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Vol. 294, Issue 2, 613-619, August 2000
Departments of Cellular Biology, Neurobiology and Anatomy (Z.-X.X., E.A.S.), Psychiatry and Behavioral Medicine (E.A.S.), Pharmacology and Toxicology (E.A.S.), and The Biophysics Research Institute (E.A.S.), Medical College of Wisconsin, Milwaukee, Wisconsin
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Opiate reinforcement has been hypothesized to be mediated by an
inhibition of mesolimbic 
-aminobutyric acid (GABA) release that
subsequently disinhibits ventral tegmental area (VTA) dopamine neurons.
In support of this hypothesis, this study demonstrates that when
administered directly into the lateral ventricle, the VTA, or the
ventral pallidum, but not the nucleus accumbens, -vinyl-GABA (GVG, an irreversible GABA-transaminase inhibitor, 20-50 µg) dose dependently blocked heroin (0.06 mg/kg) self-administration (SA), as
assessed by an increase in heroin SA at low doses of GVG and an initial
increase followed 1 to 2 h later by a blockade of heroin SA at
higher GVG doses. This effect lasted 3 to 5 days. In drug-naïve rats, intra-VTA GVG pretreatment also prevented or delayed acquisition of heroin SA for 2 days. This GVG effect was prevented or reversed by
systemic or intra-VTA pretreatment with the GABAB
antagonist 2-hydroxysaclofen, but not the GABAA antagonist
bicuculline. Similarly, coadministration of heroin with
aminooxy-acetic acid (1-4 mg/kg) or
ethanolamine-O-sulfate (50-100 mg/kg), two reversible
GABA transaminase inhibitors, dose dependently reduced heroin
reinforcement. Coadministration of (±)-nipecotic acid (0.1-5 mg/kg)
with heroin, or intra-VTA or -ventral pallidum pretreatment with
(±)-nipecotic acid (10 µg) or NO-711 (2 µg), two GABA
uptake inhibitors, significantly increased heroin SA behavior, an
effect also blocked by systemic 2-hydroxysaclofen, but not bicuculline.
Taken together, these experiments, for the first time, demonstrate that
pharmacological elevation of mesolimbic GABA concentration blocks
heroin reinforcement by activating GABAB receptors,
supporting the GABAergic hypothesis of opiate reinforcement and the
incorporation of GABA agents in opiate abuse treatment.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Heroin
is the most rapidly acting and most abused of the opiates.
Unfortunately, its high abuse liability is not matched by effective
pharmacological therapy. Currently, the most effective treatment
strategy is opiate replacement therapy with methadone or its
derivative, l-
-acetylmethadone. However, these
drugs are accompanied by their own dependence liability, emphasizing
the need for new treatment strategies based on reducing opiate reinforcement.
The mesocorticolimbic dopamine (DA) system, which
originates in the ventral tegmental area (VTA) and projects rostrally
to the nucleus accumbens (NAcc) and the medial prefrontal
cortex, has been consistently demonstrated to play a critical
role in mediating opiate reinforcement (Bardo, 1998
). Although the
mechanisms underlying this reinforcement are still incompletely
understood, the current hypothesis is that opiates inhibit GABAergic
cells to disinhibit mesocorticolimbic system DA neurons (Johnson and North, 1992a). Several lines of evidence support this hypothesis. For
example, systemic or VTA microiontophoretic morphine increases the
firing rate of dopaminergic neurons and inhibits the firing rate of
inhibitory interneurons (Gysling and Wang, 1983; Johnson and North,
1992a). Microdialysis and electrochemical studies demonstrate an
increase in NAcc DA release after heroin administration (Spanagel et
al., 1990; Xi et al., 1998). Furthermore, opiate µ-receptors are
predominantly located on VTA GABAergic interneurons (Dilts and Kalivas,
1989), and morphine presynaptically inhibits -aminobutyric acid
(GABA) release within the medial portion of the rat midbrain (Renno et
al., 1992). We (Xi and Stein, 1998, 1999) have previously demonstrated that pharmacological down-regulation of VTA DA neuronal activity and NAcc DA release after administration of 
-opiate agonists or the GABAB agonist baclofen reduces
heroin reinforcement.
Thus, although the mechanisms of opiate action within the VTA are
emerging, it is as yet unclear whether similar actions of opiates also
occur in the NAcc. Experimental evidence has suggested both a
DA-dependent and DA-independent mechanism processing opiate reinforcement within the NAcc. For example, whereas 6-hydroxydopamine lesions within the NAcc can disrupt morphine self-administration (SA)
(Smith et al., 1985), systemic or intra-accumbal administration of DA
antagonists does not alter i.v. heroin SA (Ettenberg et al., 1982).
Destruction of NAcc presynaptic DA terminals selectively attenuates
cocaine, but not heroin, SA (Pettit et al., 1984). Opiates, when
systemically self-administered (Chang et al., 1997; Lee et al., 1999),
or locally administered into the NAcc (Hakan and Henriksen, 1989),
significantly inhibit the spontaneous firing of NAcc neurons. Because
NAcc efferent projections are mostly GABAergic (Groenewegen and
Russchen, 1984; Kalivas et al., 1993) and terminate principally in the
ventral pallidum (VP) and the VTA (Mogenson and Nielson, 1983),
two critical areas in mediating opiate reinforcement, we hypothesize
that, similar to the VTA, opiates also inhibit NAcc GABAergic
projection cells that ultimately disinhibit postsynaptic VP neurons and
VTA DA neurons. Such a mechanism may, in part, explain the proposed
DA-independent opiate reward mechanism.
To test the hypothesis that opiate reinforcement is mediated, at least
in part, by inhibiting both VTA and NAcc GABAergic cells, this study
examined the effects of elevated endogenous mesolimbic GABA
concentration on heroin SA. After being released into the synaptic
cleft where it activates specific GABA receptor subtypes, GABA is taken
up into presynaptic neuronal terminals and glial cells by GABA uptake
carriers (Krogsgaard-Larsen and Johnston, 1975), where it is further
catabolized by the enzyme GABA-transaminase (GABAT) (Sabers and Gram,
1992). Thus, the strategy used in this study was to elevate GABA
concentration by administering GABAT or GABA uptake inhibitors
systemically or directly into the lateral ventricles, VTA, NAcc, or VP
either before or during heroin SA. Our results support the GABAergic
hypothesis of opiate reinforcement by demonstrating dose- and
time-dependent SA inhibition after administration of GABA-enhancing drugs.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Surgical Preparation.
Male Sprague-Dawley rats (Sasco,
Madison, WI) weighing 250 to 350 g at the time of surgery were
individually housed and maintained on a 12-h light/dark cycle (lights
on at 8:00 PM) with free access to food and water. One hundred rats
were subdivided into five heroin SA groups: -vinyl-GABA (GVG;
n = 44), aminooxy-acetic acid (AOAA; n = 16), ethanolamine-O-sulfate (EOS; n = 8),
(±)-nipecotic acid (NipA; n = 28), and a saline
substitution group (n = 4). Based on the specific
experiment, some rats received more than one drug, and their numbers
are represented in more than one of the above groups. Under sodium
pentobarbital anesthesia (60 mg/kg i.p.), heroin SA rats were
implanted with a chronic silicone rubber jugular catheter that passed
s.c. to terminate on a head assembly. To observe the effects of central
receptor modulation on heroin SA, 96 rats were also implanted with
30-gauge stainless steel guide cannula bilaterally into the lateral
ventricles (coordinates: 0.8 mm posterior to bregma, 1.6 mm lateral to
midline, and 4.2 mm ventral to the surface of the cortex), the VTA (4.8 mm posterior to bregma, 1.0 mm lateral to midline, and 7.7 mm ventral
to the surface of the cortex), the NAcc (1.6 mm anterior to bregma, 1.6 mm lateral to midline, and 7.2-7.4 mm ventral to the surface of the
cortex), or the VP (0.3 mm anterior to bregma, 2.5 mm lateral to
midline, and 7.8 mm ventral to the surface of the cortex). Three days
were allowed for recovery from surgery before SA training.
Heroin-SA Procedure. Operant boxes (30 × 40 × 60 cm), equipped with a lever mounted on one side wall 5 cm above the cage floor, were housed in sound- and light-attenuated chambers. The i.v. catheter was connected to a syringe pump (Razel, Stamford, CT) through polyethylene tubing and a liquid commutator. Each lever press delivered an infusion of heroin (approximately 100 µl) over a 10-s period. Depending on the experiment, heroin (0.06 mg/kg) or heroin plus a GABA agent dissolved in sterile saline was administered per lever press. A 60-W white light located above the chamber was simultaneously illuminated with each drug infusion. Each SA session lasted 4 h, and each rat was tested for 5 to 9 days on a fixed ratio 1 schedule.
The effects of the GABA agents on SA behavior (GVG, 20-50 µg i.c.v., VTA, NAcc, or VP; AOAA, 1-4 mg/kg i.v.; EOS, 50-100 mg/kg i.v.; NipA, 0.1-5 mg/kg i.v. or 10-20 µg bilaterally directly into the VTA or VP) were assessed after stable SA behavior was established (within ±5% of the mean responses for 3 days of heroin alone training). Additionally, to observe the effects of GVG on heroin SA acquisition, a group of drug-naïve rats received GVG before heroin exposure. All GABA agents were purchased from Research Biochemicals International (Natick, MA) and dissolved fresh each day in sterile saline. Heroin was donated by the Resource Technology Branch, National Institute on Drug Abuse (Bethesda, MD). All injections into the lateral ventricles, the VTA, the NAcc, or the VP were delivered in a volume of 1 or 2 µl over 1 or 2 min, respectively. Intracranial (i.c.) drug injection doses were divided evenly into each hemisphere and are reported as total amount administered.Statistic Analyses. All data are presented as mean ± S.E. Student's t test and/or two-way ANOVAs were used to assess drug effect significance. A P < .05 was used throughout.
Histology. On completion of each SA experiment, rats were deeply anesthetized with pentobarbital and transcardially perfused with phosphate-buffered saline followed by 10% formalin. Brains were sectioned at 40 µm, and cannulas tips verified histologically. Only rats with properly located cannula were included in subsequent behavioral data analyses.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Heroin SA Behavior.
Typically, rats rapidly learned the
operant task and reliably self-administered heroin after 2 to 3 days of
training. Four rats with unstable SA behavior or misplaced or blocked
i.c. cannula were eliminated from the study and excluded from data
analysis. Although SA rates and interinjection intervals varied
somewhat across rats and sessions, the pattern of responses and the
mean SA rate across sessions were very stable over time (Fig.
1, heroin control curve).
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Effects of GABAT Inhibitors on Heroin SA.
When microinjected
into the lateral ventricles (i.c.v.), the irreversible GABAT inhibitor
GVG (20 µg, n = 6) significantly increased heroin SA
behavior for about 24 h, whereas a higher dose (50 µg,
n = 4) first decreased and then completely blocked SA
behavior 2 h after GVG administration, an effect that lasted for
about 3 days (Fig. 1, A and B). In an identical manner, pretreatment with GVG (20-50 µg) into the VTA also dose dependently inhibited heroin reinforcement. Although a significant increase in heroin SA was
seen after low-dose (20 µg) administration, the pattern of operant
responding after high-dose GVG (50 µg) was more complex, with an
increase in lever pressing in the first 1 to 2 h followed by a
virtual cessation during the remaining hours of the 4-h session (data
not shown). A similar pattern of responding was seen after saline
substitution during heroin SA (Fig. 1, A and B). This GVG blockade
lasted 3 to 4 days after a single VTA injection (Fig. 2A). Intra-VP administration of the same
doses of GVG also altered heroin SA with the same dose- and
time-dependent patterns as intra-VTA administration (Fig.
3, A and B). In contrast, the 50-µg
dose of GVG injected bilaterally into the NAcc had no significant
effect on heroin SA (Fig. 4). Likewise,
intra-NAcc administration of another GABAT inhibitor, AOAA (2 µg),
also had no effect on heroin SA. AOAA did, however, significantly
increase heroin SA when microinjected into the VTA (Fig. 4).
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Effects of GABA Uptake Inhibitors on Heroin SA.
When
coadministered with heroin, all doses (0.1-5 mg/kg) of NipA, a GABA
uptake inhibitor, increased heroin SA (Fig.
6A). Similarly, microinjections of NipA
into the VTA (10 µg) or the VP (10 µg) consistently increased
operant responding for heroin (Fig. 6B). Another selective GABA uptake
inhibitor, NO-711, microinjected into the VTA (2 µg), also
significantly increased heroin SA behavior (Fig. 6B). The effect of
NipA was selectively attenuated by systemic injection of 2-OH-saclofen
(2 mg/kg, n = 8), but not bicuculline (0.1 mg/kg,
n = 8) (Fig. 7). Systemic
2-OH-saclofen or bicuculline administered alone did not significantly
affect SA behavior.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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This study demonstrates, for the first time, that elevating synaptic GABA levels by direct i.c. administration of the GABAT inhibitors GVG, AOAA, or EOS, or the GABA uptake inhibitors NipA or NO-711, dose dependently reduces heroin reinforcement (defined as an increase in SA at low doses and a time-dependent SA blockade at higher treatment doses, independent of nonspecific effects on locomotion), and prevents or delays acquisition of heroin SA. This effect was seen with i.c.v., VTA, or VP injections, but not after NAcc administration. The inhibitory effects of intra-VTA GVG or systemic NipA were blocked or reversed by the GABAB antagonist 2-OH-saclofen, but not the GABAA antagonist bicuculline, suggesting an effect mediated by GABAB receptors.
VTA GABAergic Mechanism of Opiate Reinforcement.
Two types of
neurons, primary dopaminergic projection neurons and secondary
GABAergic inhibitory interneurons, have been identified within the VTA.
Both the intrinsic VTA GABAergic interneurons and GABAergic axon
terminals from the NAcc synapse onto VTA DA neurons (Johnson and North,
1992b; Kalivas et al., 1993). Systemic or iontophoretic administration
of morphine increases the firing rate of the DA neurons by binding to
µ-opiate receptors located predominantly on and inhibiting GABAergic
interneurons (Matthews and German, 1984; Dilts and Kalivas,
1989; Johnson and North, 1992a).
), 2) intra-VTA microinjections of the
GABAB agonist baclofen block opiate-induced DA
release in the VTA (Klitenick et al., 1992) and the NAcc (Kalivas et
al., 1990), and 3) intra-VTA baclofen blocks morphine-induced
conditioned place preference (CPP; Tsuji et al., 1996) and heroin SA
behavior (Xi and Stein, 1999). Similarly, baclofen alone inhibits
firing of VTA DA neurons (Johnson and North, 1992a) and reduces VTA and NAcc DA release (Klitenick et al., 1992; Xi and Stein, 1998), suggesting that VTA GABAB receptors play a
critical role in mediating endogenous GABA modulation of VTA DA
neurons. In contrast, GABAA receptors are located
mainly on VTA interneurons (Dilts and Kalivas, 1989), with their
activation disinhibiting VTA DA cells, thereby increasing NAcc DA
release (Xi and Stein, 1998).
By directly manipulating mesolimbic GABA concentration, both by
inhibiting the GABA degradation enzyme GABAT or by inhibiting GABA
uptake, the current data support the above opiate reinforcement hypothesis. In addition, intra-VTA GVG pretreatment not only
blocked heroin-reinforced SA but also prevented or delayed acquisition of heroin SA in drug-naïve rats, and did so for up to 4 days after a single injection. This effect was blocked or reversed by i.v.
or intra-VTA pretreatment with the GABAB
antagonist 2-OH-saclofen, but not by the GABAA
antagonist bicuculline, suggesting that the GVG effect was mediated by
increased GABA concentration acting on VTA GABAB
receptors. These data are consistent with our previous reports
demonstrating that the selective GABAB agonist
baclofen, but not the GABAA agonist muscimol,
blocks heroin reinforcement (Xi and Stein, 1998, 1999). Because
administration of GVG, AOAA, and EOS had no significant effects on
spontaneous locomotor behavior, these data suggest a specific
GABA-induced reinforcement blockade, rather than a nonspecific effect
on motor behavior.
The relatively long duration inhibitory effect of GVG administration on
heroin SA is consistent with the drug's irreversible effect on GABA
transaminase, requiring de novo synthesis of new enzyme. For example,
GVG dose dependently increases brain GABA concentration for more than
48 h (Jung et al., 1977; Qume and Fowler, 1996). It should be
noted, however, that GVG also inhibits GABA uptake, which may have
contributed to its strong inhibitory effect on heroin reinforcement
(Christensen et al., 1991; Jolkkonen et al., 1992).
Consistent with the ability of GVG to reduce heroin reinforcement, GVG
also is known to decrease DA release in the NAcc and the striatum
(Morgan and Dewey, 1998) and can significantly antagonize cocaine-induced CPP (Morgan et al., 1997) and locomotor behavioral sensitization (Dewey et al., 1997). Taken together, these data suggest
that heroin and cocaine share a common mesolimbic GABAergic reinforcement mechanism.
Finally, the reversible GABAT inhibitors, AOAA and EOS, also dose
dependently reduced heroin reinforcement. Low doses of both drugs
increased, whereas high doses completely blocked heroin SA behavior.
However, in contrast to the central effect of GVG, intra-VTA
administration of AOAA only increased heroin SA, an effect that lasted
for less than 24 h; complete SA blockade was never seen with any
dose tested. This latter observation is consistent with the
pharmacological properties of AOAA acting as a competitive, reversible
GABAT inhibitor (Qume and Fowler, 1996). Similarly, coadministration of
heroin with NipA, a GABA uptake inhibitor (Krogsgaard-Larsen and
Johnston, 1975), significantly increased SA within a wide dose range,
while administration of NipA or NO-711 into either the VTA or VP also
only increased heroin SA, suggesting partial heroin reinforcement
reduction. Incomplete blockade of heroin reinforcement by NipA, even at
a dose 50 times higher than its minimal effective dose, may suggest
that GABA uptake mechanisms play a secondary role to GABAT degradation
in synaptic GABA removal. Taken together, however, these data strongly
support a role for both VTA and NAcc GABA in heroin reinforcement.
NAcc GABAergic Mechanism of Opiate Reinforcement.
Several
lines of evidence suggest that, in addition to the VTA, the NAcc is
also involved in processing opiate reinforcement. When assessed by
either SA or CPP, intra-accumbal injections of opiates exert
reinforcing (Van der Kooy et al., 1982; Goeders et al., 1984)
effects that can be blocked by intra-NAcc administration of opiate
antagonists (Vaccarino et al., 1985). While specific neurochemical
mechanisms are still poorly understood, it has been proposed that
opiate-induced NAcc DA release plays a critical role, possibly by
inhibiting NAcc GABAergic efferent cells (Swerdlow et al., 1990;
Bourdelais and Kalivas, 1992). However, several pieces of evidence
conflict with this DA hypothesis. For example, while 6-hydroxydopamine
NAcc lesions have been reported to disrupt opiate reward (Smith et al.,
1985), systemic or intra-accumbal administration of DA antagonists does
not alter heroin SA (Ettenberg et al., 1982), and destruction of NAcc
presynaptic DA terminals selectively attenuates cocaine but not heroin
SA (Pettit et al., 1984). Electrophysiological studies have shown that
local microiontophoretic application of morphine into the NAcc (Hakan
and Henriksen, 1989), or i.v. SA of heroin (Chang et al., 1997; Lee et
al., 1999), markedly suppresses NAcc neuronal activity. These data
suggest that both a DA-dependent and a DA-independent mechanism may
exist within the NAcc to mediate opiate reinforcement. However, the
precise circuitry of such a proposed DA-independent reinforcement
mechanism is still unclear.
; Kalivas et al., 1993), opiate inhibition of NAcc
GABA neurons can disinhibit both the target VP neurons and the VTA DA
projection neurons. As such, the former action will produce a
DA-independent opiate reinforcement, whereas the latter will potentiate
the mesolimbic DA-dependent mechanism in a positive feedback manner. In
the present experiment, GVG administered into the VP or VTA, two main
NAcc GABAergic projection areas, dose dependently reduced heroin
reinforcement, supporting this GABAergic disinhibitory hypothesis.
VP GABAergic Mechanism of Opiate Reinforcement.
Although the
VP serves as a major anatomical target of NAcc efferent projections and
provides inputs to the medial prefrontal cortex, amygdala, and lateral
hypothalamus, systems subserving drug-taking behavior (Groenewegen et
al., 1993), its role in mediating opiate reward is less well
understood. Pallidal GABAergic fibers project back to the NAcc and the
VTA to form a complex local modulatory circuit (Kalivas et al., 1993;
Churchill and Kalivas, 1994). In this study, intra-VTA administration
of GVG, AOAA, or NipA significantly reduced heroin reinforcement,
suggesting that the VP projections to VTA DA neurons play an important
role in mediating opiate reinforcement. In contrast, intra-NAcc
administration of GVG or AOAA had no significant effect on heroin SA,
consistent with our previous report demonstrating that intra-NAcc
injection of the GABAB agonist baclofen had no effect on heroin reinforcement (Xi and Stein, 1999). In addition, ibotenic acid lesions of VP neurons block both heroin and cocaine SA
behavior, supporting a role for the VP in drug reinforcement (Hubner
and Koob, 1990).
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Acknowledgments |
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We thank Zachary M. Pruhs, Gregory J. Gosline, and Jun Tang who participated in this project during summer studies in the lab.
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Footnotes |
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Accepted for publication April 4, 2000.
Received for publication January 28, 2000.
1 This investigation was supported in part by National Institute on Drug Abuse Grant DA09465 and the Schering Plough Research Foundation.
Send reprint requests to: Elliot A. Stein, Ph.D., Department of Psychiatry, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: estein{at}mcw.edu
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Abbreviations |
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DA, dopamine;
GABA, -aminobutyric acid;
GABAT, GABA transaminase;
GVG, -vinyl-GABA;
2-OH-saclofen, 2-hydroxysaclofen;
SA, self-administration;
CPP, conditioned place
preference;
VP, ventral pallidum;
VTA, ventral tegmental area;
NAcc, nucleus accumbens;
AOAA, aminooxy-acetic acid;
EOS, ethanolamine-O-sulfate;
NipA, (±)-nipecotic acid;
i.c., intracranial.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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-Vinyl -GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: Effects on brain GABA metabolism in mice.
J Neurochem
29:
797-802[Medline].-aminobutyric acid agonists.
J Pharmacol Exp Ther
253:
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, 20 µg, n = 6) significantly increased
heroin SA, suggesting a partial reinforcement blockade, whereas the
high dose of GVG (
, 50 µg, n = 4) almost
completely blocked heroin SA 2 h after GVG administration. The
low-dose GVG effect lasted about 2 days, whereas the high-dose GVG
effect lasted at least 3 days. Saline substitution on days 5 and 6 (open arrow) did not maintain SA behavior in rats previously trained to
SA heroin (
, n = 4). In this and all subsequent
figures, the heroin (0.06 mg/kg/injection) alone group (
) represents
all rats (n = 30) that received 6 days of heroin SA
training. B, time course of the day 4 GVG experiment plotted as a
function of session time. **P < .01, compared with
heroin alone group.
, 50 µg, n = 8) decreased SA behavior. Both
effects lasted 3 to 4 days. B, intra-VTA pretreatment with GVG (
)-bicuculline (Bic; 0.1 mg/kg, i.v.),
blocked the GVG-induced inhibition of heroin SA (
