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Vol. 281, Issue 3, 1330-1339, 1997
Psychology Department, Durham University, Science Laboratories, South Road, Durham DH1 3LE, U.K. 1Department of Pharmacology, School of Medical Sciences, Bristol, BS8 1TD United Kingdom
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Abstract |
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 Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The effects of amphetamine and cocaine on locomotor activity in mice were studied after 3 weeks of chronic administration of ethanol by liquid diet. When testing was started 24 h after cessation of the ethanol treatment, no differences were seen on the first administration between the effects of the psychostimulants in controls and ethanol-treated animals, but after subsequent daily injections of amphetamine and cocaine, at doses that were insufficient to cause sensitization in controls, sensitization to both of these drugs was seen in ethanol-treated mice. When testing was started on the sixth day after cessation of the ethanol treatment, the effects of amphetamine on the first administration were significantly greater in ethanol-treated animals than in controls. After subsequent repeated daily injections, the locomotor stimulant effects of cocaine were greater in ethanol-treated mice than in controls. Administration of amphetamine for the first time 2 months after cessation of ethanol treatment also had a greater stimulant effect, compared with that in control animals. Two months after cessation of ethanol treatment, the first dose of cocaine caused a locomotor stimulation that was not seen in control animals, but sensitization was not seen after repeated cocaine administration in either group of animals. No differences in the effects of amphetamine or cocaine were seen after only 7 days of ethanol treatment. The results indicate that changes are still present in the CNS long after ethanol withdrawal hyperexcitability has subsided and that these changes result in increases in the effects of amphetamine and cocaine. Analysis of brain concentrations of the two psychostimulants suggested that metabolic changes were not responsible for the differing effects in control and ethanol-treated animals. It is possible that alterations in mesolimbic dopamine transmission are responsible for the effects of the ethanol treatment.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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One of the main characteristics of dependence on many different types of drug is the tendency of addicts to relapse into drug taking long after they have recovered from the major withdrawal symptoms. This is characteristic of dependence on ethanol and is one of the main problems in the treatment of alcoholics. Much study has been devoted to alterations in neuronal function that take place during the phase of withdrawal hyperexcitability, but until recently, less attention has been paid to more prolonged changes that might be responsible for the tendency to relapse into excessive drinking. We are currently investigating the existence of functional changes that might persist for a long time after cessation of ethanol intake.
Recently evidence has been accumulating that there are commonalties in
the mechanisms involved in dependence on drugs of different types.
Compounds such as psychostimulants (amphetamine and cocaine), opiates,
nicotine and ethanol exert their initial acute effects through
different sites, but they cause similar changes in the mesolimbic
dopamine pathway, acutely increasing transmission in the projection to
the nucleus accumbens from dopaminergic neurons in the VTA (Di Chiara
and Imperato, 1988). Evidence for alterations in transmission in this
pathway during the withdrawal phase after repeated administration of
these different types of drugs has been obtained from in
vivo dialysis measurements of extracellular dopamine
concentrations in the nucleus accumbens (Kalivas and Duffy, 1990
;
Akimoto et al., 1990; Rossetti et al., 1992;
Benwell and Balfour, 1992), while neurochemical studies on the VTA and nucleus accumbens have suggested that there are common patterns in the
effects of prolonged administration of the different types of drugs
(Nestler et al., 1994; Ortiz et al., 1995).
Repeated administration of the psychostimulants amphetamine and cocaine
causes sensitization to their locomotor stimulant actions (Segal and
Mandell, 1974) and to the liability of rodents to self-administer these
drugs (Horger et al., 1990; Wolverton et al.,
1984). A similar prolonged sensitization has been seen with opiates
(Babbini and Davis, 1972) and nicotine (Ksir et al., 1985).
This sensitization lasts long after cessation of the drug treatment,
which suggests that it may be involved in dependence on these drugs
(Robinson and Berridge, 1993).
Cross-sensitization between different drugs has been demonstrated.
Pretreatment with amphetamine increased the locomotor stimulant actions
of cocaine (Kalivas and Weber, 1988), and a prolonged effect of
amphetamine in increasing the acquisition of cocaine self-administration has been reported (Valadez and Shenk, 1994). More
complex interactions have also been seen. Nicotine, for example, was
not found to increase the locomotor stimulant actions of cocaine but
did increase the predisposition of rats to self-administer this
substance (Schenk et al., 1991; Horger et al.,
1992). Amphetamine administered directly into the VTA caused
sensitization to morphine given systemically; this effect was
demonstrated not to involve conditioning effects (Vezina and Stewart,
1990). Although ethanol can cause sensitization, this effect is
strain-dependent (Phillips et al., 1994). Concurrent
administration of ethanol and cocaine increased the anxiogenic effects
of cocaine after cessation of chronic treatment (Prather et
al., 1991). There has been little investigation of the effects of
prior administration of ethanol on sensitization to other drugs.
In the present study, we have investigated the effects of chronic ethanol treatment on the subsequent responsiveness to single and repeated administration of the psychostimulant drugs amphetamine and cocaine. The primary aim of this project was to determine whether, at comparatively long time intervals after cessation of the ethanol treatment, there was any evidence for changes in the effects of the psychostimulants that might indicate persistent neurochemical changes that could be involved in relapse. In addition, after the effects of the 3-week administration of ethanol had been discoverd, we studied the effects of a shorter, 1-week treatment to see whether the same effects were produced.
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals
Male TO mice (Bantin and Kingman, Hull, UK) were used in all studies. The weights ranged from 25 to 35 g, with no more than a 5-g range in any single experiment. Between tests the mice were housed seven per cage, at 21°C ± 1°C and 55% ± 10% relative humidity, with a 12-h light/dark cycle, the light phase being between 09:00 h and 21:00 h. They had free access to tap water and laboratory rodent chow (SDS, Edinburgh, Scotland). Fresh tap water was available throughout the liquid diet treatment.
Each treatment group contained seven mice. All drugs were given by the i.p. route, at a volume of 10 ml/kg.
Production of Physical Dependence on Ethanol
Three-week ethanol administration.
Ethanol was administered
in a liquid diet schedule (Dyets, Bethlehem, PA; Green et
al., 1990). In the liquid diet administration schedule, all mice
received a control liquid diet for an initial 3-day period to accustom
them to the diet. Ethanol-treated mice then received a diet containing
3.5% ethanol for 2 days, followed by a diet containing 5% ethanol for
9 days and then a diet containing 8% ethanol for a further 9 days.
Control groups were pair-fed a control diet balanced isocalorifically
to match the ethanol-containing diet (Green et al., 1990).
There were no significant differences between the weights of the
ethanol-treated and control mice at the end of the treatment periods.
| Day 6 24.6 ± 2.2 | |
| Day 10 22.9 ± 1.8 | |
| Day 13 23.2 ± 1.5 | |
| Day 16 25.0 ± 1.0 | |
| Day 20 31.0 ± 0.7 | |
| Day 23 28 ± 0.3 |
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Shorter ethanol administration. The effects of a shorter ethanol treatment were also studied. During this treatment the mice drank a total of 196 g/kg over 7 days. After the initial days of control diet, these animals were given a diet containing 3.5% ethanol for 2 days, followed by a diet containing 7% ethanol for 5 days. We then examined the effects of amphetamine and cocaine, using the times at which the maximal changes were seen after the longer ethanol treatment, because these results were available when this section of the study was started. The amphetamine administration was therefore begun after 6 days (withdrawal day 7), and cocaine treatment after 24 h (withdrawal day 2), from the cessation of the last ethanol treatment phase.
Repeated Administration of the Psychostimulants
The following treatment schedules were used to measure the effects of amphetamine and cocaine on locomotor activity and to produce sensitization to these effects.
| 1) First administration of drugs, measurements of effect on locomotor activity, on either day 2, day 7 or day 61 after the end of the ethanol treatment. | |
| 2) Injections of amphetamine, cocaine or saline, once daily for 8 days, beginning 24 h after the first locomotor measurements, from withdrawal day 3 to withdrawal day 10 (when tests started on withdrawal day 2), from withdrawal day 7 to withdrawal day 15 (when tests started on withdrawal day 7) or from withdrawal day 62 to withdrawal day 69 (when tests started on withdrawal day 61). | |
| 3) Test of effects of drugs on locomotor activity, 24 h after last injections (first sensitization test), on withdrawal day 10 (when tests started on withdrawal day 2), on withdrawal day 15 (when tests started on withdrawal day 7) or on withdrawal day 69 (when tests started on withdrawal day 61). | |
| 4) Injections of amphetamine, cocaine or saline, once daily for 6 days, beginning 24 h after the second locomotor measurements, from withdrawal day 11 to withdrawal day 16 (when tests started on withdrawal day 2), from withdrawal day 16 to withdrawal day 21 (when tests started on withdrawal day 7) or from withdrawal day 70 to withdrawal day 75 (when tests started on withdrawal day 61). | |
| 5) Test of effects of drugs on locomotor activity, 24 h after last injections (second sensitization test), on withdrawal day 18 (when tests started on withdrawal day 2), on withdrawal day 21 (when tests started on withdrawal day 7) or on withdrawal day 76 (when tests started on withdrawal day 61). |
A dose of 3 mg/kg amphetamine was used for both the tests and the repeated injections. A dose of 20 mg/kg cocaine was used for all the repeated injections, and 10 mg/kg was used for the tests. (We had originally intended to use a higher dose of amphetamine, 5 mg/kg, for the repeated injections, but preliminary experiments showed this to be too toxic).
Locomotor Activity
Spontaneous locomotor activity was measured using Opta-Varimex-Mini activity meters operated by the interruption of 15 infrared beams. A clear perspex cage (50 × 32 × 15 cm) containing a small amount of sawdust was placed between a metal frame containing the infrared emitters and sensors placed 1 inch apart. Prior to the test period, the animals were kept in their home cages, each of which contained seven animals. The locomotor activity measurements were all made between 9 A.M. and 2 P.M., and the studies on the different treatment groups were randomized throughout this time to avoid any bias from circadian variations in activity. No habituation time was allowed in the activity cages before the measurements started.
The activity measurements were all started 20 min after the injections of saline, amphetamine or cocaine. Mice were placed individually in novel cages, and the ambulant locomotor activity and total locomotor activity were measured for 10 min. This choice of timing was based on preliminary experiments that showed that, in this strain of mice, the effects of both amphetamine and cocaine were maximal between 20 and 30 min after injection. Parallel experiments were also carried out, which showed that this time of maximal effect was not altered by the chronic ethanol treatment. The psychostimulant doses were chosen on the basis of prior studies that showed that the locomotor activity was increased by doses of amphetamine between 1 and 5 mg/kg and doses of cocaine between 10 and 50 mg/kg; the doses used were therefore submaximal with regard to stimulation of locomotor activity.
Measurements of Responses to Handling During Ethanol Withdrawal
The severity of the withdrawal signs were estimated by the
responses to handling (Littleton et al., 1990) by an
observer who did not know the prior drug treatment. These were measured
from 3 h to 6 h, inclusive, on withdrawal day 1 after
cessation of ethanol treatment, a time that we have previously shown to
be maximal for changes in responses to handling during withdrawal. The
mice were chosen at random (n = 10 per group) before
the studies of the effects of the psychostimulant drugs.
Treatment of Animals for Measurements of Brain Concentrations of Amphetamine and Cocaine
Mice were administered ethanol by the long-term (3-week) liquid diet schedule, and controls were pair-fed control liquid diet. Beginning either on withdrawal day 6 (for amphetamine measurements) or on withdrawal day 2 (for cocaine measurements) after cessation of ethanol treatment, animals received 16 daily injections of 3 mg/kg amphetamine or 10 mg/kg cocaine. They were then left for 26 days, until withdrawal day 43 (for cocaine) or withdrawal day 48 (for amphetamine), with standard laboratory chow and water and no drug treatment. After this time interval, animals were administered 3 mg/kg amphetamine or 20 mg/kg cocaine, and the locomotor activity was measured between 20 and 30 min after the injections. The whole brains were then removed 30 min after drug administration.
Measurements of Amphetamine and Cocaine Concentrations
The brains were weighed and homogenized in 3 ml 0.1 M sulphuric acid, and 0.5 ml of the homogenate or standard solution was added to 50 µl aqueous (1 mg/ml) internal standard solution (mephentermine for the amphetamine assay and amylocaine and iprindole for the cocaine assay). Then 100 µl of 4 M ammonium hydroxide and 50 µl of n-butyl acetate were added, and the samples were mixed and centrifuged at 9950 × g for 3 min. Next, 2 µl of the upper organic layer was injected onto the chromatography column. Gas chromatography was performed on a Hewlett-Packard 5890 gas chromatograph in splitless injection mode with nitrogen phosphate detection. Calibration graphs were prepared for amphetamine, cocaine and methylecgonine. Norcaine was quantified against the cocaine standards.
Drugs
Amphetamine sulfate (Sigma Chemical Co., St. Louis, MO) and cocaine hydrochloride (BDH) were dissolved in saline (Baxter Healthcare, Norfolk, OK). The doses refer to the salt weights of the drugs.
Statistical Analysis
Statistical comparisons were made by two-way analysis of
variance, followed by the Scheffé F test for
comparison between samples. P = .05 was taken as the level of
significance. The withdrawal hyperexcitability scores were analyzed by
a nonparametric two-way analysis of variance designed for repeated
measures on the same animals (Meddis, 1984). Throughout the figures,
the sets of results grouped together were obtained from experiments
carried out concurrently, and spaces left between the columns indicate
results that were obtained on different occasions.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Tests started 24 h after cessation of ethanol treatment (day
2).
When the effects of amphetamine and cocaine were tested with
the first administration on withdrawal day 2, 24 h after cessation of the ethanol administration, there were no significant differences between the effects of amphetamine, cocaine and saline in animals that
had been given the control diet compared with the animals that received
the ethanol treatment (fig. 1A). Significant increases in the ambulant locomotor activity (P < .001) were seen at this time, when the effects of amphetamine and cocaine were compared with
the effects of saline administration, except when cocaine was given
after the ethanol treatment; when although the mean value was
increased, the difference was not significant (P < .1).
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Tests started on day 7 after cessation of ethanol treatment.
A
different pattern was seen when the effects of amphetamine and cocaine
were tested for the first time 6 days (withdrawal day 7) after the
cessation of liquid diet treatment (fig. 2), in separate
groups of mice from those in the study described above. In this case,
the first time that amphetamine was administered after the liquid diet
treatment, its effects were considerably greater in mice that had
received ethanol than in controls (P < .01). No differences were
seen in the effects of cocaine on day 7. A significant increase in
locomotor activity was seen on day 7 in all groups receiving either
amphetamine or cocaine, when comparison was made with the effects of
saline (P < .01 for the groups given ethanol treatment; P < .05 for controls).
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Tests started 2 months after cessation of ethanol treatment.
In separate groups of mice from those used in the studies described
above, the effects of amphetamine and cocaine were tested for the first
time 2 months after cessation of the liquid diet treatment (fig.
3). Amphetamine caused a significant increase in
locomotor activity in the group of mice previously given ethanol, compared with the locomotor activity after saline administration to
ethanol-treated mice (P < .01), but no significant increase was
seen in animals previously given the control liquid diet (fig. 3A). The
difference in the activities between ethanol-treated animals and
controls, each given amphetamine, failed to reach significance (P > .05). However, when the tests were carried out on withdrawal day 69, after the first set of repeated injections (fig. 3B), the effects of
amphetamine were significantly greater in ethanol-treated mice than in
controls (P < .001), and the difference between the activity
after amphetamine and that after saline administration was significant
(P < .001) for ethanol-treated animals but not for controls
(P > .05). There was no difference on day 69 in between the
activity of controls and that of ethanol-treated mice given saline
(P > .1). When the activity was measured on withdrawal day 75 (fig. 3C), after the second sensitization phase (a total of 16 daily
injections, including those on withdrawal days 61 and 69), the
difference between the effects of amphetamine in controls and
ethanol-treated mice was no longer significant (P > .1). On this
test day, the locomotor activity after amphetamine was significantly
greater in both controls and ethanol-treated animals, compared with the
activity after saline injections (P > .1).
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Shorter ethanol treatment.
The effects of a shorter (7-day)
ethanol treatment are illustrated in figure 4. The
effects of amphetamine were tested on withdrawal day 6 after the
cessation of liquid diet treatment, and study of the effects of cocaine
was begun on withdrawal day 2, because these were the times at which
pronounced changes were seen after the longer treatment. There was no
difference (P > .1) between the effects of amphetamine or cocaine
in control and ethanol-treated animals, or in the effects of saline
injections, when given for the first time (fig. 4A) or after the first
(results not illustrated) or second sensitization phase, on withdrawal day 16 for cocaine and withdrawal day 21 for amphetamine (fig. 4B). No
differences (P > .1) were seen between controls and
ethanol-treated animals in either set of tests.
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Measurement of withdrawal hyperexcitability. The results of the handling score measurements on withdrawal day 1 are shown in table 2. The results for the two ethanol treatment schedules were obtained during the withdrawal phase, before the study of the effects of amphetamine or cocaine. The severity of the withdrawal hyperexcitability was significantly greater in the mice that received the longer ethanol treatment (P < .01), when comparison was made over the whole of the measurement period by two-way analysis of variance.
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Brain amphetamine and cocaine levels. The concentrations of amphetamine, cocaine and cocaine metabolites are given in table 3. The locomotor activity measurements on withdrawal day 48 (for amphetamine) or withdrawal day 43 (for cocaine) for the animals from which the brains were taken for the concentration measurements are illustrated in figure 4C. Both amphetamine and cocaine had a significantly greater effect in the locomotor tests in animals that had previously had ethanol, compared with animals that were given the control diet (fig. 4C). However, it can be seen from table 3 that the control animals had significantly higher levels of amphetamine in the brain than the ethanol-treated animals (P < .01). The levels of cocaine and norcaine did not differ significantly between control and ethanol-treated animals, but those that had previously been fed the ethanol diet had significantly lower brain levels of methylecgonine than control animal (P < .05).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The results show that 3 weeks of ethanol administration in mice can cause changes in the CNS that far outlast the phase of withdrawal hyperexcitability, as evidenced by changes in the actions of amphetamine and cocaine. The changes were always in the same direction: an increase in the locomotor stimulant actions of these compounds, seen either after the first administration or after repeated injections of the psychostimulant drugs. The results suggest that prolonged ethanol intake may increase the effects of amphetamine and cocaine in humans and may possibly increase the dependence liability of these drugs. A more important implication of these results is that they could be used as a model for the investigation of neuronal changes that might be responsible for the pattern of frequent relapse into drinking that is common in alcoholics who have gone through withdrawal.
The changes in the effects of amphetamine and cocaine were not seen
when only 7 days of ethanol treatment were given. The severity of the
withdrawal syndrome after the 3-week treatment was significantly
greater than that after the 7-day treatment, so it is possible that the
difference in the effects of amphetamine and cocaine after the two
treatment schedules were due to differences in withdrawal severity.
However, the withdrawal from the shorter ethanol schedule was very
pronounced, the handling scores being considerably, and
significantly, higher than control values. We have previously
demonstrated marked changes in the effects of convulsant drugs and
hyperexcitability to audiogenic stimuli, as well as in the convulsive
responses to gentle handling during the withdrawal syndrome after the
shorter ethanol treatment (Watson and Little, 1995). We have also
investigated the effects of intermittent alcohol treatment on the
locomotor stimulant actions of amphetamine and cocaine, but no changes
were seen in these studies (Manley and Little, 1995).
Various forms of stress have been shown to cause sensitization to the
effect of amphetamine and cocaine (Antelman et al., 1980;
Maccari et al., 1991; DeRoche et al., 1992;
DeRoche et al., 1993). It is quite likely that the stress of
the ethanol treatment and withdrawal contributed to the increases in
the effects of cocaine and amphetamine. However, the lack of effect of
the shorter ethanol treatment on the actions of amphetamine and cocaine
suggests that the changes seen after the longer ethanol administration are unlikely to have been due entirely to stress. It is likely that
greater, or different, neurochemical changes were produced by the
longer ethanol treatment than by the shorter administration, which may
have involved the dopamine pathways on which both amphetamine and
cocaine are known to act. Sensitization to the effects of psychostimulant drugs due either to repeated administration or to
stress has been linked to changes in the mesolimbic pathway arising
from the VTA (Kalivas and Stewart, 1991; Kalivas and Duffy, 1993a,b;
Vezina and Stewart, 1990).
When it was given for the first time 24 h after cessation of the
ethanol treatment, the effects of amphetamine were unchanged, but they
were increased when tested for the first time either 6 days or 6 months
after the end of the ethanol administration. These results may reflect
a series of alterations in neuronal function after the acute withdrawal
hyperexcitability subsided. These results show some similarity to the
progressive alterations seen over several days after withdrawal from
chronic administration of amphetamine. Wolf et al. (1993)
demonstrated that 3 to 4 days after cessation of repeated amphetamine
injections, dopamine autoreceptor sensitivity was decreased in the VTA,
with no change in extracellular dopamine concentrations in the nucleus
accumbens after amphetamine administration. By 10 to 14 days after
cessation of the treatment, the autoreceptor subsensitivity had
disappeared, but the amphetamine-stimulated dopamine levels were
increased.
The present results demonstrated increased effects of cocaine in
ethanol-treated animals when this drug was given repeatedly, but not on
the first administration, 24 h or 6 days after cessation of the
ethanol treatment. This was in contrast to the increases in the effects
of amphetamine when given for the first time. This different pattern of
changes with amphetamine and cocaine may have been due to the doses
used, because the dose of amphetamine was slightly higher on the
dose-response curve for increases in locomotor activity than the dose
of cocaine, or it may reflect differences in the mechanisms of action
of the two psychostimulants. Full dose-response curves to the
psychostimulants could not be established after the ethanol treatments
because of the extremely large numbers of chronically treated animals
this would have required. In control animals, some tolerance appeared
to occur to the stimulant effects of cocaine after repeated
administration, whereas the opposite pattern was seen after the ethanol
treatment. Tolerance to the reinforcing effects of cocaine (Katz
et al., 1993; Li et al., 1994), to its effects on
dopamine uptake (Izenwasser and Cox, 1992) and to its cardiovascular
actions (Johansson et al., 1992) has been reported. Whether
tolerance or sensitization is seen may be determined by the dose used
and the treatment regime, but results have not been entirely
consistent, and the mechanisms of the changes are not fully understood.
When cocaine was given 2 months after cessation of ethanol treatment in
the present study, an increase in activity was seen in ethanol-treated
animals, but not in controls. This was evident on first administration
of cocaine and after the first, but not after the second, set of
repeated injections; significant tolerance was not seen in these
results. Greater effects of cocaine were also seen in ethanol-treated
animals when tests were made 26 days after the second set of repeated injections (fig. 4C).
The changes in the measured effects of cocaine and amphetamine on locomotor activity were unlikely to be influenced by the development of stereotyped behavior. Throughout all the studies, the mice were observed very carefully before, after and during the measurements of locomotor activity. No stereotyped behavior was seen at any of the doses used of either cocaine or amphetamine, either on first administration or after repeated injections. Prior studies in control animals showed that stereotypy was seen in this TO strain of mice at doses of 10 mg/kg and above of amphetamine and at doses of 50 mg/kg and above of cocaine. No other abnormal behavior was seen in the animals, and they appeared quite normal on each occasion before the administration of the psychostimulants. No differences in body weight were seen between the treatment groups at any time.
In rats, sensitization can be associated with changes in the timing of
stereotypy and locomotor stimulant phases (Leith and Kuczenski, 1982).
However, experiments carried out in parallel that examined the time
course of activity in amphetamine-sensitized animals, over a 1-h period
after amphetamine administration, revealed that in ethanol-treated
animals the time of maximal effect of the psychostimulant was between
20 and 30 min after administration (results not illustrated), the same
time at which maximal effects had been seen in the preliminary studies
in naive animals.
The similar effects of psychostimulants and ethanol on dopamine release
in the mesolimbic system were in the Introduction. Results from
dopamine receptor binding studies after prolonged ethanol
administration have not been consistent, several groups finding no
changes (e.g., Hietala et al., 1990), but the
great majority of these studies investigated changes soon after ethanol withdrawal. One study, however (May, 1992), demonstrated an increase in
the affinity of the high-affinity state of the D1 receptor in striatal
membranes 7 months after the cessation of ethanol treatment. Studies of
the effects of dopamine agonists after chronic ethanol administration
have reported both decreases (Tabakoff et al., 1978) and
increases (Lai et al., 1980) in behavioral responses, but
again these studies were made within a short time of cessation of
ethanol treatment. Fahlke et al. (1995) reported that
amphetamine had a greater locomotor stimulant effect in rats with a
high ethanol intake than in those with a low intake, when tested 3 weeks after the cessation of ethanol drinking. Repeated amphetamine
administration increased ethanol intake in rats (Fahlke et
al., 1994). Experiments are under way in our laboratory to
determine whether the changes in the effects of amphetamine and cocaine
seen in the present study were due to alterations in the terminal
areas, such as the nucleus accumbens, causing changes in dopamine
release or to alterations in the firing of the neurons in the VTA.
Analysis of the brain psychostimulant concentrations revealed lower
amphetamine levels in the brains of animals previously treated with
ethanol, but behaviorally, these animals were more sensitive to the
locomotor effects of amphetamine. Although cocaine also had a greater
effect on animals previously treated with ethanol than on control
animals, the brain concentrations did not differ significantly between
the two treatment groups, although levels of methylecgonine were
decreased in ethanol-treated animals. It is unlikely that the latter
difference was involved in the differences between control and
ethanol-treated animals, as methylecgonine has been reported to
decrease the effects of cocaine (Schuelke et al., 1996). It
appears, therefore, that although the ethanol treatment did cause some
long-term changes in the pharmacokinetics of the psychostimulants, such
changes do not account for the behavioral changes observed in these
experiments.
In conclusion, the results demonstrate that chronic ethanol treatment can cause increases in the effects of amphetamine and cocaine that last considerably longer than the withdrawal hyperexcitability. The appearance of these changes was dependent on the duration and pattern of ethanol intake. These results are of relevance to the problem of relapse drinking, prevalent among alcoholics, and to multi-drug abuse.
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Acknowledgments |
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We thank the Medical Research Council for financial support for this work. S.J.M. holds a Bristol University Postgraduate Scholarship.
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Footnotes |
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Accepted for publication February 4, 1997.
Received for publication May 2, 1996.
Send reprint requests to: H. J. Little, Psychology Department, Durham University, Science Laboratories, South Road, Durham DH1 3EL, United Kingdom.
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Abbreviation |
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VTA, ventral tegmental area.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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differences between rats with low or high preference for alcohol.
Alcohol
12: 363-367, 1995[Medline].doses required, stereospecificity and actions of Bay-K-8644.
Psychopharmacology
100: 387-392, 1990[Medline].an incentive-sensitisation theory of addiction.
Br. Res. Rev.
18: 247-291, 1993.This article has been cited by other articles:
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  C. J. Slawecki, C. Somes, and C. L. Ehlers EFFECTS OF CHRONIC ETHANOL EXPOSURE ON NEUROPHYSIOLOGICAL RESPONSES TO CORTICOTROPIN-RELEASING FACTOR AND NEUROPEPTIDE Y Alcohol Alcohol., May 1, 1999; 34(3): 289 - 299. [Abstract] [Full Text] [PDF]
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