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Vol. 288, Issue 1, 211-220, January 1999
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, Republic of China (Y.W.); and Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado (R.K.F., M.R.P)
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Abstract |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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We previously found that beta adrenergic agonists such as norepinephrine and isoproterenol potentiate the depressant actions of ethanol (EtOH) on cerebellar Purkinje neurons. Furthermore, antagonism of the beta adrenergic effects of endogenously released catecholamines with timolol reduced EtOH-induced depressions of neuronal activity in that brain area. In the present study, we further investigated the hypothesis that activity of the endogenous noradrenergic innervation to the cerebellar cortex can potentiate this EtOH action. We investigated the interaction of synaptically released catecholamines on EtOH-induced depressions of cerebellar Purkinje neurons in three different experiments: (1) endogenous catecholamine release was facilitated by applying the catecholamine uptake inhibitor desmethylimipramine, (2) activity of the noradrenergic innervation of the cerebellar cortex from locus ceruleus was increased by causing acute withdrawal from 7 days of chronic morphine treatment with the opiate antagonist naloxone, and (3) the noradrenergic innervation of the cerebellum was activated directly by electrical stimulation of the locus ceruleus. We found that all three conditions potentiated EtOH-induced depressions in the cerebellum and that this potentiation of ethanol effects could be antagonized by the systemic administration of the beta adrenergic antagonist propranolol. Furthermore, morphine withdrawal also caused potentiation of the depressant effects of phencyclidine, which are known to be regulated by the endogenous catecholamine innervation in this brain area. Taken together with our previous data demonstrating a beta adrenergic facilitation of EtOH actions in this brain area, the present results suggest that the activity of endogenous noradrenergic synapses can regulate the depressant effects of EtOH on cerebellar Purkinje neurons.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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We previously
found that the depressant effects of ethanol (EtOH) on cerebellar
Purkinje neurons are potentiated by the beta adrenergic
receptor agonist isoproterenol (Lin et al., 1994
). Furthermore, we and
others reported that both isoproterenol and the catecholamine
neurotransmitter norepinephrine (NE) facilitate the potentiating effect
of subdepressant EtOH doses on GABA-induced depressions of Purkinje
neurons (Lin et al., 1993a; Lee et al., 1995). Recently, we reported
that this action is mediated by an EtOH interaction with the cAMP
second messenger system (Freund and Palmer, 1997), which was reported
to mediate the cellular actions of beta adrenergic receptor
activation (Sessler et al., 1989; Cheun and Yeh, 1992; Freund and
Palmer, 1997). Consistent with this conclusion, EtOH was found to
increase isoproterenol- or guanine nucleotide-stimulated adenylate
cyclase activity (Luthin and Tabakoff, 1984; Bode and Molinoff,
1988). In the absence of exogenous stimulation of these mechanisms,
however, we and others found that EtOH either does not alter or
antagonizes GABA-induced depressions of most Purkinje neurons (Harris
and Sinclair, 1984; Siggins et al., 1987; Freund et al., 1993). Even
so, we did find that EtOH causes a small potentiation of GABA-induced
depressions on about 20% of cerebellar Purkinje neurons in
Sprague-Dawley rats (Freund et al., 1993). This effect was antagonized
by timolol (Lin et al., 1994), suggesting that it may be mediated by
endogenous catecholamines. Similarly, the depressions of neuronal
firing caused by higher EtOH doses were reduced by local timolol
applications on 20% of the same cells (Lin et al., 1994). These data
suggest that activity of the endogenous NE innervation to the
cerebellar cortex might regulate the expression of these EtOH actions.
The primary catecholamine innervation of the cerebellum is a
noradrenergic afferent pathway from the nucleus locus ceruleus (LC) in
the molecular layer of the cerebellar cortex (Bloom et al., 1971; Olson
and Fuxe, 1971). The heaviest innervation is in the region of the
proximal dendrites of Purkinje neurons (Landis et al., 1975; Bloom and
Battenberg, 1976). Electrical stimulation of the LC mimics the
electrophysiological effects of locally applied NE or cAMP analogs on
Purkinje neurons (Siggins et al., 1971a,b; Hoffer et al., 1973; Moises
and Woodward, 1980; Moises et al., 1981), and these effects of LC
stimulation are eliminated both by the blockade of NE synthesis and
storage and by destruction of the NE innervation of cerebellum with
6-hydroxydopamine (Hoffer et al., 1973). Thus, input from this pathway
might well mediate the endogenous beta adrenergic regulation
of EtOH mechanisms in cerebellar Purkinje neurons suggested above.
Not only are the catecholamine pathways from the LC excited by
electrical stimulation but also withdrawal induced by the mu opiate receptor antagonist naloxone after chronic morphine treatment has been reported to cause increased synaptic release of NE (Rossetti et al., 1993), as well as activation of LC neurons (Rasmussen et al.,
1990; Akaoka and Aston-Jones, 1991). These latter studies report that
rats receiving chronic morphine injection over 7 days developed
excitation of LC neurons for more than 3 h after the systemic
injection of naloxone. Furthermore, microinjection of another opiate
antagonist, methylnaloxonium directly into the LC of morphine-dependent
rats induced behavioral signs of withdrawal (Maldonado et al., 1992).
These data, together with the observation that neither mu
opioid receptors nor mu receptor mRNA is present in the
cerebellar cortex (Mansour et al., 1994), suggest that the activation
of noradrenergic mechanisms in the cerebellum during morphine
withdrawal results from increased input from the LC innervation of that
brain area. Thus, if endogenous NE can regulate acute ethanol actions
in the cerebellum, this beta adrenergic effect might be
accentuated during naloxone-induced morphine withdrawal.
In the present study, we investigated EtOH effects in the cerebellum under conditions of elevated endogenous noradrenergic input. We approached this question by studying EtOH-induced depressions of Purkinje neurons while elevating synaptic NE levels using three different experimental paradigms: (1) endogenously released NE was elevated by blocking reuptake with desmethylimipramine (DMI); (2) the NE innervation of the cerebellum was acutely activated by inducing withdrawal with naloxone in morphine-dependent rats; and (3) the noradrenergic input to the cerebellum was activated by electrical stimulation of the LC. We found that all three approaches to elevating endogenous catecholamine activity in the cerebellum potentiated the depressant effects of EtOH in this brain area.
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Materials and Methods |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Male Sprague-Dawley rats, initially weighing 200 g, were housed in the Laboratory Animal Care Center with a 12-h light/dark cycle, and food and water were provided ad libitum. Most animals weighed between 250 to 400 g at the time of recording, but morphine-tolerant animals were slightly older (350-450 g) because of the time required to establish tolerance.
The experiments reported here were carried out in accordance with the Declaration of Helsinki and with the "Guide for the Care and Use of Laboratory Animals" as adopted and promulgated by the National Institutes of Health.
Electrophysiology.
Animals were anesthetized with 1.25 g/kg
urethane and placed in a stereotaxic frame. Body temperature was
monitored by a rectal thermistor probe and maintained at 37°C by a
heating pad. The cisterna was opened at the foramen magna to reduce
brain pulsation, the skull and other superficial tissues over the
cerebellar vermis were removed, and the dura was opened to expose the
underlying brain. The exposed brain was covered with 2% agar. Two- and
three-barrel micropipettes, constructed as previously described (Palmer
et al., 1986), were then stereotaxically lowered into the 5th or 6th
vermal lobules of the cerebellum. One 5 M NaCl-filled barrel (2.5-3.0 M
) was used to record spontaneous Purkinje neuron firing rates, identified by their characteristic discharge pattern (Eccles et
al., 1967). Other barrels of each micropipette were used to apply EtOH
and other drugs locally into the microenvironment of each cell from
which recordings were taken.
). Ejection pressure was regulated
with a pneumatic valve, and the timing of drug applications was
controlled by a computer-regulated crystal clock circuit. We used
previously described controls for local anesthesia and pH effects as
well as for artifactual responses to pressure-ejected drugs (Palmer et
al., 1986). In addition, 10 mg/kg propranolol HCl (5 mg/ml in 0.9%
saline, pH 7.0, Sigma) was administered i.p., and 1 mg/kg naloxone (1 mg/ml in 0.9% saline, pH 7.0, Sigma) was injected s.c. The naloxone
injections were repeated once per hour to maintain an effective dose
because of the short duration of action of this opiate antagonist.
For electrical stimulation of the LC, a bipolar stimulation electrode
was stereotaxically placed 12 mm caudal of bregma and 1.2 to 1.5 mm
lateral of midline. The electrode was angled 20° from vertical and
was lowered 4.0 to 5.0 mm below the brain surface ventrorostrally. The
placement of the stimulation electrode was characterized by the
stimulation-evoked depression of the spontaneous firing of a cerebellar
Purkinje neuron. For this verification of LC electrode placement, a
40-V stimulation was delivered in a 10-Hz, 4-s train of 200-µs
monophasic pulses. The interaction of LC activation with EtOH responses
in the cerebellum was evaluated by reducing the stimulus parameters to
30 V and applying it as a prolonged 6-Hz train of 200-µs monophasic
pulses. Control stimulations were made by raising the electrode into
the brain tissue overlying the LC.
Chronic Morphine Treatment and Morphine Withdrawal.
Twenty-eight adult male Sprague-Dawley rats were divided into two
groups. Tolerance and dependence were induced in one group by
administering two doses of morphine (40 mg/ml in 0.9% saline, pH 7.0)
each day at 9 AM and 4 PM so that each animal received a morphine dose
of 40 mg/kg s.c. on the first day, 60 mg/kg s.c. on the second day, and
80 mg/kg s.c. from day 3 to day 7, as has been previously described
(Eidelberg and Bond, 1972). Similar injection volumes of 0.9% saline
were given s.c. to the control rats for the same 7-day period. On the
morning of the 8th day, morphine withdrawal was induced by
administering 1 mg/kg naloxone s.c. (repeated hourly in longer
experiments). and the animals either were tested for behavioral
sensitivity to ethanol-induced ataxia during morphine withdrawal by
monitoring loss of righting response or were investigated
electrophysiologically to determine changes in neuronal sensitivity to
EtOH before and during morphine withdrawal.
; Wang and Lee, 1993). Animals were placed into an
observation chamber consisting of clear Plexiglas walls and a metal
floor that was maintained at 55.0 ± 0.5°C. The day before
testing, animals were placed on the nonfunctioning hot-plate for 1 min.
The rats were brought to the test room 2 h before testing, and the
ambient temperature during testing was 27 ± 1°C. The latency of
licking a hind paw or jumping off the plate (vigorous lifting of both
rear paws) was taken as the measure of nociceptive threshold (Maixner
et al., 1982; Lin et al., 1993b). Cutoff time, the point at which the
animal was removed from the hot-plate even if it had not yet responded,
was set at 40 s to prevent tissue injury. Each animal was tested
before and 20 min after the morning morphine or saline-control
treatment on days 0 and 7 of the chronic treatment paradigm. Morphine
analgesia was calculated as the percentage of maximum possible effect
from response latencies normalized to the maximum possible
effect (Lin et al., 1993b; Wang and Lee, 1993) as follows:
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Ethanol-Induced Ataxia. Six control and six chronically morphine-treated animals were used in a preliminary behavioral investigation to determine the feasibility of the more time-consuming electrophysiological study. For this experiment, morphine tolerant and control animals were treated with 1 mg/kg naloxone s.c. and 10 min later were given a single ethanol dose of 3 g/kg b.wt. i.p. as a 15% (w/v) solution in 0.9% saline. Each animal was then tested for duration of loss of the righting response (sleep time in min) to the EtOH administration, and additional naloxone doses (1 mg/kg s.c.) were administered at 1-h intervals after the first treatment to maintain morphine withdrawal.
Our protocol for estimating sleep time was similar to that used in the selective breeding of the LS and SS mice and has been published in detail elsewhere (Palmer et al., 1987a). Briefly, rats were given a
single i.p. ethanol injection and tested for the duration of loss of
the righting response while supported on plastic V-shaped troughs. To
be counted as recovered, each rat was required to right itself in the
trough three consecutive times within a 1-min period. All sleep time
measurements were conducted between 8 AM and noon. All 12 rats were
tested simultaneously, and room temperature was maintained at 27°C to
minimize the hypothermic reaction to ethanol (Moore and Kakihana, 1978;
Malcolm and Alkana, 1981).
Statistics and Experimental Design. Although several neurons can be sampled per animal when all drugs are delivered locally from multibarrel micropipettes, only one cell was studied in each animal in conjunction with the systemic administration of either naloxone or propranolol. In the case of both drugs, EtOH data was collected from a given cell both before and after systemic drug administration. Then, 10 min (naloxone) or 30 min (propranolol), respectively, were allowed for drug absorption before data collection after systemic drug administration. Statistical significance was determined for each experiment using either a paired t test or a one-way analysis of variance (ANOVA) followed by a Student-Newman-Keuls multiple comparisons test, as indicated in the text.
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Results |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Potentiation of EtOH by Blocking the Reuptake of Endogenous
NE with DMI.
Spontaneous synaptic levels of endogenously released
catecholamine were facilitated with the NE uptake inhibitor DMI, and any subsequent beta adrenergic potentiation of EtOH
effects on Purkinje neurons was monitored. The local pressure
application of EtOH from micropipettes caused repeatable slowing of the
spontaneous firing of cerebellar Purkinje neurons, and the subsequent
pressure application of DMI from another barrel of the same pipette
consistently potentiated these EtOH-induced depressions (Fig. 1). This
effect was reversible and repeatable on a given neuron and was
significant (p < .0001, paired t
test; t = 
6.81, df = 47) over the 48 neurons studied in 21 animals (Fig. 2A). This interaction is likely mediated by
a beta adrenergic mechanism because the observed
DMI-induced potentiation of these EtOH effects was significantly
attenuated when repeated 30 to 60 min after the systemic administration
of propranolol (10 mg/kg, i.p.) on all seven cells studied in seven animals (Fig. 2B; p < .001, paired
t test; t = 6.22, df = 6). The
depression of Purkinje neuron spontaneous firing by DMI, which is
likely mediated by the alpha adrenergic actions of NE
(Granholm and Palmer, 1988), was unaltered by the propranolol treatment.
Morphine Tolerance and Potentiation of EtOH-Induced Ataxia During Opiate Withdrawal. The effectiveness of the chronic morphine treatment used in this experiment was assayed by determining the analgesia caused by acute morphine treatment using a tail-flick test. Twenty rats were chronically treated twice daily with injections of either morphine or a control saline solution (see Materials and Methods). The animals that were chronically treated with morphine for 7 days developed tolerance to the analgesic effect of an acute morphine injection (Table 1). This effect was significant over the 10 rats studied (ANOVA: p < .0001; F = 16.1, df = 39, followed by a Newman-Keuls multiple range test: p < .001, q = 8.193), whereas morphine-induced analgesia after 7 days of chronic morphine treatment was not significantly different from that caused by a control saline injection either before morphine treatment or after 7 days of chronic saline treatment.
As a preliminary study to determine the feasibility of using opiate withdrawal to investigate endogenous NE influences on EtOH electrophysiology, we determined the effect of opiate withdrawal on EtOH-induced ataxia using a "sleep time" behavioral test (Palmer et al., 1987a). Withdrawal was induced acutely by the s.c. administration of 1 mg/kg naloxone, an opiate antagonist, and supplemental s.c. injections of 1 mg/kg naloxone were made once an hour thereafter. Three
of the six chronic morphine-treated animals, which were withdrawing
from morphine effects in this fashion, died after the administration of
systemic EtOH (3 g/kg i.p.). The mean loss of righting response to a
systemic EtOH dose for the remaining three animals was significantly
longer from that of the six animals that were chronically treated with
control saline injections and then given the same naloxone treatment
before behavioral testing (215.7 ± 11.72 versus 162.5 ± 12.3 min, p < .05, t test;
t = 2.718, df = 7).
Potentiation of EtOH-Induced Neuronal Depressions During Opiate
Withdrawal.
Activation of noradrenergic nerve terminals by
naloxone-induced morphine withdrawal was used to study the influence of
this catecholamine pathway on EtOH effects in the cerebellum. The
average responsiveness of a single cerebellar Purkinje neuron to the
depressant effects of locally applied EtOH was determined in vivo
before and 10 to 30 min after 1 mg/kg s.c. naloxone administration in each of 16 animals. PCP, which is principally a noradrenergic uptake
inhibitor in this preparation (Marwaha et al., 1980; Palmer et al.,
1987b), was applied to the same cells to assess the effectiveness of
the noradrenergic pathway activation during opiate withdrawal. Eleven
of the animals were chronically treated with morphine and five were
chronically administered equivalent injections of a control saline
solution. In control animals chronically treated with saline, naloxone
administration did not alter the neuronal depressions caused by local
applications of either PCP (n = 5) or EtOH
(n = 5) on any of the five control cells studied.
Typical ratemeter records are illustrated in Fig. 3A; however, the
depressant neuronal effects of EtOH, when locally applied to Purkinje
neurons in animals chronically treated with morphine, were potentiated by the naloxone treatment (Fig. 3, B and C). This effect is likely to
be associated with increased synaptic catecholamine release in the
cerebellum because the effects of PCP, an indirect noradrenergic agonist on Purkinje neurons, were also potentiated on the same cells
during the naloxone-induced withdrawal in these animals. Thus, morphine
withdrawal caused statistically significant increases (paired
t tests) in the depressions of Purkinje neuron firing caused by local applications of both EtOH (p < .01, n = 7; t = 4.28, df = 6; Fig. 4, A versus B) and PCP (p < .001, n = 11; t = 6.93, df = 10;
Fig. 4, C versus D).
Potentiation of EtOH-Induced Neuronal Depressions During Electrical
Stimulation of the LC.
Purkinje neuron responsiveness to local
EtOH applications was determined before and during activation of
noradrenergic afferents to the cerebellum by electrical stimulation of
the LC in vivo. The stimulating electrode was stereotaxically placed in
the LC so that electrical stimulation caused depressions of the
Purkinje neuron being recorded (Fig. 5A), and the stimulus voltage was then reduced until no large change in spontaneous activity was observed. LC stimulation caused potentiation of the depressant effects
of locally applied EtOH (Fig. 5, B and C), and this effect was
statistically significant (p < .001, paired
t test; t = 5.53, df = 53)
among the 54 neurons studied in 29 rats (Fig. 6A). The potentiation of
EtOH effects in the cerebellum by the activation of LC inputs to that
brain area was probably mediated by a beta adrenergic
mechanism because this effect was antagonized by the systemic
administration of 10 mg/kg propranolol i.p. (Fig. 7) on all six neurons
studied (Fig. 6B; ANOVA: p < .001;
F = 11.4, df = 23, followed by a Newman-Keuls
multiple range test: p < .05, q = 7.067). The LC-induced depression of Purkinje
neuron firing, which is primarily mediated by the alpha
adrenergic actions of NE (Granholm and Palmer, 1988), was unaltered by
the propranolol treatment (Fig. 7).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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We previously reported that the depressant effects of locally
applied EtOH on cerebellar Purkinje neurons are partially antagonized by the beta adrenergic antagonist timolol (Lin et al.,
1994). These data suggested that the endogenous noradrenergic input to the cerebellum might regulate EtOH effects in that brain area. In the
present study, we tested this hypothesis by monitoring the effect of
elevating endogenous catecholamine synaptic activity on EtOH-induced
depressions of Purkinje neurons. We used three different approaches to
investigate this interaction: (1) the spontaneous level of synaptically
released catecholamine was elevated with local applications of the
catecholamine uptake antagonist DMI; (2) the activity of the input from
the LC to the cerebellar cortex was elevated by eliciting opiate
withdrawal; and (3) the noradrenergic innervation of cerebellar
Purkinje neurons was directly activated by electrical stimulation of
the LC. EtOH-induced depressions of Purkinje neuron firing were
potentiated in all three experiments. These data support the hypothesis
that endogenous activity of the catecholamine innervation of Purkinje
neurons from the LC can regulate EtOH mechanisms in these cells.
A beta adrenergic mechanism probably mediates the
potentiation of EtOH-induced depressions observed in this study because systemic applications of the beta adrenergic antagonist
propranolol antagonize the ability of both DMI and electrical
stimulation of the LC to potentiate the actions of EtOH in the present
experiments. Furthermore, acute opiate withdrawal caused potentiation
of not only EtOH actions but also the depressant effects of locally
applied PCP. The responsiveness of cerebellar Purkinje neurons to
PCP-induced depressions is known to be dependent on, and indicative of,
catecholamine synaptic activity in that brain area (Marwaha et al.,
1980; Palmer et al., 1987b) and, thus, is an indication of increased
catecholamine synaptic input to these cells with naloxone-induced
opiate withdrawal in the current experiments. Although DMI application
and LC stimulation also caused direct depressions of spontaneous
activity, these effects were apparently not mediated by a
beta adrenergic mechanism because they were not prevented by
the same propranolol administrations that blocked the observed
potentiations of EtOH effects. These findings are consistent with our
previous observation that the depressant effects of LC pathway
activation on cerebellar Purkinje neurons are mediated by an
alpha adrenergic mechanism of action (Granholm and Palmer,
1988).
LC stimulation has been previously reported not only to cause
depression of spontaneous Purkinje neuron firing (Siggins et al.,
1971a; Hoffer et al., 1973; Granholm and Palmer, 1988) similar to that
observed in the present study but also to potentiate Purkinje neuron
responses to afferent input (Moises and Woodward, 1980; Moises et al.,
1981). Of particular interest in those studies is the finding that the
depressant effects of GABA on these cells is potentiated by LC
stimulation through a beta adrenergic mechanism of action.
This effect is mimicked by the local application of the beta
adrenergic agonists at doses that have little effect on spontaneous
activity (Waterhouse et al., 1982; Sessler et al., 1989; Lin et al.,
1993a) and involves a cAMP/protein kinase A second messenger system
(Siggins et al., 1971b; Sessler et al., 1989; Cheun and Yeh, 1992). We
(Lin et al., 1993a) and others (Lee et al., 1995) previously found that
EtOH potentiation of the depressant effects of GABA on cerebellar
Purkinje neurons also involves a beta adrenergic mechanism
of action, and we recently reported that EtOH influences the cAMP
regulation of GABA responsiveness in these same cells (Freund and
Palmer, 1997). Perhaps the potentiation of EtOH-induced depressions by
LC afferent activation observed in the present study involves a similar
interaction of EtOH with the beta adrenergic facilitation of
endogenous GABA mechanisms in this brain area. We did previously find
that EtOH-induced depressions of Purkinje neuron activity involve
activation of the GABAA receptor mechanism
(Freund et al., 1993). We reported that beta adrenergic antagonists only partially antagonize this effect, which suggests that EtOH-induced depressions are not dependent on this
catecholamine mechanism (Lin et al., 1994). However, in the same
study, we report that beta adrenergic agonists will
routinely potentiate EtOH depressions on Purkinje neurons. In the
present study, we find that the activation of endogenous noradrenergic
nerve terminals in the cerebellum by LC stimulation causes a similar effect.
During this study, we collected preliminary evidence that LC activation
during acute opiate withdrawal not only potentiates EtOH-induced
depressions of cerebellar Purkinje neurons but also results in the
prolongation of EtOH-induced behavioral ataxia measured by "sleep
time." These data are consistent with previous studies indicating
that the sensitivity of cerebellar Purkinje neurons to the depressant
effects of EtOH closely correlates with sensitivity to EtOH-induced
behavioral ataxia (Palmer et al., 1987a). The observed changes in EtOH
sleep time likely were not due to influences of chronic morphine
treatment on EtOH metabolism because we previously found that the same
chronic morphine treatment did not result in any changes in EtOH
clearance from the blood compared with EtOH-naïve or
saline-treated control rats (Wang and Lee, 1993). These data suggest
that the activity of LC afferents not only facilitates the cerebellar
actions of EtOH but also influences some related EtOH-induced
behaviors. Indeed, we found not only that both ethanol-induced
electrophysiological and behavioral responses are potentiated during
morphine withdrawal but also that some morphine-withdrawing animals
died after a systemic EtOH dose (3 g/kg) that was never lethal in
control animals. These are preliminary data and require
conformation; however, they imply that acute replacement of opiate
with alcohol in opiate-addicted patients could be potentially dangerous.
The present data suggest that the endogenous catecholamine innervation
to the cerebellum can regulate the EtOH responsiveness of Purkinje
neurons. Thus, the expression of those EtOH actions that are
influenced by this beta adrenergic mechanism may vary among behavioral states depending on the associated activity of the
innervation from the LC. Furthermore, the neuronal effects of EtOH on a
given cerebellar neurotransmitter mechanism, such as
GABAA responsiveness, also appear to depend on
the activity of this noradrenergic innervation (Lin et al., 1993a; Lee
et al., 1995). Clearly, the actions of EtOH on isolated
neurotransmitter mechanisms in a simple system lacking this innervation
would not accurately reflect the role of that mechanism in mediating
the cellular actions of EtOH in the cerebellum in vivo. Indeed, we recently found that postsynaptic differences in beta
adrenergic responsiveness between cerebellar Purkinje neurons from LAS
and HAS rats, which were selectively bred for low and high behavioral responsiveness to alcohol treatment, respectively, explain the differential expression of both EtOH-sensitive neuronal responses to
GABA as well as rapid acute neuronal tolerance to EtOH effects between
these two rat lines (Pearson et al., 1997). The characterization of
such influences will require further investigation; however, it is
clear that the LC innervation influences EtOH mechanisms in this brain
area in vivo.
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Footnotes |
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Accepted for publication July 31, 1998.
Received for publication February 23, 1998.
1 This work was supported by U.S. Public Health Service Grants AA11465 and AA03527 and by Republic of China, Department of Health Grant DOH87-HR-612. M.R.P. was supported by ADAMHA Research Scientist Development Award AA00102.
Send reprint requests to: Dr. Ronald K. Freund, Department of Pharmacology, Box C-236, University of Colorado Health Sciences Center, Denver, CO 80262. E-mail: Ron.Freund{at}UCHSC.edu.
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Abbreviations |
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DMI, desmethylimipramine;
LC, locus ceruleus;
EtOH, ethanol;
GABA, 
-aminobutyric acid;
ANOVA, analysis of
variance;
NE, norepinephrine;
i.p., intraperitoneally;
PCP, phencyclidine;
s.c., subcutaneously.
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References |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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-aminobutyric acid receptors to ethanol involves a cyclic AMP/protein kinase A second-messenger mechanism.
J Pharmacol Exp Ther
280:
1192-1200
- vs. 
-specificity.
Brain Res
459:
256-264[Medline].-aminobutyric acid.
Brain Res
687:
12-21[Medline].-aminobutyric acid-induced depression of cerebellar Purkinje neurons to the potentiative effects of ethanol by beta adrenergic mechanisms in rat brain.
J Pharmacol Exper Ther
265:
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 A. A. Patkar, R. Gopalakrishnan, P. C. Naik, H. W. Murray, M. J. Vergare, and C. A. Marsden CHANGES IN PLASMA NORADRENALINE AND SEROTONIN LEVELS AND CRAVING DURING ALCOHOL WITHDRAWAL Alcohol Alcohol., May 1, 2003; 38(3): 224 - 231. [Abstract] [Full Text] [PDF]
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