Abstract
The curve-shift (rate-frequency) paradigm was used to quantify the interaction of cocaine administration with the rewarding effects of lateral hypothalamic electrical stimulation. First, eight animals were tested at 48-h intervals with increasing doses of cocaine (0.5, 1, 2, 4, 8, 16 or 32 mg/kg i.p.); tests with saline were given on intervening days. Cocaine produced dose-orderly leftward shifts of the functions relating response rate to stimulation frequency, which reduced, for each animal, the amount of stimulation required to sustain responding; the two highest doses of the drug shifted the mean rate-frequency curve by 0.47 log units, more than doubling the rewarding potency of the brain stimulation. Baseline thresholds did not change between tests. Next, evidence for sensitization or tolerance was sought from five additional groups of animals, one group given 4 mg/kg and two groups given 16 mg/kg of cocaine at 48-h intervals, and another two groups maintained for 7 days with thrice-daily injections of 10 mg/kg of cocaine or saline. Consistent with results seen in other brain stimulation reward paradigms, there was no evidence of tolerance or sensitization to cocaine’s reward-potentiating effects as quantified in the rate-frequency paradigm.
Cocaine (Crow, 1970; Esposito et al., 1978; Frank et al., 1992; Kokkinidis and McCarter, 1990) and several other habit-forming drugs (Gardner 1992; Wise 1980, 1996; Wise and Rompré, 1989) are not only rewarding2 in their own right; they also increase lever-pressing that is maintained by the rewarding effects of lateral hypothalamic electrical stimulation. When tested in the “curve-shift” paradigm (Frank et al., 1987; Gallistel, 1987; Maldonado-Irizarry et al., 1994; Miliaressis et al., 1986) these drugs increase the potency of rewarding stimulation, shifting to the left the functions relating response rate to the frequency, intensity or train length (Frank et al., 1987; Gallistel and Karras, 1984; Gallistel and Freyd, 1987). The curve-shift paradigm offers what is essentially a traditional dose-response analysis of brain stimulation reward (Liebman, 1983) in which it is inferred that leftward or rightward shifts reflect treatments that increase or decrease, respectively, the rewarding potency of the stimulation (Edmonds and Gallistel, 1974). Upward or downward shifts, on the other hand, are caused by changes in the response demands of the task (Edmonds and Gallistel, 1974; Stellar and Neeley, 1982); such shifts, when seen after drug or other experimental treatments and in the absence of changes in response demands, are interpreted as reflecting treatment-induced changes in the response capacity of the animal (Edmonds and Gallistel, 1974; Stellar and Neeley, 1982).
Psychophysicists of brain stimulation reward (Edmonds et al., 1974; Gallistel 1978; Gallistel et al., 1981;Miliaressis et al., 1986) have argued that the most useful metric of drug-induced changes in the rewarding potency of brain stimulation is the amount of stimulation that must be given to offset a given drug treatment and restore the level of an animal’s performance to baseline. The emerging consensus (Gallistel 1987; Gallistel and Freyd 1987; Miliaressis et al., 1986; Wise and Rompré, 1989) is that stimulation frequency (the number of stimulation pulses per reward) is the most useful stimulation parameter in drug studies. Rate-frequency determinations have been used to quantify the reward-enhancing effects of systemic amphetamine (Gallistel and Freyd, 1987; Gallistel and Karras, 1984; Wise and Munn, 1993), morphine (Carlezon and Wise 1993b), nicotine (Bauco and Wise, 1994) and phencyclidine (Carlezon and Wise, 1993a), and of central injections of amphetamine (Colle and Wise, 1988) and morphine (Bauco et al., 1993). In the present investigation this approach was used to assess the effects of cocaine across the full range of its effective doses.
In addition, the effects of repeated dosing were assessed by use of this metric. Although it has been widely believed that there is tolerance to the habit-forming effects of addictive drugs, sensitization has been shown to develop to some effects of amphetamine (Piazza et al., 1990) and cocaine (Horger et al., 1990, 1992). Although it is difficult to quantify progressive changes in the rewarding efficacy of drugs in drug self-administration (see,e.g., Gerber and Wise, 1989; Winger et al., 1989) and conditioned place-preference (Bozarth, 1987) paradigms, several drugs augment the rewarding effects of brain stimulation and this effect usually predicts the drug’s rewarding effects (Wise, 1996). Studies of the effects of cocaine by use of rate (Kokkinidis and McCarter, 1990) or rate-duration measures (Frank et al., 1988) suggest that there is no sensitization and little, if any, tolerance to the reward-enhancing effects of medial forebrain bundle electrical stimulation. The present study was designed to examine these questions with the rate-frequency curve-shift paradigm.
Methods
Subjects.
Forty-five 300- to 350-g male Long-Evans rats (Harlan Sprague Dawley, Indianapolis, IN) were used. They were housed individually in polyethylene cages with wood chip bedding and free access to food and water. Lighting was maintained on a normal 12-h light/dark cycle; the animals were tested at the end of the dark phase.
Surgery.
Each animal was implanted bilaterally with monopolar stainless steel electrodes (0.25-mm diameter) insulated with varnish (Formvar), except for the rounded tip, under sodium pentobarbital anesthesia (65 mg/kg i.p.). Atropine (0.6 mg/kg i.p.) was administered 20 min before the anesthetic to minimize bronchial secretions,. Flat-skull coordinates were 2.5 mm posterior to bregma, 1.7 mm lateral to the midline and 8.0 mm ventral to the skull surface. Four stainless steel screws were used to anchor each electrode; the screws were wrapped with uninsulated wire that served as an anode. The electrode and screw assembly was embedded in dental cement.
Apparatus.
Stimulation was controlled by a microprocessor-based system that controlled the delivery of stimulationvia a constant current generator (Mundl, 1980) connected to each animal by flexible leads through a mercury commutator that allowed the animal free movement. Each animal was tested in a 26 × 26-cm cage with an operant lever protruding 2.5 cm from the rear wall at a height of 7.5 cm from the floor. The operant lever controlled a microswitch connected to the current generator. Each test cage was enclosed within a larger wooden chamber that reduced external noise and visual distractions.
Procedure.
Self-stimulation testing began 7 days after surgery. The animals were placed in test boxes and allowed to explore without experimenter-administered stimulation. Each initially investigatory depression of the operant lever resulted in delivery of a 200-msec train of 0.1-msec rectangular cathodal pulses to the selected electrode. Each stimulation train was followed by an 800-msec “time-out” period when responding was not reinforced; the purpose of the time-out was to allow significant decay (Black et al., 1985) of proactive post-pulse “priming” effects of earned stimulation (Gallistel et al., 1974), which thus increased the sensitivity of the paradigm to changes in drug-induced response-reinforcement per se (see “Discussion”). Initial stimulation frequency was 72 Hz, and initial current intensity was 100 μA (a low level). If the animal did not learn to lever-press for stimulation at this intensity the current was increased daily in 50-μA increments until the animal learned to lever press reliably or until the current intensity reached an upper limit of 800 μA. Once a current level was reached that established steady responding at a minimum rate of 30 lever presses per minute, the current was fixed and the animal was allowed to lever press freely for 1 h/day on 3 consecutive days. If the animal did not continue lever-pressing or if the stimulation produced aversive side effects (e.g., gross head or body movements to one side, spinning, retreating to a corner of the test cage, vocalization or jumping) the animal was retested with use of the contralateral electrode. One or two test sessions were sufficient to produce reliable lever-pressing in each of the animals reported in the present experiments; no animals were dropped from the present experiment because of failure to learn the task or to meet this criterion for stability.
After the initial screening phase the animals were acclimatized to the rate-frequency paradigm. Here, testing began with high-frequency stimulation that sustained responding at maximal levels and progressed, incrementally, to low-frequency stimulation that would not sustain responding. Each tested frequency was available for 50 sec; a sample of five “priming” trains (1 per second) was administered at each new frequency. Test trials were separated by 5 sec with the pulse frequency decreased by 0.05 log units (approximately 12%) between trials. Response rate was determined for each 50-sec trial; each rate-frequency determination covered 12 to 15 stimulation frequencies and took 12 to 15 min. For each animal the initial (highest) pulse frequency tested was 0.05 log units greater than the pulse frequency at which maximal (asymptotic) responding had been recorded on the previous test day; frequency was decreased until the animal failed to respond at two consecutive frequencies.
Nine rate-frequency determinations were made each day. After the first few days of rate-frequency determinations, current intensity was adjusted so that the “threshold” stimulation frequency (see below) was between 35 and 65 Hz. Once responding for a given animal was stable in this range, stimulation intensity was fixed for that animal for the remainder of the experiment. Drug testing began when mean daily self-stimulation thresholds varied by less than 10% across 3 consecutive days of testing.
Independent groups of animals were tested in six treatment conditions (table 1). Dose-response data were collected from a group of eight animals that received a single injection of each dose of cocaine (0.5, 1, 2, 4, 8, 16 and 32 mg/kg i.p.) in ascending order on alternate days; on the intervening days these animals were tested after injections of vehicle (saline). The remaining five groups were tested under repeated conditions with fixed doses. Two groups were tested five times, at 48-hr intervals after 4 mg/kg (n = 8) or 16 mg/kg (n = 6) of cocaine; these animals were tested after vehicle (saline) injections on the intervening days. Eight additional animals were similarly tested five times, at 48-hr intervals, after i.p. injections of 16 mg/kg of cocaine; however, these animals were maintained in their home cages, without testing, on days intervening cocaine tests.
A comparison of thrice-daily with once-daily injections was made in two additional groups of animals. The thrice-daily injection regimen was designed to induce, acute or within-session(Kalant, 1977; LeBlanc et al., 1975) tolerance to the rewarding effects of self-administered cocaine; it was adapted from the protocols of Emmett-Oglesby and Lane (1992) and of Frank et al. (1988). During the thrice-daily regimen the animals in one group (n = 7) received injections of cocaine every 8 h (5:00 a.m., 1:00 p.m., and 9:00 p.m.); the other group (n = 8) received saline on the same schedule. On each day of the thrice-daily regimen the animals received their first injection in their test cage and the subsequent two injections in their home cage. Self-stimulation was assessed on days 1, 2, 3, 5, 6 and 7 of the thrice-daily regimen; before and after the 5:00a.m. injection. On day 1 for the 5:00 a.m.injection animals were administered cocaine 10 mg/kg or saline; the subsequent two injections (home cage) were 20 mg/kg cocaine or saline. On day 2 animals were administered cocaine 20 mg/kg or saline for each of the three injections. On day 3 animals were administered cocaine 20 mg/kg or saline for the 5:00 a.m. injection. Because of the deaths of three of these animals subsequent thrice-daily cocaine injections were given at the dosage of 10 mg/kg. After the thrice-daily cocaine and saline treatment regimens, the two groups were tested for baseline reward thresholds and responses to 10 mg/kg of cocaine. These tests occurred 1, 2, 3, 6, 9, 12 and 15 days after the last treatment injection.
Each drug or vehicle test consisted of a baseline assessment in which three rate-frequency functions were determined before the injection (the first of these was treated as a “warm-up” period and the data were not used for subsequent statistical comparisons) and a postinjection assessment. The duration of the postinjection assessment varied depending on the treatment involved. In the dose-response and sensitization experiments the postinjection determinations involved assessing two rate-frequency determinations per hour for 5 h (2 h in the low-dose cocaine sensitization experiment). Lever-pressing was not reinforced or recorded during the remainder of each hour. In the thrice- or once-daily cocaine comparison three rate-frequency curves, each lasting approximately 15 min, were taken after the injection.
The effects of drug and vehicle treatments on self-stimulation thresholds (see below) and maximal rates of responding were evaluated statistically with two-way, Treatment (dosage) × Time (hour or day), analysis of variance.
Confirmation of electrode placements.
At the end of testing each animal was anesthetized and a 1.5 mA anodal current was passed for 15 sec through the stimulating electrode. The animals were then perfused with physiological saline followed by 10% formaldehyde. Next, the brains were immersed in a formalin-cyanide solution (10% formaldehyde, 3% potassium ferrocyanide, 3% potassium ferricyanide and 0.5% trichloroacetic acid) for 15 min. This solution forms a blue reaction product with iron particles that have been expelled by the anodal current into the tissue around the electrode tip. After storage for at least 1 week in 10% formaldehyde the brains were frozen, sliced into 40-μm sections and stained with thionin for determination of electrode placements relative to the drawings and coordinates ofSwanson (1992).
Estimation of self-stimulation threshold.
Self-stimulation frequency thresholds were defined as the minimum stimulation frequency required to sustain lever pressing at greater than chance rates. Because of the greater variability of responding at stimulation frequencies near threshold levels, threshold estimates involved extrapolation and curve fitting based on the more reliable range of stimulation frequencies. A regression line was fitted to the data points for the frequencies estimated, by interpolation, to sustain responding at 20%, 30%, 40%, 50% and 60% of maximum, and threshold was estimated as the point at which this regression line crossed the abscissa (Miliaressis et al., 1986).
Drug.
Cocaine hydrochloride was dissolved in sterile physiological saline and administered i.p.; dosage is expressed as the salt.
Results
Cocaine caused leftward and upward shifts of the functions relating the logarithm of stimulation frequency (stimulation “dose”: Yeomans, 1975) to response rate in each of the six groups of tested animals. The leftward and the upward shifts were each dose-orderly (fig. 1) and were observed in each group of tested animals. There were no significant differences (F7,49 = 0.84, P > .55) in the slopes of the rising portions of the curves (estimated for each animal before averaging by computer algorithm from the threshold estimating procedure). A tendency to perseverate when receiving low stimulation frequencies, well characterized in the case of amphetamine (Olds and Travis, 1970), was seen with the higher cocaine dosages. The leftward shifts in the curves were reflected in a significant decrease in threshold as a function of cocaine dosage (fig.2; F7,49 = 12.92, P < .01); the upward shifts were reflected in a significant increase in maximum rate as a function of dosage (F7,49 = 6.79, P < .01). At the 16 mg/kg dose (the dose producing the largest average decrease in threshold) cocaine reduced the threshold frequency by 0.47 log units, which represents a 3.1-fold increase in the rewarding potency of the stimulation.
No significant day-to-day changes in predrug (baseline) responding occurred in any of the six groups of animals.
Time courses of the effects of cocaine at various dosages are shown in figure 3. Thresholds were decreased (and maxima increased: not shown) for 1 to 2 h with the lower doses and for approximately 3 h with the higher doses. Mean thresholds for the first two determinations (first hour) were used to compare cocaine effects across doses.
The mean thresholds for the first two determinations (first hour after injection) were also used to compare cocaine effects (4 or 16 mg/kg) across days. There were no significant differences in the effects of cocaine on self-stimulation thresholds across days (fig.4, top panel; Treatment × Days interaction: F4,76 = 0.44, P > .05) or maximum response rates (fig. 4, bottom panel,F4,76 = 0.59, P > .05). Moreover, thresholds were lowered, and maximum rates elevated, significantly in the two groups of animals injected with 16 mg/kg compared with the group injected with 4 mg/kg cocaine (main effect of Treatment:F2,19 = 42.21, P < .05;F2,19 = 6.28, P < .05, respectively).
In the comparison between thrice-daily and once-daily injection regimens, no significant differences occurred in the threshold-lowering effects of 10 mg/kg cocaine [when days 2 and 3 (20 mg/kg dose) are excluded from the analysis; fig. 5, top panel; F10,60 = 0.79, P > .05]. Although maximum rates were significantly elevated in the cocaine group throughout the thrice-daily injection regimen this effect decreased markedly with once-daily injections (fig. 5, bottom panel;F10,60 = 2.98, P < .01). The means of three threshold determinations were used for the comparisons across days. Moreover, there were no significant differences between groups during the once-daily injection regimen in the threshold-lowering effect of 10 mg/kg cocaine (F1,6 = 0.00, P > .05) nor in the ability of cocaine to increase maximum rates (F1,6 = 0.02, P > .05).
All electrode tips were within the boundaries of the medial forebrain bundle at the level of the lateral hypothalamus (fig.6).
Discussion
As shown with several other habit-forming drugs (Wise, 1996), cocaine decreased brain stimulation reward thresholds by producing parallel leftward shifts in the functions relating response rate to stimulation frequency. These findings are consistent with findings from rate-duration (Frank et al., 1988, 1992) and rate-intensity (Kokkinidis and McCarter, 1990) paradigms and extend earlier studies to characterize the full range of reward-potentiating cocaine dosages. Inasmuch as the stimulation frequency determines the “dose” of rewarding stimulation per lever-press (Yeomans, 1975), the leftward shifts in the rate-frequency functions are equivalent to leftward shifts in the brain stimulation reward “dose-effect” function (Liebman, 1983; Wise, 1996). Thus cocaine increases the rewarding potency of the stimulation rather than the response capacity (Edmonds and Gallistel, 1974; Stellar and Neeley, 1982) of the animals. We interpret this finding as reflecting a summation between the rewarding effects of the drug and the rewarding action of lateral hypothalamic stimulation (Wise et al., 1992; Wise, 1996).
The present findings suggest that the threshold dose of cocaine for potentiating brain stimulation reward is approximately 2 mg/kg. This dose produced noticeable but marginally significant results in the first half-hour after injection. Maximal effectiveness was seen with the 16 mg/kg dose; this dose produced an average 65% reduction in the stimulation frequency required to sustain minimal responding. The 32 mg/kg dose produced longer lasting potentiation but did not appear to produce a greater magnitude of potentiation.
In the present experiment an 800-msec “time-out” was given after each 200-msec train of rewarding stimulation; this corresponds to a fixed interval (1-sec) schedule of reinforcement and was used to minimize the rapidly decaying (Gallistel, 1969; Gallistel et al., 1974; Reid et al., 1973) proactive “priming” effects of each earned stimulation train. There are at least two sets of consequences of stimulation that contribute to the control of rate of responding: the priming effect (Deutsch and Howarth, 1963; Gallistel, 1969; Gallistel et al., 1974; Reid et al., 1973) and the reinforcing effects (Deutsch and Howarth, 1963; Gallistel et al., 1974); it is for this reason that brain stimulation reward specialists tend to use the term “reward,” implying the sum of the two factors, rather than the term “reinforcement,” which does not reflect the contribution of the priming effect (Wise, 1989).
It is not clear whether cocaine augmented the rewarding effects of the stimulation by summating with the priming effect or one of the reinforcing effects of the stimulation. Cocaine clearly canaugment the priming effect of stimulation (Esposito et al., 1978). The priming (Esposito et al., 1979; see alsoWasserman et al., 1982)3 and the reinforcing (operant: Fouriezos and Wise, 1976; Franklin, 1978; Pavlovian:Ettenberg and Duvauchelle, 1988) effects of stimulation are all attenuated by dopamine antagonists, as are both the incentive-motivational (Spyraki et al., 1987) and reinforcing (operant: de Wit and Wise, 1977; Pavlovian: Spyrakiet al., 1987) effects of cocaine. Inasmuch as cocaine was given independent of the behavior of the animal, it did not, by definition, qualify as an operant reinforcer (Skinner, 1937). Inasmuch as its effects were proactive (they were reflected in behavior that occurred after drug administration and absorption) it is reasonable to assume that the incentive-motivational (priming) effect of cocaine summated with the rewarding effect of the stimulation. That the priming effects of cocaine should summate with the rewarding effects of stimulation is consistent with the hypothesis that the neural substrates of incentive motivation and operant reinforcement are homologous (Bindra, 1972; Wise, 1989; Wise and Bozarth, 1987). However, we cannot rule out the possibility that cocaine could amplify the sensitivity of the reward system and thus have augmented brain stimulation reward by amplifying the response-contingent effects of the stimulation.
The hypothesized common denominator of incentive-motivation and reinforcement involves the brain mechanisms of forward locomotion, the common response to all positive reinforcers (Glickman and Schiff, 1967;Perkins, 1968; Schneirla, 1959; Wise and Bozarth, 1987). However, the effects of cocaine and other psychomotor stimulants show sensitization or “reverse-tolerance” with repeated administration (Babbini and Davis, 1972; Post and Rose, 1976; Stripling and Ellinwood, 1976), whereas the reward-potentiating effects of cocaine in the present experiment clearly did not. This finding is consistent with most previous reports of the effects of repeated treatment with cocaine (Frank, et al., 1988,1992), amphetamine (Wise and Munn, 1993; but see Predy and Kokkinidis, 1984), morphine (Bauco et al., 1993; Schenk et al., 1981), nicotine (Bauco and Wise, 1994) and phencyclidine (Carlezon and Wise, 1993a) on brain stimulation reward. While it might be argued that since brain stimulation reward experience is capable of sensitizing animals to amphetamine (Ben-Shahar and Ettenberg, 1994) we may have maximally sensitized our animals during brain stimulation reward training. However, the reward enhancing effects of amphetamine fail to show sensitization even in animals with extensive brain stimulation reward experience; indeed, sensitization to the locomotor-stimulating effects of amphetamine have been demonstrated in the same animals and in response to the same amphetamine injections that potentiated brain stimulation reward but failed to show sensitization of this reward-potentiating action (Wise and Munn, 1993). These findings would appear to falsify the narrow hypothesis (Wise and Bozarth, 1987) that the brain mechanisms of forward locomotion are homologous with the brain mechanisms of the drug potentiation of brain stimulation reward. Against this view, and also inconsistent with the hypothesis that the reward-potentiating and direct rewarding effects of cocaine are homologous, is the report that the direct rewarding effects of cocainedo undergo sensitization with repeated intoxication (Horgeret al., 1990). Insofar as the mechanisms of forward locomotion and reward appear to have dopaminergic modulation and the region of the nucleus accumbens in common, and insofar as dopamine modulates multiple sets of parallel circuits in this part of the brain (Alexander and Crutcher, 1990), the present data suggest that it may be different subsets of cortico-striatal-thalamo-cortical subcircuitry that play roles in the two closely associated phenomena.
We cannot explain why maximum rates of responding during intoxication with 16 mg/kg of cocaine differed depending on whether the animals were given saline tests on the days intervening cocaine or were left in their home cages without testing on the intervening days. These findings suggest that the maximum response rate may be a function of more than simple motoric capacity, but do not suggest what other factors might be involved. Evidence that left-right and up-down shifts in rate-frequency functions are independent of one another (Edmonds and Gallistel, 1974; Rompré and Wise, 1989; Stellar and Neeley, 1982) is supported by the fact that cocaine-induced threshold shifts were not affected by whatever differentially altered cocaine-induced response maxima.
The present data are inconsistent with the commonly held notion that there is necessarily profound and long-lasting tolerance to the habit-forming actions of drugs of abuse. With the exception of acute or “within-session” tolerance (LeBlanc et al., 1975), where tolerance to the rewarding effects of cocaine have been clearly demonstrated (Emmett-Oglesby and Lane, 1992; Emmett-Oglesby et al., 1993; Fischman et al., 1985), recent evidence generally disputes the assumption of tolerance to the specific rewarding actions of both psychomotor stimulants and opiates. Prior experience with amphetamine (Piazza et al., 1990) or cocaine (Horger et al., 1990) is reported to increase rather than decrease the rewarding effectiveness of subsequent amphetamine or cocaine, reducing the threshold dose to establish an operant response habit or reducing the amount of training necessary to establish stable operant performance. Moreover, amphetamine and nicotine are reported to cross-sensitize rats to the reinforcing effects of cocaine (Horgeret al., 1992). Prior amphetamine or morphine experience has also been reported to sensitize animals to the ability of amphetamine, morphine or cocaine to establish conditioned place preferences (Lett, 1989). Although the present data do not suggest sensitization to the reward-enhancing effects of cocaine, they also do not support the suggestion that there is between-session tolerance to these effects.
It is somewhat surprising that the present data also fail to offer any evidence for acute tolerance to the reward-enhancing effects of cocaine; inasmuch as acute tolerance has been shown for the direct rewarding effects of cocaine, the direct rewarding and reward-enhancing effects of cocaine have been argued to involve a common reward mechanism in the brain (Wise, 1996; Wise and Bozarth, 1987). An obvious factor is dosage. The treatment regimen in which acute tolerance has been shown in rats (Emmett-Oglesby and Lane, 1992; Emmett-Oglesbyet al., 1993) is 20 mg/kg, thrice-daily for 7 days. This dosage regimen proved fatal for some of our animals, perhaps because the first dose each day was given during sessions of intracranial self-stimulation. Our failure to observe acute tolerance involved half the dosing regimen of Emmett-Oglesby et al. (1993). Still, when their animals were tested at several time points after the final injection, Frank et al. (1988, 1992) found no evidence of acute tolerance in animals treated with 25 or 30 mg/kg thrice- daily for 3 days. Tolerance is generally assumed to reflect drug-opposite neuroadaptations and dopamine depletion (Dackis and Gold, 1985), and elevated brain stimulation reward thresholds (Leith and Barrett, 1976) have been suggested as reward-relevant consequences of such neuroadaptations. Evidence of elevated self-stimulation thresholds has been found when animals are allowed to self-administer cocaine (Markou and Koob, 1991), and in this case the animals received approximately the same daily dose of cocaine (on average, 27 mg/kg/day) as given in the present study. In Markou and Koob’s study, however, the drug was given intravenously every few minutes rather than intraperitoneally every 8 h as in the present study. Thus the Markou and Koob regimen involved more continuous intoxication. Markou and Koob saw immediately elevated brain stimulation reward thresholds after as little as 6 h of cocaine self-administration, when their animals were still intoxicated with satiating levels of cocaine. This is surprising because the acute effect of intoxicating doses of cocaine is a decrease in brain stimulation reward threshold and because the increased reward thresholds are assumed to be a rebound consequence of drug intoxication (Solomon and Corbit, 1973), which is expected only after the drug is metabolized and the drug effect wears off. The other known opponent-process neuroadaptation to cocaine, extracellular dopamine depletion (Parsons et al., 1991; Robertson et al., 1991), has been reported 10 days after termination of a cocaine treatment regimen of 20 mg/kg once-daily for 10 days (Parsons et al., 1991), and 7 days after termination of a regimen of 30 mg/kg once-daily for 18 days (Robertsonet al., 1991). Compared with the treatment regimens in this study, these treatment regimens involve less daily cocaine in the first case and less chronic intoxication in both cases. Thus it would appear that while acute tolerance to cocaine can occur with high-dose and chronic treatment regimens, it seems not to be a simple consequence of the dopamine depletion reported with dosing regimens more modest than those used in the present study.
Footnotes
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Send reprint requests to: Roy A. Wise, Concordia University, CSBN H-1013, 1455 deMaisonneuve Blvd., West, Montreal, Quebec, Canada H3G 1 M8.
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↵1 Supported by grants to R.A.W. from National Institute on Drug Abuse (United States) and Fonds pour la Formation de Chercheurs et l’Aide à la Recherche (Québec) and by a predoctoral fellowship (P.B.) from the Medical Research Council of Canada.
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↵3 Note that the failure suggested in the title ofWasserman et al. (1982) is reflected in only the first few trials of each session. The decay of this “spared” priming effect undergoes a rapid extinction-like process that suggests it is a memory-dependent holdover from prior reinforcement (see Skinner, 1933). The robust component of the priming effect is memory independent (Gallistel et al., 1974) and should thus not undergo extinction; it is absent in the neuroleptic-treated animals of this experiment. Wasserman et al. (1982) did not see a sustained priming effect in neuroleptic-treated animals and Espositoet al. (1979), whose paradigm offers an uncontaminated measure of priming effects, saw neuroleptic-induced loss of stimulation effectiveness. Thus, although there may be a memory-dependent contribution to the priming effect that is not dopamine-dependent for its expression (it almost certainly is dopamine-dependent for its development: Beninger and Hahn, 1983; Beninger and Phillips, 1980), the robust effect of priming is lost in neuroleptic-treated animals.
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↵2 The term “reward” is used here to reflect the combined effects of reinforcement (of which there are two types) and of “priming” or “incentive motivation” which are usually confounded in these experiments (Wise, 1989). See “Discussion.”
- Received March 27, 1997.
- Accepted August 26, 1997.
- The American Society for Pharmacology and Experimental Therapeutics