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Vol. 288, Issue 3, 1053-1073, March 1999
Preclinical Pharmacology Laboratory, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland
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Abstract |
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Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, with a high frequency of concurrent use in humans. This study examined the effects of chronic caffeine exposure on 1) rates of acquisition of a nicotine discrimination (0.1 or 0.4 mg/kg, s.c., training doses) and 2) the pharmacological characteristics of the established nicotine discrimination in male Sprague-Dawley rats. Once rats learned to lever-press reliably under a fixed ratio of 10 schedule for food pellets, they were randomly divided into two groups; 12 animals were maintained continuously on caffeine added to the drinking water (3 mg/ml) and another 12 control rats continued to drink tap water. In each group of water- and caffeine-drinking rats, there were six rats trained to discriminate 0.1 mg/kg of nicotine from saline and six rats trained to discriminate 0.4 mg/kg of nicotine from saline. Regardless of the training dose of nicotine, both water- and caffeine-drinking groups required a comparable number of training sessions to attain reliable stimulus control, although there was a trend for a slower acquisition in the caffeine-drinking group trained with 0.1 mg/kg of nicotine. Tests for generalization to different doses of nicotine revealed no significant differences in potency of nicotine between water- and caffeine-drinking groups. The nicotinic-receptor antagonist mecamylamine blocked the discriminative effects of 0.1 and 0.4 mg/kg nicotine with comparable potency and efficacy in water- and caffeine-drinking groups. There was a dose-related generalization to both the 0.1 and 0.4 mg/kg nicotine cue (maximum average of 51-83%) in water-drinking rats after i.p. treatment with d-amphetamine, cocaine, the selective dopamine uptake inhibitor GBR-12909, apomorphine, and the selective dopamine D1 receptor agonist SKF-82958, but not in caffeine-drinking rats (0-22%). There was no generalization to the nicotine cues after i.p. treatment with caffeine or the selective D2 (NPA) and D3 (PD 128,907) dopamine-receptor agonists in water- and caffeine-drinking rats. The dopamine-release inhibitor CGS 10746B reduced the discriminative effects of 0.4 mg/kg nicotine in water-drinking rats, but not in caffeine-drinking rats. There was no evidence of development of tolerance or sensitization to nicotine's effects throughout the study. In conclusion, chronic caffeine exposure (average, 135 mg/kg/day) did not affect the rate of acquisition of the nicotine discrimination, but it did reduce the dopaminergic component of the nicotine-discriminative cue. The reduction of the dopaminergic component of the nicotine cue was permanent, as this effect was still evident after the caffeine solution was replaced with water in caffeine-drinking rats. That nicotine could reliably serve as a discriminative stimulus in the absence of the dopaminergic component of its discriminative cue may differentiate nicotine from "classical dopaminergic" drugs of abuse such as cocaine and amphetamine.
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Introduction |
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Epidemiological
surveys in humans show that smokers tend to smoke more cigarettes while
drinking coffee, and they also drink significantly more coffee than
nonsmokers (Istvan and Matarazzo, 1984
; Brown and
Benowitz, 1989
; Swanson et al., 1994
, 1997
). It is now generally
accepted that this positive correlation can be ascribed to interactions
between nicotine and caffeine, the main psychoactive constituents of
tobacco and coffee, respectively (Rose and Behm, 1991
; Swanson et al.,
1994
, 1997
; Griffiths and Mumford, 1995
). Little is known,
however, of the neuropharmacological and psychopharmacological
mechanisms or of their behavioral consequences that may contribute to
the concurrent use of nicotine and caffeine in humans. Pharmacokinetic
factors such as a shorter half-life of caffeine or nicotine in
coffee-drinking smokers or behavioral factors such as stress or anxiety
can only partially explain their concurrent use (Brown and Benowitz,
1989
; Swanson et al., 1994
, 1997
), suggesting that other factors are
involved (Istvan and Matarazzo, 1984
).
Both nicotine and caffeine, when administered alone, can have
qualitatively comparable, often biphasic, dose-dependent effects on a
variety of nonoperant and operant measures of behavior (for review, see
Carney et al., 1985
; Stolerman, 1990
; Nehlig et al., 1992
). These
behavioral effects include, for example, increases in locomotor
activity (Holtzman, 1983
; Lee et al., 1987
; Nikodijevi
c et al.,
1993
) and rates of schedule-controlled responding (White, 1988
;
Goldberg et al., 1989
; Newland and Brown, 1997
; Jaszyna et al., 1998
)
followed by decreases as doses of the drugs increase. Moreover, both
nicotine and caffeine can each serve as discriminative stimuli (Winter,
1981
; Stolerman et al., 1984
; Carney et al., 1985
; Rosecrans, 1989
;
Griffiths et al., 1990
) and reinforcing stimuli under certain
conditions (Goldberg and Henningfield, 1988
; Heishman and Henningfield,
1992
; Griffiths and Mumford, 1995
; Rose and Corrigall, 1997
) in
laboratory animals and human subjects. Nicotine and caffeine, when
coadministered acutely, have been shown to produce additive-in-nature
stimulation of locomotor activity and increases in rates of operant
responding maintained under a fixed-interval schedule of food
reinforcement in rats (Lee et al., 1987
; White, 1988
) and monkeys
(Howell and Landrum, 1997
). Acute pretreatment with caffeine also
produced significant increases in rates of responding for i.v. nicotine
self-administration in squirrel monkeys (Yasar et al., 1997
). Caffeine,
however, is consumed chronically by humans, and behavioral responses to
caffeine can be altered by repeated administration (see review by
Jacobson et al., 1996
), as observed with other psychomotor stimulant
drugs (Goudie and Emmett-Oglesby, 1989
; Stewart and Badiani, 1993
), suggesting the need for more studies of the effects of chronic caffeine
exposure on nicotine's behavioral actions.
It has been well documented that daily exposure to "physiological"
doses of caffeine (equivalent to the caffeine content in two to three
cups of coffee) results in the development of tolerance to the
diuretic, cardiovascular, and some, but not all, of the behavioral
effects of caffeine in humans (Benowitz, 1990
; James, 1991
; Nehlig et
al., 1992
). Likewise, chronic caffeine exposure in rodents results in
the development of tolerance to the stimulant effects of caffeine on
locomotor activity and rates of food-reinforced responding, and its
effects as a discriminative stimulus (Holtzman and Finn, 1988
;
Nikodijevi
c et al., 1993
; Lau and Falk, 1994
; Newland and Brown,
1997
; Jaszyna et al., 1998
). There is no clear predictive pattern of
change in the behavioral effects of psychomotor-stimulant drugs that
are produced by chronic caffeine exposure in experimental animals. For
example, chronic caffeine exposure markedly potentiated the stimulatory
effects of nicotine on locomotor activity (Shoaib et al., 1996
),
whereas the response to amphetamine and cocaine remained unchanged
(Holtzman, 1983
; Finn and Holtzman, 1987
; Holtzman and Finn, 1988
;
Nikodijevi
c et al., 1993
). In contrast, chronic caffeine
exposure potentiated the response-rate increases produced by
amphetamine and cocaine, but not by nicotine, in rats responding under
a fixed interval (FI) schedule of food reinforcement (Jaszyna et al.,
1998
). Chronic caffeine exposure, however, increased rates of
acquisition of i.v. self-administration of both nicotine (Shoaib et
al., 1996
) and cocaine (Horger et al., 1991
) relative to control rats.
To our knowledge there are no published reports on how chronic caffeine
exposure might change the discriminative stimulus properties of
psychomotor stimulant drugs. There is some experimental evidence
suggesting that acute presession treatment with caffeine can potentiate
the discriminative stimulus effects of cocaine in rats (Harland et al.,
1989
; Gauvin et al., 1990
), and combinations of caffeine with other
over-the-counter drugs such as phenylethylamine can produce new
entities distinct from their component elements and can mimic the
discriminative cue of amphetamine and cocaine (Holloway et al., 1985
;
Gauvin et al., 1989
). Thus, there are reasons to speculate that chronic
caffeine exposure may change the subjective effects of psychomotor
stimulants, including nicotine.
In the present study, we adopted from Holtzman (1983)
and Jaszyna et
al. (1998)
a method of chronically exposing rats to caffeine in their
drinking water to examine possible changes in the subjective effects of
nicotine using a drug discrimination procedure. Drug discrimination
procedures have been successfully used to examine subjective effects of
a wide range of psychoactive drugs under a variety of experimental
conditions in both animals (e.g., Colpaert, 1987
; Samele et al., 1992
)
and humans (e.g., Kamien et al., 1993
). With these procedures,
discriminability of a drug (percentage of subjects acquiring
discrimination) and rate of acquisition of the discrimination are first
established and then qualitative properties of the discriminative cue
are assessed in generalization tests with other drugs permitting
identification of receptor(s) mediating discriminative-stimulus
properties of the drug (e.g., Colpaert, 1987
; Wiley et al., 1996
). All
three characteristics of the discriminative effects of nicotine in rats
chronically exposed to caffeine, in comparison to those of in control
rats, were evaluated in the present study.
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Materials and Methods |
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Subjects. Thirty experimentally naive, male Sprague-Dawley rats, weighing 250 to 280 g at the beginning of the study, were used. Rats were acclimated to laboratory conditions and allowed to free feed for 2 weeks. Their body weights were then reduced to about 80% of free-feeding by limiting access to food. Rats continued to be kept on a restricted diet to maintain their weights at about 80 ± 5.0% of the weight of age-matched control rats until the end of the study. Rats were housed individually in stainless steel cages in a temperature- and humidity-controlled room with a 12-h light/dark cycle (7:00-19:00 h lights on).
Drugs.
The drugs and their sources were as follows:
(
)-nicotine hydrogen tartrate (Sigma Chemical Company, St.
Louis, MO), caffeine base (Sigma), mecamylamine HCl (Research
Biochemicals International, RBI, Natick, MA), CGS 10746B
(5-(4-methyl-1-piperazinyl)imidazo[2,1-b][1,3,5]-benzothiadiazepine maleate; a gift from Novartis Pharmaceutical Corp., Summit,
NJ), d-amphetamine (National Institute on Drug Abuse,
Rockville, MD), cocaine HCl (National Institute on Drug Abuse),
GBR-12909 2·HCl (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dichloride; RBI), R(
)-apomorphine HCL
(R(
)-10,11-dihydroxyapomorphine hydrochloride; RBI), (±)-SKF-82958
HBr
((±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; RBI), R(
)-NPA HCl
(R(
)-10,11-dihydroxy-N-n-propylnoraporphine hydrochloride; RBI), S(+)-PD 128,907 HCl
(S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride; RBI). GBR-12909 was suspended in 40% (w/v)
hydroxypropyl-
-cyclodextrin (RBI), CGS 10746B was dissolved in
sterile water, and the remaining drugs were dissolved in sterile 0.9%
NaCl saline. The pH of nicotine solutions was adjusted to 7.0 with
dilute NaOH. When necessary, mild heat and sonication were applied to
prepare solutions of the drugs. Except for nicotine and caffeine, doses
of drugs are expressed as milligrams of salt per kilogram of body
weight measured before the start of the session. Doses of nicotine and
caffeine refer to the free base forms. The drugs were administered
either s.c. (nicotine and mecamylamine) or i.p. (the remaining drugs) in a volume of 1.0 ml/kg of body weight.
Apparatus. Standard operant chambers (Coulbourn Instruments Inc., Lehigh Valley, PA) located singly in sound-attenuating plastic cubicles were used. Each chamber contained two levers separated by a recessed tray into which a pellet dispenser could deliver 45-mg food pellets (Bio-Serv, Inc., Frenchtown, NJ), a house light that was centrally mounted on the front wall below the ceiling, and a device producing white noise to mask extraneous sounds. Each press of a lever with a force of 0.4 N through 1 mm was recorded as a response and was accompanied by an audible click. The chamber was controlled by a computer using MED-PC software (Med Associates, Inc., East Fairfield, VT).
Training Procedure. Twenty-four rats were trained to press the lever for food on a fixed ratio (FR) schedule of reinforcement 5 days a week (Monday through Friday), always between 9:30 AM and 12:00 PM. At the start of each session, the white house light was turned on and in its presence 10 consecutive responses on the active lever delivered a food pellet (a fixed-ratio 10 schedule; FR 10) and initiated a 3-s timeout during which lever presses had no programmed consequences and the chamber was dark. After each timeout, the house light was turned on and food was again available. Each session lasted 15 min. The location of the active lever (left versus right) was randomly changed for each session to reduce position preferences during the training period. Once all rats responded reliably under the FR 10 schedule, they were divided into two groups: water-drinking rats and caffeine-drinking rats. Twelve animals received free access in their home cages to caffeine in tap water (3 mg/ml caffeine anhydrate base), whereas the other 12 control rats continued to drink tap water. Daily caffeine intake was estimated once every week throughout the remainder of the study based on the rat's body weight and 24-h fluid consumption of the established caffeine concentration (mg/kg per individual rat). Daily water intake in water-drinking rats was monitored for comparison. Training was continued for 2 weeks to eliminate temporal effects of caffeine on behavior in rats.
Acquisition of Nicotine Discrimination.
Water- and
caffeine-drinking rats were then divided into four groups of six rats
each and trained, as described previously (Shoaib and Stolerman, 1996
),
under the FR10 schedule of food delivery to respond on one lever after
s.c. injection of nicotine and on the other lever after s.c. injection
of an equivalent volume of saline vehicle. Two groups of rats (water-
and caffeine-drinking) were trained to discriminate 0.1 mg/kg of
nicotine from saline and two groups of rats (water- and
caffeine-drinking) were trained to discriminate 0.4 mg/kg of nicotine
from saline. For half the rats in each group, the right lever was the
drug lever and for the other half, the left lever was the drug lever.
This remained constant throughout the study. Injections of nicotine or
saline were given s.c. 10 min before the session.
Tests for Generalization or Antagonism. Test sessions were identical to training sessions with the exception that 10 responses on either lever resulted in delivery of a food pellet. There were no more than two test sessions conducted per week (usually on Tuesdays and Fridays) and there were regular training sessions with either nicotine or saline injections conducted on the other days to ensure robust stimulus control. Only rats that continued to meet the above criteria for stimulus control were tested. If a rat failed to meet criteria for stimulus control during one of the training sessions, it remained in the training condition until at least five consecutive sessions were completed in which criteria were met.
In generalization tests, rats were injected with different doses of a drug (including injection with drug vehicle) to determine the degree to which the drug generalized to nicotine. In antagonism tests, the ability of a drug to block the discriminative stimulus properties of nicotine was determined. To do so, rats were injected with a putative blocking agent in different doses (or its vehicle) first, at a time appropriate to its onset of action, and then with the training dose of nicotine (or saline) 10 min before the session. All drugs were given in doses that ranged from those without behavioral effects to doses which decreased response rates (the choice of doses was additionally confirmed by literature searches). Each dose of a respective drug was tested in a randomized order. After all doses of one drug were tested, a 1-week washout period was allowed before the next drug was tested. During this one-week period, rats continued under the training condition for maintenance of stimulus control.Sequence of Testing. The following parameters, in order of their assessment, were compared in water- and caffeine-drinking rats: 1) rates of acquisition of the nicotine discrimination, 2) discrimination of different doses of nicotine (0.025-0.8 mg/kg; 10 min before test session) to establish dose-response functions, 3) ability of the nicotinic-receptor antagonist, mecamylamine (0.01-1.0 mg/kg; 20 min before test sessions), to block the discriminative stimulus actions of nicotine, and 4) abilities of a variety of drugs that act at different receptors to generalize to the nicotine-discriminative stimulus. The drugs studied (doses and pretreatment times in parentheses) were: caffeine (1.0-56 mg/kg; 15 min), d-amphetamine (0.3-3.0 mg/kg; 10 min), cocaine (0.3-17 mg/kg; 10 min), the selective dopamine-uptake inhibitor GBR-12909 (3.0-17 mg/kg; 15 min), the nonselective dopamine agonist apomorphine (0.1-0.3 mg/kg; 10 min), the selective D1, D2, and D3 dopamine-receptor agonists, SKF-82958 (0.01-0.17 mg/kg; 10 min), NPA (0.001-0.01 mg/kg; 10 min), and PD 128,907 (0.03-0.3 mg/kg; 15 min), respectively, and 5) ability of the dopamine-release inhibitor, CGS 10746B (3.0-30 mg/kg; 30 min before test sessions), to block the discriminative-stimulus actions of nicotine. Dose-response functions for nicotine were redetermined after the above tests to assess whether any tolerance or sensitivity to nicotine had developed over time or as a result of different treatments. Finally, the ability of amphetamine (0.3-3.0 mg/kg; 10 min) to generalize to the nicotine discriminative stimulus was assessed in rats subjected to a double crossover design in which caffeine was either removed or added to the drinking water of caffeine- and water-drinking rats, respectively.
Measurement of Plasma Caffeine Concentration.
A separate
group of six rats was maintained on a restricted diet as above and was
continuously exposed to caffeine (3.0 mg/ml) added to their drinking
water. Daily caffeine intake was monitored once per week. After 3 weeks, the rats were sacrificed at the time when the
nicotine-discrimination study would typically be performed and blood
samples were collected into 10-ml sterile tubes containing EDTA as an
anticoagulant. Tubes were centrifuged at 3500 rpm/min for 15 min to
separate plasma from blood cells. Plasma samples were then transferred
to transport tubes. Measurements of plasma caffeine concentration were
commercially performed at Labstat Incorporated (Kitchener, Ontario,
Canada) according to the HPLC method described in detail by Muir et al.
(1980)
.
Data Presentation and Statistical Analysis. The percentage of nicotine-appropriate responses during each training or test session was obtained by dividing the number of responses on the nicotine-appropriate lever by the total number of responses on both levers during a session. The response rate (expressed as responses per second) during each session was calculated by dividing the total number of responses on both levers during a session by total session length (in seconds). Average values (± S.E.M.) for individual rats in each of the four groups were calculated. The percentage of nicotine-appropriate responses was considered as a measure of discrimination performance. The average response rate provided a second measure of the behavioral effects of treatment, a measure that was independent of the distribution of responses between the two levers. Additionally, daily fluid intake in milliliters per kilogram was calculated in water- and caffeine-drinking rats based on measured individual body weights and intakes of fluid. The daily fluid intakes of known caffeine concentration were then used to estimate intakes of caffeine in individual rats (in milligrams per kilogram per day) throughout the study. Daily caffeine intake and plasma caffeine concentration were expressed as mean ± S.E.M.
For the purpose of comparative presentation of experimental data, dose-response functions for each testing condition were plotted in paired graphs. The top graphs in Figs. 2 through 9 show absolute percentages (± S.E.M.) of nicotine-appropriate lever selections, whereas the bottom graphs show mean percentage changes (± S.E.M.) from baseline rates of responding after corresponding treatments in water- and caffeine-drinking rats. For each tested drug, the mean response rate during treatments with drug vehicle served as an individual baseline rate of responding (untransformed values shown in Fig. 10) An arc-sin transformation was used to normalize distributions of percentages of nicotine-appropriate lever selections in generalization and antagonism tests (Shoaib and Stolerman, 1996| |
Results |
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Acquisition of Nicotine Discrimination. All 24 rats met the criteria for stimulus control (Fig. 1). There were, however, significant differences among the groups in the number of training sessions necessary before rats met the criteria for stimulus control (H3= 11.655; p = .009). Water- and caffeine-drinking rats trained to discriminate 0.4 mg/kg nicotine from saline acquired the task within a comparable number of training sessions (p >.05) ranging from 28 to 43 (mean ± S.E.M.: 37.2 ± 2.3) and from 29 to 56 (mean ± S.E.M.: 43.0 ± 4.3), respectively. A significantly longer period of training was required for rats that were trained with the lower 0.1 mg/kg dose of nicotine (p <.05 versus rats trained with the 0.4 mg/kg nicotine dose). At the 0.1 mg/kg training dose of nicotine, the number of training sessions required for water- and caffeine-drinking rats to meet the criteria of stimulus control ranged from 38 to 94 (mean ± S.E.M.: 60.3 ± 8.0) and from 39 to 115 (mean ± S.E.M.: 85.5 ± 12.0), respectively (Fig. 1). There was a trend for caffeine-drinking rats to show a slower rate of acquisition of discriminative-stimulus control with the 0.1 mg/kg training dose of nicotine (Fig. 1), but this did not reach statistical significance (p >.05). Caffeine exposure did not effect rates of responding. At the end of acquisition training, response rates after 0.4 mg/kg of nicotine or saline in water-drinking rats (mean ± S.E.M.: 2.01 ± 0.22 or 1.57 ± 0.10 responses/s, respectively) were not significantly different (p > .05) from those after 0.4 mg/kg of nicotine or saline in caffeine-drinking rats, (1.89 ± 0.28 or 1.48 ± 0.09 responses/s, respectively). Similarly, response rates after 0.1 mg/kg of nicotine or saline in water-drinking rats (mean ± S.E.M.: 2.19 ± 0.28 or 1.88 ± 0.20 responses/s, respectively) were not significantly different (p >.05) from those after 0.1 mg/kg of nicotine or saline in caffeine-drinking rats, (1.82 ± 0.28 or 1.67 ± 0.14 responses/s, respectively).
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Dose-Response Tests with Nicotine and Blockade of the Nicotine Cue by Mecamylamine in Water- and Caffeine-Drinking Rats. The percentage of nicotine-appropriate lever-press responses increased as the dose of nicotine increased in both groups, regardless of the training dose of nicotine (Fig. 2; Table 1). In both water- and caffeine-drinking rats trained with the 0.4-mg/kg dose of nicotine, the 4-fold lower dose of nicotine (0.1 mg/kg) engendered nicotine-appropriate responding in all rats, whereas lower 0.05- and 0.025-mg/kg doses of nicotine yielded either partial or no generalization. In contrast to the rats trained with 0.4 mg/kg of nicotine, rats trained with 0.1 mg/kg of nicotine showed only partial or no generalization when nicotine dose was reduced 2- or 4-fold below the training dose. There were no statistical differences in the potency of nicotine as a discriminative stimulus between water- and caffeine-drinking rats regardless of training dose (Tables 1 and 2; Fig. 2). A nicotine dose of 0.8 mg/kg markedly and significantly (p <.05) decreased response rates but 0.4 mg/kg and lower doses of nicotine had little effect on response rates of water- or caffeine-drinking rats in rats trained with either 0.4 or 0.1 mg/kg of nicotine (p >.05). There were no significant differences in effects on response rates of graded doses of nicotine between water- and caffeine-drinking rats trained with either 0.4 mg/kg or 0.1 mg/kg of nicotine (p >.05; Table 1).
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Tests for Generalization to Caffeine, Amphetamine Cocaine, and GBR-12909. In rats trained to discriminate 0.4 mg/kg of nicotine from saline, caffeine (1.0-56 mg/kg) failed to engender nicotine-appropriate responding in water-drinking rats or in caffeine-drinking rats (Fig. 2; Table 3). The maximum percentage of nicotine-appropriate responses was 35.1% (S.E.M., ± 20.5) after 56 mg/kg of caffeine in water-drinking rats and it did not reach the assigned level of statistical significance (p >.05 versus vehicle). In water-drinking rats, caffeine produced dose-dependent and biphasic changes in rates of responding (Table 3). Rates of responding increased after lower doses of caffeine (1.0 and 3.0 mg/kg) and decreased significantly after higher doses of caffeine (30 and 56 mg/kg). In contrast, in caffeine-drinking rats, there were no increases in rates of responding after lower doses of caffeine, but 30 to 56 mg/kg of caffeine did decrease response rates. There was a statistically significant interaction between two factors (water/caffeine drinking and dose of caffeine; F4,40= 2.643, p = .048), indicative of a trend in caffeine-drinking rats to show tolerance to the rate increasing effects of lower doses of caffeine (1.0 and 3.0 mg/kg) (Fig. 2). Higher doses of caffeine (10-56 mg/kg) produced dose-dependent decreases in rates of responding with comparable (p >.05) potency and efficacy in water- and caffeine-drinking rats (Fig. 2, Tables 3 and 4), indicative of the lack of tolerance to the rate-decreasing effects of caffeine in rats chronically exposed to caffeine.
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Tests for Generalization to Nonselective and Selective Dopaminergic Agents. The nonselective D1/D2 dopamine receptor agonist, apomorphine, significantly and dose-dependently generalized to the nicotine cue in water-drinking groups, with a maximal effect of 66.6% (S.E.M., ± 21.1) at 0.17 mg/kg and 63.9% (S.E.M., ± 18.0) at 0.3 mg/kg in rats trained to discriminate saline from 0.4 mg/kg and 0.1 mg/kg of nicotine, respectively (Fig. 6; Tables 4 and 5). Apomorphine, in contrast, failed to generalize to the nicotine cue in caffeine-drinking rats, regardless of the training dose of nicotine (p >.05 versus vehicle). Apomorphine also significantly and dose-dependently decreased rates of responding (Fig. 6). The rate-decreasing potency and efficacy of apomorphine were comparable (p >.05) in water- and caffeine-drinking rats, regardless of the training dose of nicotine (Tables 4 and 5; Fig. 6).
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Antagonism of the Nicotine Cue with the Dopamine-Release Inhibitor CGS 10746B. The dopamine-release inhibitor, CGS10746B, when administered 10 min before the training dose of 0.4 mg/kg of nicotine, dose-dependently, but not completely, reduced the discriminative effects of nicotine in water-drinking rats but not in caffeine-drinking rats (Fig. 3; Table 4). The most effective doses of CGS10746B appeared to be 10 and 17 mg/kg (reduction of the percentage of nicotine-appropriate responses from 100% to 38.8% (S.E.M., ± 21.2) and 47.7% (± 18.3), respectively, p <.05 versus 0.4 mg/kg of nicotine alone. These doses of CGS 10746B also significantly decreased the rate of responding. A higher dose of CGS 10746B (30 mg/kg) almost completely suppressed responding. In contrast to the different effects of CGS1076B upon the discriminative effects of nicotine in water- and caffeine-drinking rats, CGS 10746B dose-dependently and with a comparable (p >.05) efficacy and potency reduced rates of responding in water- and caffeine-drinking rats (Table 4).
Re-evaluation of the Dose-Response Curves of the Discriminative-Stimulus Effects of Nicotine. Dose-response functions for the discriminative-stimulus effects of nicotine were re-evaluated in each group after completion of the above-mentioned tests. In each group, nicotine again produced dose-dependent increases in the percentage of nicotine-appropriate responding with a comparable (p >.05) potency in water- and caffeine-drinking rats, regardless of the training dose of nicotine (Fig. 8; Tables 1 and 2). Likewise, the discriminative-stimulus effects of nicotine did not change significantly over time (Fig. 8). This was further confirmed by comparable ED50 values of nicotine (Table 2). Similarly, the effects of nicotine on rates of responding did not differ between water-and caffeine-drinking rats, and the effects of nicotine on rates of responding did not change over the time (p >.05) (Fig. 8; Table 1 and 2).
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Generalization of Amphetamine to the Nicotine Cue in Rats When the Water- and Caffeine-Drinking Conditions Were Reversed. In rats trained to discriminate 0.4 mg/kg of nicotine from saline, caffeine solution (3 mg/ml) was substituted for water solution in water-drinking rats and caffeine solution was replaced with water solution in caffeine-drinking rats. Rats were then allowed 3 weeks to habituate to the new drinking solutions, during which time they were kept in their home cages with no training. After 3 weeks, the ability of amphetamine (10 min before testing, i.p.) to generalize to the 0.4-mg/kg nicotine cue was re-evaluated (Fig. 9; Table 6). The water-drinking group of rats, in which amphetamine had previously fully generalized to the nicotine cue, no longer showed generalization of amphetamine to the nicotine cue after 3 or more weeks of caffeine exposure. Surprisingly, the caffeine-drinking group of rats, in which amphetamine had previously failed to generalize to the nicotine cue, continued to show no generalization to the nicotine cue with amphetamine after 3 or more weeks maintenance on water.
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Absolute Values of Rates of Responding during the Study. Absolute values of rates of responding after administration of the appropriate vehicle under the testing condition were grouped (Fig. 10) and analyzed for changes in the baseline levels that might result from repeated exposure to different compounds or chronic caffeine exposure. One-way repeated measures ANOVA revealed a stable baseline level of responding throughout the study in water- (F12,58 = 1.649, p = .103) and caffeine- (F12,58 = 0.525, p = .888) drinking rats trained to discriminate 0.4 mg/kg of nicotine from saline and in water- (F9,45 = 1.008, p = .449) and caffeine- (F9,45 = 1.750, p = .105) drinking rats trained to discriminate 0.1 mg/kg of nicotine from saline. There were also no significant differences between water- and caffeine-drinking groups trained with 0.4 mg/kg (F1,101 = 0.259, p = .622) or 0.1 mg/kg of nicotine (F1,87 = 4.677, p = .056) according to two-way repeated measures ANOVA. In the groups trained with 0.1 mg/kg of nicotine, however, there was a tendency for water-drinking rats to show higher levels of baseline responding than caffeine-drinking rats.
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Daily Intake and Plasma Concentration of Caffeine in Caffeine-Drinking Rats. The bottom plot in Fig. 10 shows the daily intake of caffeine The daily caffeine intake ranged from 93.9 ± 15.2 to 199.2 ± 17.1 mg/kg in the group of rats trained to discriminate 0.4 mg/kg of nicotine from saline, and from 86.1 ± 9.1 to 187.9 ± 8.0 mg/kg in the group of rats trained to discriminate 0.1 mg/kg of nicotine from saline, with average values from 76 measurements being 138.9 ± 24.5 mg/kg/day and 131.0 ± 23.3 mg/kg/day of caffeine in these groups. Overall, throughout the study (over 11/2 years), daily caffeine intakes in these two groups were indistinguishable during acquisition training and drug testing. Consumption of caffeinated water, however, remained from 10 to 15% below that of tap water throughout the study (data not shown). The latter had no effect on food consumption, body weights, or baseline performance (Fig. 10) of rats throughout the study.
Relative to the above mentioned groups of caffeine-drinking rats, the rats used for determination of plasma levels of caffeine showed a comparable daily caffeine intake (ranged from 131.6 ± 8.1 to 167.3 ± 18.2 mg/kg/day) that resulted in a mean plasma caffeine concentration of 29.11 ± 6.61 µg/ml.| |
Discussion |
|---|
|
|
|---|
In the present study, chronic caffeine exposure during acquisition of a nicotine discrimination by rats changed the qualitative nature of the nicotine discrimination without affecting the rate at which the discrimination was acquired. The effect of chronic exposure to caffeine on the acquired nicotine cue in the present study appeared to be selective to its dopaminergic component, since a number of dopaminergic compounds, including amphetamine, cocaine, GBR-12909, apomorphine, and SKF-82958, failed to generalize to the nicotine cue in caffeine-drinking rats, whereas there was a complete or partial generalization with these compounds in water-drinking rats. However, chronic caffeine exposure did not appear to change the nicotinic component of the nicotine cue, as there were no differences between caffeine- and water-drinking rats in the nicotine dose-response functions nor in the ability of the nicotinic-receptor blocker mecamylamine to block the nicotine discriminative cue.
Rates of acquisition of nicotine discrimination for both lower and
higher doses of nicotine in the present study with rats were similar to
those reported in the literature (Chance et al., 1977
; Stolerman et
al., 1984
; Rosecrans, 1989
). As with Shoaib et al. (1997)
, there was no
evidence for the development of either tolerance or sensitization to
the discriminative stimulus effects of nicotine over time as a result
of repeated treatment with nicotine and with various other compounds in
the generalization and antagonism tests (Fig. 8). For example, the
effects of graded doses of nicotine on rates of responding at the end
of the study were comparable to those at the beginning of the study.
Furthermore, the present findings from the generalization and
antagonism tests generally resembled previous findings. Specifically,
nicotine discrimination has been reported to be dose-related, with
ED50 values typically ranging from 0.04 to 0.1 mg/kg depending on the training dose and conditions (Stolerman, 1988
;
Rosecrans, 1989
; Schechter and Meehan, 1992
; Shoaib et al., 1997
). In
the present study, the ED50 values of nicotine
ranged from 0.044 to 0.088 mg/kg. The noncompetitive nicotinic-receptor
antagonist mecamylamine dose-dependently blocked the discriminative
stimulus effects of nicotine in the present study (Fig. 3) with
comparable potency and efficacy to those found in the earlier studies
(Romano et al., 1981
; Stolerman et al., 1983
, 1984
). The present
findings with partial generalization of amphetamine, cocaine, and the
nonselective dopamine receptor agonist apomorphine to the nicotine cue,
as well as the failure of caffeine to generalize to the nicotine cue
(Figs. 2, 4, 5, and 6), have also been previously reported (Chance et
al., 1977
; Stolerman et al., 1984
; Rosecrans, 1989
). Finally, the
dopamine-release inhibitor CGS 10746B has previously been shown to
attenuate a nicotine discrimination in rats (Schechter and Meehan,
1992
). In the present study, the blocking effect of CGS 10746B was also incomplete and its behavioral effects were characterized by a small
separation between doses attenuating the discriminative-stimulus effect
of nicotine and those producing a marked reduction in rates of responding.
In a previous study with Long-Evans rats trained to discriminate
nicotine from saline, 5.0- and 30-mg/kg doses of GBR-12909 failed to
generalize to the nicotine cue (Corrigall and Coen, 1994
); the higher
dose produced complete suppression of responding in four of six rats.
In the present study, however, GBR-12909 produced full generalization
in water-drinking Sprague-Dawley rats to both the 0.1- and 0.4-mg/kg
nicotine cues at doses of 10 and 13 mg/kg (intermediate doses of
GBR-12909 not studied by Corrigall and Coen, 1994
) and partial
generalization at 5.6 mg/kg. Higher doses of GBR-12909, as with
Corrigall and Coen (1994)
, suppressed responding. Given that there is a
symmetrical generalization between GBR-12909 and cocaine in rats and
monkeys (Melia and Spealman, 1991
; Witkin et al., 1991
; Spealman,
1993
), likely due to overlapping pharmacological mechanisms of action
(Feldman et al., 1997
), and that cocaine partially generalized to the
nicotine cue (present study and Stolerman et al., 1984
), partial
generalization of GBR-12909 to the nicotine cue would have been expected.
The role of D1 and D2 dopamine receptors in the mediation of
nicotine's discriminative stimulus effects has been studied by Stolerman and coworkers. The selective D1 dopamine-receptor
agonist SKF 38393 partially generalized to the nicotine cue (Stolerman and Reavil, 1989
). Moreover, the selective D1 dopamine antagonist SCH
23390 significantly attenuated nicotine discrimination, whereas two
neuroleptics with selectivity for D2 dopamine receptors had no effect
(Reavil and Stolerman, 1987
). In the present study, the
selective D1 dopamine-receptor agonist SKF-82958 generalized to the
nicotine cue in water-drinking rats, whereas the selective D2
dopamine-receptor agonist NPA produced only saline-appropriate responses (Fig. 7), supporting these earlier findings indicating involvement of D1 but not D2 dopamine receptors in mediation of the
discriminative-stimulus effects of nicotine in rodents.
It has recently been suggested that D3 dopamine autoreceptors may be
involved in the pathogenesis of neuropsychiatric disorders such as
schizophrenia and drug addiction, and the potential clinical use of
selective D3 dopamine receptor agonists is now being explored (Caine
and Koob, 1993
; Acri et al., 1995
; Lamas et al., 1996
; Levant, 1997
;
Sanger et al., 1997
; Witkin et al., 1998
). Stimulation of D3 dopamine
autoreceptors by selective compounds results in a dose-dependent
inhibition of dopamine release in vivo and in vitro, and also has been
implicated in blocking the reinforcing effects of amphetamine and
cocaine (for review see Levant, 1997
). Of importance for the present
study, the discriminative stimulus effects of D3 dopamine-receptor
agonists (e.g., 7-hydroxydipropylaminotetralin hydrobromide, PD
128,907) are similar to those of cocaine and the nonselective
dopamine receptor agonist apomorphine in both rats and monkeys (Acri et
al., 1995
; Lamas et al., 1996
; Sanger et al., 1997
). Thus, the
selective D3 dopamine receptor agonist PD 128,907 was tested in the
present study to verify the extent to which it was similar to the other
dopaminergic compounds that partially generalized to the nicotine cue.
PD 128,907 engendered only saline-appropriate responses in
water-drinking rats up to doses that markedly suppressed responding.
Moreover, chronic caffeine exposure in caffeine-drinking rats did not
change the discriminative or response rate-decreasing effects of PD
128,907. Although more studies will be needed to assess the role of D3
dopamine autoreceptors in mediating the discriminative stimulus effects
of nicotine, the present study provides the first evidence suggesting
their minimal role and adds to accumulating evidence differentiating the nicotine cue from those of other psychomotor stimulants such as
amphetamine and cocaine.
It has been observed for a number of pharmacologically diverse drugs,
including nicotine, that the results of generalization tests can vary
depending on the training dose of drug (Stolerman et al., 1984
; Mumford
and Holtzman, 1991
; Schechter, 1997
). Typically, pharmacological
specificity in drug discrimination studies decreases with lower and
increases with higher doses of a training drug. In the present study, a
4-fold difference in the training dose of nicotine was insufficient to
produce marked differences in the pharmacological specificity of the
nicotine cue. Patterns of generalization to dopaminergic agents were
qualitatively identical for the lower and higher training doses of
nicotine in water-drinking rats. Likewise, ED50
values calculated from dose-response functions were statistically
comparable (Table 4). Only in the case of cocaine did different
nicotine-training doses quantitatively affect the outcome. Cocaine
appeared more efficacious in producing nicotine-appropriate responses
in water-drinking rats trained with 0.1 mg/kg of nicotine relative to
water-drinking rats trained with 0.4 mg/kg of nicotine (83.2% versus
50.7%).
Different training doses of nicotine also had little effect on its
final potency as a discriminative stimulus after acquisition. When
dose-response functions of nicotine's discriminative stimulus effects
were evaluated, immediately after all rats met the criteria of stimulus
control, the ED50 values for nicotine were
similar in water- and caffeine-drinking rats trained with 0.1 mg/kg
relative to 0.4 mg/kg of nicotine (Table 2). However, when
dose-response functions were re-evaluated after generalization and
antagonism tests were completed, the ED50 values
for nicotine were 1.9-fold lower in water-drinking rats and 2.4-fold
lower in caffeine-drinking rats trained with 0.1 mg/kg of nicotine
relative to rats trained with 0.4 mg/kg of nicotine. Furthermore, the
ED50 values for mecamylamine needed to block the
discriminative effects of the 0.1-mg/kg training dose of nicotine were
5.1-fold lower in water-drinking rats and 3.8-fold lower in
caffeine-drinking rats relative to the doses needed to block the
discriminative effects of the 0.4 mg/kg training dose of nicotine. As
expected (Stolerman et al., 1984
), a 4-fold decrease in the training
dose of nicotine appeared sufficient to significantly (1.6- and
2.0-fold; p <.05) decrease the rate of acquisition of the
nicotine discrimination in both water- and caffeine-drinking rats.
A large body of evidence suggests that nicotine exerts stimulus control
of behavior primarily by activation of nicotinic acetylcholine (ACh)
receptors in the brain (Stolerman, 1990
; Wiley et al., 1996
). Thus,
drugs that show high affinity for nicotinic ACh receptors in the
central nervous system dose-dependently and stereoselectively generalize to a nicotine-discriminative cue with potencies positively correlating with their binding affinities for nicotinic ACh receptors (Wiley et al., 1996
). The discriminative stimulus effects of nicotine, however, are not exclusively specific to nicotine-like drugs, as some
dopaminergic compounds have been shown to produce partial generalization to the nicotine cue. Such a dopaminergic component of
the discriminative stimulus properties of nicotine might be explained
by neuroanatomical studies showing that many nicotinic ACh receptors
are located on presynaptic dopamine-containing neurons in brain regions
potentially involved in mediating the discriminative stimulus effects
of nicotine (Koob, 1992
; Dani and Heinemann, 1996
; Shoaib and
Stolerman, 1996
; Wonnacott et al., 1996
). Such presynaptic nicotinic
ACh receptors, when activated by nicotine, can lead to release of
dopamine into the synaptic cleft in the striatum and cortex (Nisell et
al., 1995
; Wonnacott et al., 1996
). In the present study, chronic
caffeine exposure appeared to eliminate the dopaminergic component of
the discriminative stimulus effects of nicotine. All dopaminergic
compounds that generalized to the nicotine cue in water-drinking rats
failed to generalize to the nicotine cue in caffeine-drinking rats,
regardless of their specific pharmacological mechanism of action upon
dopaminergic transmission. This effect of chronic caffeine exposure
appeared to be independent of the training dose of nicotine. In
contrast, the primary component governing the discriminative stimulus
properties of nicotine remained unchanged by chronic caffeine exposure,
suggesting that caffeine produced changes downstream from activation of
nicotinic ACh receptors. This speculation is strengthened by the
results of antagonism tests with mecamylamine and CGS 10746B.
Mecamylamine equieffectively blocked the discriminative stimulus
effects of nicotine in both water- and caffeine-drinking rats. In
contrast, CGS 10746B partially blocked the discriminative stimulus
effects of nicotine in water-drinking rats but not in caffeine-drinking
rats. The behavioral effects of CGS 10746B on rates of responding
however, did not differ between water- and caffeine-drinking rats.
The failure of dopaminergic compounds to generalize to the nicotine cue
in caffeine-drinking rats in the present study is unlikely due to an
inability of rats chronically exposed to caffeine to respond to
dopaminergic drugs. Similar regimens of caffeine exposure in rats
failed to change amphetamine- and cocaine-induced stimulation of
ambulatory activity but potentiated that of nicotine (Holtzman, 1983
;
Finn and Holtzman, 1987
; Shoaib et al., 1996
). More recently, we have
shown that a chronic regimen of caffeine exposure, identical with that
in the present study, markedly potentiated the response-rate increasing
effects of amphetamine and cocaine, but not those of nicotine, in rats
responding under a FI schedule of food reinforcement (Jaszyna et al.,
1998
). In contrast, caffeine-drinking rats appeared to be less
sensitive to the response-rate decreasing effect of the selective D1
dopamine receptor agonist SKF-82958 than water-drinking rats, but
sensitivity to the behavioral effects of the selective D2 dopamine
receptor agonist NPA remained unaffected by chronic caffeine exposure.
Chronic caffeine exposure also appears to have no effect on the overall
behavior of rats, as there were no differences in FR or FI rates of
responding between water- and caffeine-drinking rats throughout the
previous study by Jaszyna et al. (1998)
and throughout the present
study (Fig. 10). Furthermore, the baseline level of ambulatory activity
in caffeine-drinking rats did not differ from that of water-drinking
rats (Shoaib et al., 1996
). Thus, it can be concluded that chronic
caffeine exposure changed the discriminative stimulus properties of
nicotine and these changes could be due to specific pharmacological
effects of caffeine on the dopaminergic component of nicotine's
discriminative cue.
In the present study, rats were exposed to caffeine for 2 weeks before
acquisition training was initiated. Chronic caffeine exposure had
little effect on rates at which rats learned to discriminate nicotine
from saline, as the number of sessions required for robust stimulus
control was comparable in water- and caffeine-drinking rats. There was,
however, a trend for acquisition of the 0.1-mg/kg nicotine
discrimination to be retarded in caffeine-drinking rats. It is possible
that chronic caffeine exposure weakened the discriminative stimulus cue
of nicotine, and in turn, more training sessions were needed to
establish stimulus control. Given that there were no changes in the
nicotinic component but marked changes in the dopaminergic component of
the discriminative stimulus cue of nicotine, as revealed by later
studies, it seems reasonable to speculate that chronic caffeine
exposure reduced this dopaminergic component and thus retarded the
acquisition of the 0.1 mg/kg of nicotine discrimination. Because 0.4 mg/kg of nicotine would produce stronger stimulation of nicotinic
receptors than 0.1 mg/kg, this could overshadow the effect of caffeine
on the dopaminergic component of the nicotine cue during the
acquisition phase. There was also a trend for caffeine-drinking rats
trained with 0.1 mg/kg of nicotine to show lower response rates than
water-drinking rats trained with the same dose of nicotine (Fig. 10).
This could additionally affect the rate of acquisition of the nicotine
discrimination in this group. Nevertheless, the general lack of effect
of chronic caffeine exposure on rates of acquisition of the nicotine
discrimination were somewhat surprising based on our previous findings
that Sprague-Dawley rats chronically exposed to the same concentrations
of caffeine in their drinking water acquired self-administration of
i.v. nicotine significantly faster and reached higher rates of
responding than did water-drinking control animals (Shoaib et al.,
1996
). This apparent difference may be attributed to different brain
regions mediating the discriminative and reinforcing effects of
nicotine (Stolerman and Shoaib, 1991
; Nisell et al., 1995
; Shoaib and
Stolerman, 1996
) and/or to different dose thresholds for
caffeine to produce facilitation and retardation of these effects.
Caffeine appeared to have both acute and long-lasting effects on the
discriminative stimulus properties of nicotine. In contrast to
water-drinking rats, amphetamine engendered only saline-appropriate responses in rats chronically exposed to caffeine (Fig. 4). When caffeine solution was replaced by tap water and dose-response functions
for amphetamine were re-evaluated in the same subjects 3 weeks later,
amphetamine still failed to generalize to the nicotine cue (Fig. 9).
This suggests that chronic caffeine exposure during the acquisition
phase and subsequent testing and training phases produced long-lasting
changes in the discriminative stimulus properties of nicotine, as no
caffeine or its metabolites would be expected 21 days after termination
of chronic caffeine exposure in rodents (Bonati et al., 1984-1985
;
Gasior et al., 1996
). On the other hand, although amphetamine was shown
to generalize to the nicotine cue in water-drinking rats (Fig. 4), when
tap water was replaced by caffeine solution and amphetamine was
re-evaluated 3 weeks later, amphetamine failed to generalize to the
nicotine cue. This suggests that chronic caffeine exposure can also
qualitatively change the properties of an established nicotine cue. It
is important to note that there was no training during this 3-week
period to avoid retraining animals under new conditions in terms of
water and caffeine exposure.
Chronic oral exposure to caffeine in the drinking water, as in the
present study, has previously been shown to produce rapid, complete,
and insurmountable tolerance to the stimulatory effects of caffeine on
behavior in rats (Holtzman, 1983
; Finn and Holtzman, 1987
; Newland and
Brown, 1997
; Jaszyna et al., 1998
), and similar tolerance is seen after
repeated daily i.m. injections of caffeine in monkeys (Katz and
Goldberg, 1987
; Howell and Landrum, 1997
). Although caffeine intake in
rats remained stable throughout the present study, week-to-week
variations were considerable (Fig. 10). Similar degrees of variation in
oral caffeine intake have been reported (Holtzman, 1983
; Jaszyna et
al., 1998
). To minimize these variations, each dose of a respective
drug was tested in a randomized order. Nevertheless, the present
regimen of chronic caffeine exposure had no effect on body weights,
baseline levels of FR responding (Fig. 10), FI responding (Jaszyna et
al., 1998
), or on ambulatory activity (Shoaib et al., 1996
).
In the present study, the plasma level of caffeine in rats drinking
water containing 3 mg/ml caffeine and showing an average 135 mg/kg/day
caffeine intake was, on average, 29.11 µg/ml. Such a plasma
concentration of caffeine is comparable to those measured in rats after
a single bolus injection of behaviorally active 20- to 40-mg/kg doses
of caffeine (e.g., Modrow et al., 1981
; Hirsh, 1984
; Nehlig et al.,
1992
; Lau and Falk, 1994
). In humans, an oral dose of 1 mg/kg of
caffeine (equivalent to the caffeine content in one cup of coffee)
produces plasma concentrations of 1 to 2 µg/ml, whereas doses of 5 to
8 mg/kg (equivalent to the caffeine intake of a heavy coffee drinker)
would produce plasma concentrations of about 8 to 10 µg/ml (e.g.,
Benowitz, 1990
; James, 1991
; Sawynok, 1995
). Any direct comparisons of
doses and plasma levels of caffeine in experimental animals relative to
humans ought to be interpreted with extreme caution, because there are large between-species differences in metabolism and sensitivity to the
stimulatory effects of caffeine (James, 1991
). In general, a dosage
correction based on differences in metabolic weight predicts a 3- to
4-fold reduction of an equivalent caffeine dose in humans relative to
rats (James, 1991
). Similarly, and again very approximate, a dosage
correction based on differences in sensitivity to the stimulatory
effects of caffeine on operant behavior predicts a 3- to 16-fold
reduction of an equivalent caffeine dose in nonhuman primates (e.g.,
Katz and Goldberg, 1987
; Howell and Landrum, 1997
) relative to rats
(e.g., Logan et al., 1989
; Horger et al., 1991
; Jaszyna et al., 1998
).
A pharmacological explanation for the qualitative changes in the
discriminative stimulus properties of nicotine produced by chronic
caffeine exposure in the present study can only be speculative at this
point, as there are no neurochemical data directly correlating changes
in the discriminative stimulus effects of nicotine or other psychomotor
stimulant drugs with changes produced by chronic caffeine exposure at
the receptor level. Caffeine acts as a competitive, nonselective A1/A2
adenosine receptor antagonist at "physiological concentrations" and
has been shown to change the amount and function of central A1 and A2
adenosine receptors after chronic treatment (for review, see Nehlig et
al., 1992
; Jacobson et al., 1996
). The existence of an antagonistic
interaction between adenosine and dopamine receptors in the brain has
been confirmed in behavioral and biochemical studies (Ferre et al.,
1992
). It appears that specific adenosine receptors are colocalized
with specific dopamine receptors (A1 with D1 and A2 with D2,
respectively) at postsynaptic membranes in the striatum. Functionally,
activation of A1 adenosine receptors results in the inhibition of D1
dopamine receptor-mediated increases in cAMP levels. Likewise,
activation of A2 adenosine receptors inhibits D2 dopamine
receptor-mediated decreases in cAMP levels. Therefore, caffeine, by
blocking A1 and A2 adenosine receptors, can remove the inhibitory tone
of endogenous adenosine from D1 and D2 dopamine receptors, which in
turn can lead to the stimulation of dopaminergic neurotransmission in
the brain (Ferre et al., 1992
; Fredholm et al., 1996
). In line with
this hypothesis, the role of dopamine in the behavioral effects of
caffeine has been well documented in both animals and humans, and is
the subject of a recent review by Garrett and Griffiths (1997)
.
In the present study, overstimulation of dopaminergic neurotransmission in rats chronically exposed to caffeine could overshadow increases in dopamine produced by training doses of nicotine during the acquisition and testing phases of the nicotine discrimination. With the dopaminergic component of the nicotine cue blunted by constant exposure to caffeine, rats might need to use a finer set of criteria for discriminating the effects of nicotine plus caffeine from those of saline plus caffeine than they would for simply discriminating drug (nicotine) from no drug (saline). Thus, chronic caffeine exposure might change the neurochemical substrates of the nicotine cue from dopaminergic to nondopaminergic mechanisms (e.g., glutamatergic). The neurochemical substrates of the nicotine cue in animals chronically exposed to caffeine remain to be determined.
In conclusion, the present study provides evidence that the
discriminative properties of nicotine can be markedly changed by
chronic caffeine exposure. Changes produced by chronic caffeine exposure appear to be selective to the dopaminergic component of
nicotine's discriminative cue. Nicotine, however, could reliably serve
as a discriminative stimulus even in the absence of the dopaminergic
component of its discriminative cue. This reinforces the notion that
the dopamine neurotransmitter system plays a secondary role in the
discriminative stimulus properties of nicotine. Furthermore, the
present findings add to accumulating evidence differentiating nicotine
from "classical dopaminergic " drugs of abuse such as cocaine and
amphetamine. Finally, involvement of other neurotransmitter systems in
the effects observed in the present study cannot be ruled out and
warrants further study given that caffeine can alter the density and
function of a number of different receptors in the brain
(Jacobson et al., 1996
).
| |
Acknowledgments |
|---|
We thank Dr. James Goldberg for helpful comments about the manuscript, Eric Thorndike (Preclinical Pharmacology Laboratory, National Institute on Drug Abuse) for his programming assistance, Dr. H. Cooper Eckhardt (Novartis Pharmaceuticals Corporation) for help with obtaining CGS 10746B, and J. Zavitsky (Labstat Incorporated) for measuring plasma caffeine concentrations.
| |
Footnotes |
|---|
Accepted for publication October 8, 1998.
Received for publication July 14, 1998.
3 A Visiting Fellow in the National Institutes of Health Visiting Program of the Fogarty International Center, Bethesda, MD. Permanent address: Department of Pharmacology, Medical University School, Lublin, Poland.
4 Present address: Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, United Kingdom.
5 Present address: Division of Gerontology and Geriatric Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
1 This work was supported by National Institute on Drug Abuse/National Institutes of Health, Baltimore MD.
2 Animals used in these studies were maintained in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care and all experimentation was conducted in accordance with the guidelines of the Institutional Care and Use Committee of the National Institute on Drug Abuse, National Institutes of Health, and the Guide for Care and Use of Laboratory Animals (National Research Council, 1996, National Academy Press, Washington, DC). Preliminary findings of this study were presented at the Annual Meeting of the International Behavioral Neuroscience Society, San Diego, CA, April 24-27, 1997 [Gasior M, Shoaib M, Yasar S and Goldberg SR (1997) Qualitative changes in the discriminative properties of nicotine produced by chronic caffeine exposure in rats. Abstract of the International Behavioral Neuroscience Society 6:54] and during the XIIIth Congress of the Polish Pharmacological Society, Katowice, Poland, September 13-16, 1998 [Gasior M and Goldberg SR (1998) Influence of chronic caffeine exposure on the behavioral effects of nicotine: Implications for abuse potential. Pol J Pharmacol 50 (Suppl):61].
Send reprint requests to: Maciej Gasior, M.D., Ph.D., Preclinical Pharmacology Laboratory, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: mgasior{at}intra.nida.nih.gov
| |
Abbreviations |
|---|
ACh, acetylcholine; FI, fixed interval; FR, fixed ratio.
| |
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