Phillips et al., 1982). The reinforcing action of psychomotor stimulants is also attenuated by dopamine-receptor blocking drugs (Yokel & Wise, 1975, 1976). Lesions of the dopamine-terminal field in the nucleus accumbens disrupt intravenous stimulant self- administration (Lyness et al., 1979; Roberts et al., 1977, 1980, and amphetamine has been shown to be self-administered directly into this brain site (Hoebel et al., 1983).
These data suggest that the reinforcing actions of both opioids and psychomotor stimulants are mediated by the ventral tegmental dopamine system. This has led to speculation that a common reward substrate may be involved in the rewarding effects of these two pharmacologically distinct classes of drugs (Bozarth & Wise, 1983b; Wise & Bozarth, 1981, 1982).
The ventral tegmental dopamine system has terminals in several brain regions including the frontal cortex and amygdala, but most work regarding the effects of lesions on drug self-administration has focused on the terminal field located in the nucleus accumbens. Dopamine-depleting lesions of this site attenuate psychomotor stimulant self-administration (Lyness et al., 1979; Roberts et al., 1977, 1980). Recently, it has been reported that similar lesions fail to modify heroin intake (Pettit et al., 1984; also Bozarth & Wise, unpublished observation). This finding has been interpreted by some to suggest that opioid reinforcement involves mechanisms other than those mediating psychomotor stimulant reinforcement (e.g., Koob, 1985). This conclusion, however, neglects evidence that psychomotor stimulant reinforcement may also involve projections of this system outside of the nucleus accumbens: (a) psychomotor stimulants are self-administered directly into the frontal cortical projections of this system (Goeders & Smith, 1983; Phillips et al., 1981), and (b) some residual responding for intravenous stimulant drugs is present even after lesions of the nucleus accumbens (Roberts et al., 1980). Thus, other terminal projections of this system may be involved in reward from psychomotor stimulants. Another approach to assessing the importance of the ventral tegmental dopamine system in reinforcement from systemic opioid injections is to lesion the cell bodies of this system (viz., directly at the ventral tegmentum) and simultaneously deplete all of the terminal projections of this system. Previous work has shown that dopamine-depleting lesions at the ventral tegmentum effectively disrupt psychomotor stimulant self-administration (Bozarth & Wise, unpublished observation, see Addendum; Roberts & Koob, 1982).
Rats were stereotaxically microinjected with 6-OHDA (8 mg/2 ml) into the ventral tegmentum and received intravenous catheters. Some subjects were pretreated with pargyline (50 mg/kg, i.p.) and desmethylimipramine (25 mg/kg, i.p.) to selectively destroy dopamine-containing neurons (n=15), while other received 6-OHDA alone which depletes both dopamine an norepinephrine (n=13). After 7 to 10 days recovery from the surgical procedure, the subjects were tested for the acquisition of a lever-pressing response to self-administer heroin (0.1 mg/kg/infusion) during 2-hour daily sessions. Testing continued for a total of 20 days. Other unlesioned subjects were tested for heroin (n=14) and saline (n=7) self-administration. Data from the second hour of testing were used to minimize the effects of session duration on mean hourly response levels (Bozarth, unpublished observation).
Figure 1 shows the mean levels of drug intake across the 20 days of testing for the 6-OHDA lesioned groups, for the unlesioned group, and for control animals tested for saline self-administration. Unlesioned subjects learned to self-administer heroin while those injected with 6-OHDA showed responding similar to saline control animals. Figure 2 compares the effects of 6-OHDA-only (dopamine and norepinephrine depletions) and 6-OHDA plus pargyline and desmethylimipramine (dopamine-specific depletions); the fact that similar effects on behavior were produced by both treatments suggests that the lesion effect was due to dopamine depletions and that noradrenergic systems are not involved. The level of drug intake was also shown to be related to the extent of lesioning (see Figure 2).
Figure 1: The effect of 6-OHDA lesions on intravenous heroin self-administration. 6-OHDA lesioned; heroin control; saline control. The data depict the Means and SEMs of 5-day blocks of testing. Note: Figure was revised from original publication and includes additional subjects tested with 6-OHDA lesions.
Figure 2: The effects of 6-OHDA lesions on intravenous heroin self-administration. Data represent the last 5-day block of testing. Numeric values inside the bars indicate the number of animals tested in each condition; numeric values below the bars depict the level of dopamine remaining after lesioning. Control dopamine levels in the ventral tegmentum were 11.09 ± 2.33 pg/mg.
To determine if nonspecific effects on motor activity could account for the effect of these dopamine-depleting lesions on heroin intake, a separate group of rats was tested for the acquisition of a lever-pressing response to receive food. Rats with ventral tegmental lesions who were food-deprived to 80% of their ad libitum weight learned to lever-press for food at rates comparable to unoperated control subjects (means = 94 ±18 and 103 ±19 per 20 minutes, respectively; n=11/group; see Addendum). This rules out any possible effect of these lesions on general motor activity and suggests that the effect of these lesions is specific to drug-reinforced responding.
The results from Experiment I appear to confirm the hypothesis that opioid and psychomotor stimulant reinforcement involve a common neural substrate. If both classes of drugs derive their reinforcing actions by the activation of this ventral tegmental system, the activation by one of these drugs should render activation by the other redundant. That is, the opioid action in the ventral tegmental area should be equivalent to psychomotor stimulant activation in the terminal fields of this system.
Animals given noncontingent injections of a drug while intravenously self-administering that compound show a pause in their responding for drug. This is probably related to the subjectsí attempts to maintain a constant level of rewarding drug action (Wise, 1985; Yokel, 1985). If opioids are rewarding because of their action at the ventral tegmental dopamine-containing cell bodies and psychomotor stimulants are rewarding because of their action in the dopamine-terminal fields of the same system, then opioid activation at the ventral tegmentum should cause a significant change in the intravenous self-administration of psychomotor stimulants.
Rats were stereotaxically implanted with unilateral cannulae in the ventral tegmental area and received intravenous catheters. After 5 to 7 days recovery from the surgical procedure, they were trained to intravenously self-administer cocaine (1 mg/kg/infusion) during daily 6-hour test sessions. Once patterns of responding for cocaine stabilized (usually within 10 to 15 days of testing), the subjects were unilaterally microinjected with drug vehicle (i.e., Ringerís solution) into the ventral tegmental area. Next, a series of central morphine injections (0.3 to 10.0 mg/0.5 ml Ringerís solution) were begun with microinjection challenges occurring on every third day of testing. After the completion of this phase of testing, the central morphine challenge of intravenous cocaine self-administration was repeated but with narcotic antagonist injections 20 minutes prior to testing (naltrexone hydrochloride, 3 mg/kg, i.p.). This latter test should determine if the effect of central morphine injections is due to a specific opiate-receptor mediated action or is the result of some nonspecific physico-chemical interaction.
Changes in cocaine intake after morphine microinjections are shown in Figure 3. There was a dose-dependent decrease in responding for intravenous cocaine, and the time-course of this effect corresponded to the time-course of other morphine effects from central injections (Bozarth, unpublished observations). Pretreatment with naltrexone had no effect on control levels of responding for cocaine but it antagonized the effect of central morphine on cocaine intake (see Figure 4). These data indicate that central morphine injections can cross-substitute for systemic cocaine reinforcement and that this is due to a specific effect mediated by opiate receptors.
Figure 3: The effect of noncontingent ventral tegmental morphine injections on intravenous cocaine self-administration. All microinjections were unilateral in 0.5 ml Ringerís solution. Ventral tegmental injections were given 1 hour into the test session.
Figure 4: Dose-response analysis illustrated the effect of noncontingent ventral tegmental morphine injections on responding for intravenous cocaine. Data represent the percent inhibition of normal drug intake during the time of peak drug action (i.e., 1 and 2 hours after microinjections). The dose-response curve was shifted to the right by systemic naltrexone injections 20 minutes prior to testing.
There are two points that deserve special mention regarding the effect of ventral tegmental morphine on responding for intravenous cocaine injections. First, morphine microinjections produce a response slowing and not a true response pause. This would be expected from unilateral activation of a reward substrate that is bilaterally activated by systemic cocaine injections: the intravenous cocaine effect produced on the side contralateral to the morphine injection should continue to contribute to the net reinforcing impact of this experimental condition. Second, an examination of the individual data records reveals that the inter-response times for cocaine self-administration increase following ventral tegmental morphine injections and gradually return to baseline values in an orderly fashion. If the effect of these microinjections on cocaine intake were the result of some nonspecific effect on general motor activity, such orderly data would not be expected. Also, these morphine microinjections have been reported to increase (not decrease) locomotor activity (Joyce & Iversen, 1979), and several subjects increased responding on an "inactive" lever while they decreased lever pressing on the cocaine associated lever; thus these microinjections might increase lever pressing in a nonspecific fashion, but they would be unlikely to produce a nonspecific decrease in drug intake.
The experiments reported in this paper confirm the importance of the ventral tegmental dopamine system in opioid reinforcement and strengthen the notion that opioid and psychomotor stimulant reinforcement may involve the activation of a common reward substrate. Although dopamine-depleting lesions of the nucleus accumbens produce different effects on heroin and cocaine self-administration (Bozarth & Wise, unpublished observations; Pettit et al., 1984), depletions at the level of the dopamine-containing cell bodies of the ventral tegmentum produce similar effects on the intravenous self-administration of both classes of compounds (see Addendum). Furthermore, the demonstration that morphine microinjected into the ventral tegmental area results in a dose-dependent attenuation in responding for intravenous cocaine provides direct support for the hypothesis that opioids activate the same rewarding neural pathway as psychomotor stimulants.
The notion that opioids and psychomotor stimulants may activate the same reward pathway is consistent with their well documented effects on brain stimulation reward (e.g., Esposito & Kornetsky, 1978). These and other addictive drugs lower thresholds (Esposito & Kornetsky, 1978) and increase rates of lever pressing (Reid & Bozarth, 1978) for brain stimulation reward. The important role of dopamine in the rewarding effects of electrical brain stimulation (Fibiger, 1978; Wise, 1978) and its apparent role in psychomotor stimulant and opioid reinforcement have prompted speculation about a common neural circuit underlying these rewarding effects (Wise & Bozarth, 1984). Whether additional mechanisms are involved in the long-term maintenance of heroin self-administration remains to be determined.
Lydia Alessi performed neurochemical analysis for Experiment I. Aileen Murray and Martha Asselin were responsible for animal surgeries and behavioral testing in Experiments I an II, respectively. Naltrexone hydrochloride was generously donated by Endo Laboratories (Garden City, NY). M.A.B. is a University Research Fellow sponsored by the Natural Sciences and Engineering Research Council of Canada. This research was supported by grants from the Medical Research Council (Canada) and the National Institute on Drug Abuse (U.S.A.).
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Figure 5: Comparison of the effects of ventral tegmental 6-OHDA
lesions on intravenous heroin and cocaine self-administration. Subjects
were tested for the acquisition of drug self-administration across 20 days
of testing. The figure shows the mean (± SEM ) percentage of control
drug-intake levels for the last 5-day block of testing.
Figure 6: Failure of ventral tegmental 6-OHDA lesions to affect
learning to lever press for a food reinforcer. The figure shows the mean
(± SEM) number of lever presses for control and for 6-OHDA lesioned
subjects across three daily test sessions.