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NEUROPHARMACOLOGY
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California
Received March 30, 2004; accepted June 28, 2004.
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Abstract |
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; Wise 1996). Several lines of evidence indicate that 5-hydroxytryptamine (serotonin) (5-HT) systems heavily modulate mesolimbic DA activity. Indeed, the VTA receives a dense serotonergic innervation, and serotonergic manipulations in the VTA modulate the behavioral and neurochemical effects produced by cocaine (for review, see Walsh and Cunningham, 1997).
A growing body of evidence indicates that 5-HT1B receptors play an important role in modulating the behavioral, neurochemical, and cellular effects of cocaine (Callahan and Cunningham, 1995, 1997; Parsons et al., 1998, 1999; Rocha et al., 1998; Castanon et al., 2000; Przegalinski et al., 2001). Although the neural mechanisms involved in these processes have not been elucidated, several recent studies implicate the VTA as an important locus for the modulatory influence of 5-HT1B receptors on cocaine-induced behaviors. For example, neurochemical and electrophysiological investigations have shown that 5-HT1B receptors in the VTA exert an excitatory influence on mesolimbic DA cell activity (Cameron and Williams, 1994, 1995; Yan and Yan, 2001a). Moreover, intra-VTA administration of the selective 5-HT1B receptor agonist CP 93,129 dose dependently potentiates the discriminative stimulus properties of cocaine, whereas intra-VTA administration of the selective 5-HT1B receptor antagonist GR 55562 attenuates cocaine discrimination (Filip et al., 2003). Further support for an involvement of VTA 5-HT1B receptors in the modulation of cocaine-induced behaviors comes from a recent study that used viral-mediated gene transfer to overexpress 5-HT1B receptors in NAcc projection neurons (Neumaier et al., 2002). Microinjections of viral vectors containing the 5-HT1B receptor gene into the NAcc shell resulted in increased 5-HT1B receptor expression in the VTA, and animals treated in this manner displayed increased cocaine-induced motor activation and cocaine-induced conditioned place preference relative to control animals receiving blank vector injections.
Although the neurochemical mechanisms involved in the modulation of cocaine-induced behaviors by VTA 5-HT1B receptors are not known, it is likely that this process involves a modulation of cocaine-induced increases in mesolimbic DA neurotransmission. The VTA receives GABA afferents from the NAcc, and this feedback system provides tonic inhibitory regulation of midbrain DA cell activity. 5-HT1B receptor mRNA is translocated to axon terminals (Bruinvels et al., 1994), and because 5-HT1B mRNA is densely expressed in the NAcc (Bruinvels et al., 1994) and there is a high density of 5-HT1B binding sites in the VTA (Bruinvels et al., 1993, 1994), it is possible that 5-HT1B receptors are expressed on GABAergic terminals in the VTA. 5-HT1B receptors exert an inhibitory control over neuronal activity through a negative coupling with adenylate cyclase, and thus activation of VTA 5-HT1B receptors may reduce local GABA release, thereby disinhibiting the mesolimbic DA projection as supported by recent electrophysiological experiments (Johnson et al., 1992a; Cameron and Williams, 1994, 1995).
Based on this construct, it may be hypothesized that VTA 5-HT1B receptors modulate the behavioral effects of cocaine by altering cocaine-induced increases in NAcc DA levels. The present study was designed to directly test this hypothesis by characterizing the effects produced by pharmacological manipulation of VTA 5-HT1B receptors on cocaine-induced increases in NAcc DA levels in Wistar rats. An in vivo microdialysis probe implanted in the VTA was used to locally administer various doses of a 5-HT1B agonist, a selective 5-HT1B antagonist, or an agonist/antagonist combination. A second microdialysis probe implanted in the ipsilateral NAcc was used to monitor DA efflux after a peripheral cocaine injection. To investigate a possible GABAergic link in this process, amino acid content in the VTA dialysates were also monitored. Glutamate (GLU) levels in the VTA were also monitored based on evidence that 5-HT1B heteroreceptors can modulate release of this excitatory amino acid (Muramatsu et al., 1998).
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Materials and Methods |
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) atlas. The animals were allowed to recover for 4 to 5 days before experimentation.
Microdialysis Testing. At least 12 h before dialysis testing, microdialysis probes were lowered into each brain region (active membrane length was 2 mm for NAcc and 1 mm for VTA) as described in Parsons et al. (1999) and were perfused overnight with artificial cerebrospinal fluid (aCSF) at a rate of 0.2 µl/min. The next day, the perfusate flow rate was increased to 0.6 µl/min for the NAcc probes and to 1.1 µl/min for the VTA, and the probes were allowed to equilibrate for at least 1 h before the experiment. Dialysate samples were then collected at 10-min intervals from both probes throughout each phase of the experiment and were immediately frozen and stored for subsequent analysis. After a 30-min baseline sampling period, animals received intra-VTA perfusions of aCSF containing either drug-free aCSF (N = 6), the selective 5-HT1B agonist CP 93,129 (30 µM; N = 5, or 100 µM; N = 6), the selective 5-HT1B antagonist GR 55562 (100 or 300 µM; N = 4 in each group), or a combination of CP 93,129 and GR 55562 (100 µM CP 93,129 and 300 µM GR 55562; N = 6). The latter group received GR 55562 alone for 20 min before the solution containing the agonist/antagonist combination. To control for a possible effect of CP 93,129 on VTA 5-HT1A receptors, an additional group was perfused with the 5-HT1A agonist 8-OH-DPAT (100 µM; N = 6). Twenty minutes later, all animals in the groups described above received an intraperitoneal injection of cocaine (10 mg/kg), followed by an additional 60 min of dialysate collection. To evaluate neurochemical effects produced by activation or blockade of VTA 5-HT1B receptors in the absence of cocaine, two additional groups of animals received either CP 93,129 (100 µM; N = 6) or GR 55562 (300 µM; N = 5), followed 20 min later by a systemic injection of saline. Dialysate neurotransmitter levels were not adjusted by in vitro recovery values. The doses of 5-HT1B compounds were chosen based on the reported affinity of these compounds for 5-HT1B receptors (Macor et al., 1990) and on previous reports that have observed significant neurochemical effects of these compounds when delivered locally by reverse dialysis (Yan and Yan, 2001a).
Analytical Procedures. Dopamine was quantified from 5-µl volumes of dialysate injected onto a microbore high-performance liquid chromatography system equipped with a 1 x 100-mm column (3-µm BetaBasic packing material, C18 stationary phase; Keystone, Bellefonte, PA) and eluted using a mobile phase composed of a 50 mM NaH2PO4 (monohydrate) buffer (pH 3.92) with 17% (v/v) acetonitrile, 0.27 mM Na2-EDTA, 0.4% (v/v) triethylamine, and 3.27 mM decane sulfonic acid delivered at 30 µl/min by a model 500D syringe pump (Isco, Lincoln, NE). Dopamine was detected with an amperometric detector (model MP 1304; Princeton Applied Research, Princeton, NJ) using dual glassy carbon working electrodes (BAS Bioanalytical Systems Inc., West Lafayette, IN), set at 700 and -10 mV. Dopamine concentrations were determined using an external calibration curve.
Dialysate amino acid content was determined using capillary electrophoresis with laser-induced fluorescence detection. Derivatization of the amino acids was achieved by mixing 6 µl of microdialysate with 9 µl of 40 mM borate buffer (pH 10.5) containing 3.8 mM KCN and 1 µl of 5 mM naphthalene-2,3-dicarboxaldehyde in MeOH. This mixture was allowed to react at room temperature in the dark for 30 min before placing the samples in the refrigerated (10°C) sample tray of the capillary electrophoresis instrument (Agilent Technologies, Wilmington, DE). The derivatized dialysate was subsequently loaded onto a 90-cm fused silica capillary (30 µm inner diameter; sample loading by 50 mbar pressure for 10 s), and the amino acids were separated using +15 kV and a background electrolyte solution consisting of 100 mM borate buffer (pH 9.2) containing 30 mM SDS and 2 mM hydroxypropyl-
-cyclodextrin. The amino acids were detected using a laser-induced fluorescence detector (Zetalif; Picometrics, Ramon Ville, France) equipped with a 442-nm HeCd laser (30 mW; Melles Griot, Carlsbad, CA). External calibration standards were run in duplicate and were interspersed throughout the sample run. The limits of quantitation were approximately 1 nM for each of the analytes. All reagents and amino acid standards were from Sigma-Aldrich (St. Louis, MO).
Probe Placement. To provide functional verification of correct probe placement (Rahman and McBride, 2002), the GABAA antagonist bicuculline (100 µM) was perfused through the VTA probe upon completion of the 5-HT1B/cocaine manipulations. Only rats that exhibited at least a 2-fold bicuculline-induced increase in NAcc DA levels were included in our analyses. Probe placements were also verified histologically under a microscope by comparing 60-µm brain slices using the Paxinos and Watson (1988) atlas.
Statistical Analyses. Alterations in dialysate concentrations of DA, GABA, and GLU were analyzed using repeated measures analysis of variance with intra-VTA drug treatment as a between-subjects factor and time as a repeated measure. Significant interaction effects were further analyzed using post hoc analyses to compare treatment groups using Fisher's protected least significant difference test, p < 0.05.
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The effects of intra-VTA CP 93,129 administration on NAcc DA levels after peripherally administered cocaine are shown in Fig. 1. In control rats receiving drug-free aCSF through the VTA probe, peripheral cocaine administration significantly (p < 0.01) increased NAcc dialysate DA levels to approximately 375% of pre-cocaine baseline levels and significantly (p < 0.05) decreased VTA GABA levels to approximately 81% of pre-cocaine baseline levels. There was no significant effect of cocaine on VTA dialysate GLU levels. Intra-VTA CP 93,129 administration produced a significant and dose-dependent [F(20,140) = 4.6; p < 0.0001] facilitation of cocaine-induced increases in NAcc DA levels to peak levels of 508 and 882% of pre-cocaine baseline levels for 30 and 100 µM perfusate CP 93,129 concentrations, respectively. Concurrently, intra-VTA CP 93,129 administration produced a significant and dose-dependent [F(20,140) = 1.9; p < 0.01] facilitation of cocaine-induced decreases in VTA GABA levels to 68 and 54% of pre-cocaine baseline levels for 30 and 100 µM perfusate CP 93,129 concentrations, respectively. The results for NAcc DA and VTA GABA were consistent with subsequent post hoc analyses on the area under the curve, which were calculated by subtracting basal values for each time point after cocaine administration (i.e., each dialysate value for samples 6-11; p < 0.05). There was no significant effect of any CP 93,129 concentration on VTA GLU levels after peripheral cocaine administration.
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As shown in Fig. 2, the potentiation of cocaine-induced increases in NAcc DA produced by intra-VTA CP 93,129 (100 µM) was completely reversed by co-perfusion with the selective 5-HT1B receptor antagonist GR 55562 (300 µM) [F(20,150) = 9.03; p < 0.0001]. Concurrent measures of VTA GABA revealed that the potentiation of cocaine-induced decreases in VTA GABA produced by CP 93,129 administration was also significantly blocked by coperfusion with GR 55562 [F(20,150) = 2.2; p < 0.003]. The statistical findings for NAcc DA and VTA GABA were consistent with subsequent post hoc analyses on the area under the curve (p < 0.05).
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As shown in Fig. 3, there was no significant effect of GR 55562 (300 µM) on either cocaine-induced increases in NAcc DA levels [F(10, 80) = 0.2; N.S.] or cocaine-induced decreases in VTA GABA levels [F(10, 80) = 1.6; N.S.], and no significant effect of GR 55562 on VTA GLU levels [F(10, 70) = 1.5; N.S.]. The statistical findings for NAcc DA and VTA GABA and GLU were consistent with subsequent post hoc analyses on the area under the curve (p < 0.05).
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Two control groups were included that received intra-VTA administration of CP 93,129 or GR 55562 followed by peripheral saline administration. The control group receiving intra-VTA administration of 100 µM CP 93,129 displayed a significant [F(5,10) = 3.2; p < 0.005] increase in NAcc DA levels with a maximal increase of approximately 143% of baseline (Fig. 4). Intra-VTA administration of 100 µM CP 93,129 also produced a significant decrease [F(5,10) = 2.3; p < 0.05] in VTA GABA levels relative to baseline. This manipulation did not significantly alter VTA dialysate levels of GLU. The ability of intra-VTA CP 93,129 administration to facilitate NAcc DA levels is consistent with the findings of Yan and Yan (2001a). The control group receiving intra-VTA administration of 300 µM GR 55562 followed by peripheral saline did not display any significant alterations in NAcc DA [F(4,10) = 0.56; N.S.], VTA GABA [F(4,10) = 1.1; N.S.], or VTA GLU [F(4,10) = 1.4; N.S.] levels (Fig. 5).
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The possible involvement of 5-HT1A receptors in the effect of intra-VTA CP 93,129 was examined by testing the effect of intra-VTA administration of the 5-HT1A/7 agonist 8-OH-DPAT on cocaine-induced alterations in NAcc dialysate DA levels. There was no significant effect of intra-VTA 8-OH-DPAT (100 µM) on cocaine-induced alterations in NAcc DA [F(10,100) = 1.0; N.S.] levels (data not shown).
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Discussion |
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). The present study also extends these observations by demonstrating that the VTA is one locus in the brain where 5-HT1B receptors can modulate the neurochemical effects produced by peripherally administered cocaine. The selective involvement of 5-HT1B receptors in the effects produced by CP 93,129 is indicated by the reversal of the 5-HT1B agonist effect by coadministration of the selective and structurally dissimilar 5-HT1B receptor antagonist GR 55562. Moreover, the effect of intra-VTA CP 93,129 on cocaine-induced increases in NAcc DA was not mimicked by the intra-VTA administration of the 5-HT1A/7 agonist 8-OH-DPAT. This observation coupled with the very low affinity of CP 93,129 and GR 55562 for other 5-HT receptor subtypes (Koe et al., 1992; Lamothe et al., 1997) suggests a selective role for VTA 5-HT1B receptors in the present observations.
Previous work from our laboratory also demonstrated that systemic administration of a 5-HT1B agonist facilitates cocaine-induced decreases in VTA GABA levels (Parsons et al., 1999). The present findings suggest that these effects are mediated at least in part via activation of VTA 5-HT1B receptors, because direct activation of 5-HT1B receptors in this region also facilitates cocaine-induced decreases in VTA GABA levels. Consistent with previous work by others (Yan and Yan, 2001a,b), we also observed that intra-VTA 5-HT1B agonist administration modestly decreased VTA GABA levels and increased NAcc DA efflux in the absence of cocaine. Together, our findings suggest that 5-HT1B receptors in the VTA modulate NAcc DA transmission indirectly via alterations in GABA transmission. Because mesolimbic DA neurons originating in the VTA are under tonic inhibitory control from a GABA efferent pathway from the NAcc, the reduction in VTA GABA levels produced by activation of 5-HT1B sites produces an overall disinhibition of the mesolimbic DA projection. This disinhibition in turn likely produces the enhanced dopaminergic response to peripheral cocaine administration observed in the present experiments.
Previous work by others has also led to the hypothesis that mesolimbic DA activity is modulated by 5-HT in the VTA (Guan and McBride, 1989), perhaps through a 5-HT1B receptor-mediated modulation of VTA GABA release. For example, using intracellular recordings of DA neurons in rat midbrain slices Johnson et al. (1992a) demonstrated that 5-HT1B receptor activation inhibits GABA release onto GABAB but not GABAA receptors. In accordance with these findings [3H]GABA release from isolated VTA slices was found to be reduced by 5-HT1B agonist application (Yan and Yan, 2001b), and 5-HT1B receptor stimulation was found to reduce electrically evoked GABAB-mediated inhibitory postsynaptic potentials in DA neurons of rat VTA slices in a manner similar to that produced by cocaine (Cameron and Williams, 1995). Moreover, cocaine-induced reductions in electrically evoked GABAB inhibitory postsynaptic potentials in DA neurons of rat VTA slices were found to be mediated through 5-HT1B receptor activation (Cameron and Williams, 1994). The present observations extend these findings by using a within- animal in vivo preparation to demonstrate that activation of VTA 5-HT1B receptors facilitates cocaine-induced decreases in VTA GABA efflux and thereby potentiates the effects of peripherally administered cocaine on NAcc DA levels. It is noted, however, that the present data do not rule out the possibility that activation of 5-HT1B autoreceptors in the VTA blunts cocaine-induced increases in VTA 5-HT levels, thereby reducing the influence of 5-HT receptors that exert an inhibitory modulation of mesolimbic DA activity.
Several lines of evidence indicate that in addition to regulating GABA release, 5-HT1B heteroreceptors also provide an inhibitory modulation of GLU release (Muramatsu et al., 1998). Glutamatergic afferents to the VTA are thought to play an important role in regulating the activity of DA neurons in this region (Johnson et al., 1992b; Bonci and Malenka, 1999), and increased glutamatergic tone in the VTA has been reported to produce both excitatory and inhibitory effects on DA cell activity (Fiorillo and Williams, 1998; Takahata and Moghaddam, 2000). Thus, it is conceivable that the presently observed potentiation of cocaine-induced increases in NAcc DA produced by intra-VTA CP 93,129 administration results partly from a 5-HT1B receptor-mediated decrease in VTA GLU efflux. However, the lack of alteration in VTA dialysate GLU levels after any of the manipulations explored in the present experiments argues against this possibility. Although increases in VTA GLU levels have been reported after repeated cocaine administration (Kalivas and Duffy, 1998; Bell et al., 2000), our present findings are consistent with reports that acute cocaine administration does not alter VTA GLU efflux (Kalivas and Duffy, 1998; Bell et al., 2000; but see Kalivas and Duffy, 1995).
CP 93,129 is one of the most selective 5-HT1B agonists presently available (Macor et al., 1990; Koe et al., 1992). However, it was important to rule out a potential contribution of VTA 5-HT1A receptors in light of observations that DA cell activity in the VTA is increased by 5-HT1A receptor activation (Arborelius et al., 1993; Lejeune and Millan, 1998). Under the presently used conditions there was no significant effect of intra-VTA 8-OH-DPAT administration on either cocaine-induced increases in NAcc DA levels, or cocaine-induced decreases in VTA GABA levels using perfusate 8-OH-DPAT concentrations found to produce significant neurochemical effects in other studies (Kreiss and Lucki, 1994; Tao et al., 2000). Moreover, 5-HT1B agonist-induced alterations in the behavioral effects of cocaine are not mimicked by 5-HT1A agonists and are not reversed by 5-HT1A antagonists (Parsons et al., 1998). Collectively these findings indicate that 5-HT1A receptors do not contribute to the potentiation of cocaine reward or cocaine-induced neurochemical effects produced by 5-HT1B agonist administration.
Growing evidence suggests that 5-HT1B receptors play an important role in modulating the behavioral and neurochemical effects of cocaine. For example, 5-HT1B receptor activation has been shown to enhance the motor stimulant (Przegalinski et al., 2001, 2002; Neumaier et al., 2002), interoreceptive (Callahan and Cunningham, 1995, 1997; Filip et al., 2001, 2002, 2003), conditioning (Cervo et al., 2002; Neumaier et al., 2002), reinforcing (Parsons et al., 1998), and neurochemical (Parsons et al., 1999) effects of cocaine. It is important to note that although 5-HT1B agonist administration produces behavioral effects similar to some aspects of cocaine administration [e.g., increased locomotion (Chaouloff et al., 1999; O'Neill et al., 2000) and partial substitution for cocaine in discrimination tests (Callahan and Cunningham, 1995, 1997; Filip et al., 2001, 2003)], these agonists themselves produce a conditioned place aversion (Cervo et al., 2002) and do not support operant drug self-administration behavior in animals previously trained to self-administer cocaine (Parsons et al., 1998). Thus, the potentiating effects of 5-HT1B agonists on some aspects of cocaine-induced behavior (e.g., place conditioning and operant reinforcement) seem to reflect a facilitation of the behavioral effects of cocaine rather than an additive effect of behaviors produced by the 5-HT1B agonists and cocaine individually.
It is also noteworthy that although the potentiating effects of 5-HT1B agonists on cocaine-induced behaviors are dose dependently reversible by selective 5-HT1B antagonists (Parsons et al., 1998; Filip et al., 2001, 2002, 2003; Przegalinski et al., 2002), the behavioral effects of cocaine are not significantly altered by the 5-HT1B antagonists themselves (Parsons et al., 1998; Filip et al., 2001, 2002; Przegalinski et al., 2001; but see Przegalinski et al., 2002; Filip et al., 2003). The lack of behavioral effects produced by 5-HT1B blockade is consistent with the present finding that intra-VTA administration of a 5-HT1B antagonist did not alter cocaine-induced neurochemical effects. These findings suggest that although overt 5-HT1B receptor stimulation can enhance the behavioral effects of cocaine, 5-HT1B receptors do not normally contribute significantly to the behavioral effects of cocaine. Although the reasons for this discrepancy are not presently understood, it is conceivable that under normal circumstances the facilitory influence of 5-HT1B receptor activation produced by the indirect 5-HT agonist properties of cocaine is masked by the simultaneous activation of 5-HT receptors that exert an inhibitory influence on the behavioral effects of cocaine (e.g., 5-HT2C receptors; Callahan and Cunningham, 1995; Fletcher et al., 2002; Rocha et al., 2002). An interesting point in this regard is that 5-HT1B receptor binding in the NAcc, VTA, substantia nigra, and subiculum (Przegalinski et al., 2003), 5-HT1B mRNA expression in the NAcc and dorsal striatum, and 5-HT1B agonist-induced motor activation (L. H. Parsons, unpublished observations) are each increased during abstinence from repeated cocaine administration. Although potential alterations in the expression and/or function of 5-HT2C receptors during cocaine abstinence have not been explored, it is possible that the relative balance between 5-HT receptor subtypes that provide facilitory (5-HT1B) and inhibitory (5-HT2C) influences on cocaine-induced behaviors is altered after repeated cocaine exposure.
The present finding that activation of VTA 5-HT1B receptors potentiates the effect of cocaine on NAcc DA levels supports previous findings by others implicating these receptors in the regulation of mesolimbic DA activity (Cameron and Williams, 1994, 1995; Yan and Yan, 2001a). Moreover, these findings suggest that VTA 5-HT1B receptors may participate in modulating the behavioral effects produced by cocaine. This hypothesis is supported by the recent observations that VTA 5-HT1B receptors play a role in mediating the discriminative stimulus properties of cocaine (Filip et al., 2003) and that overexpression of 5-HT1B receptors in efferents of the NAcc (including the VTA) increases the locomotor activating and place conditioning effects of cocaine (Neumaier et al., 2002). In addition to the VTA, a number of recent studies also identify 5-HT1B receptors in the NAcc as possibly involved in the modulation of the behavioral effects of cocaine (Hållbus et al., 1997; Boulenguez et al., 1998; Yan and Yan, 2001a; Filip et al., 2002; Przegalinski et al., 2002). The relative influence of 5-HT1B receptors in these regions on the behavioral effects produced by cocaine is presently under investigation.
In summary, the present in vivo experiments demonstrate that activation of VTA 5-HT1B receptors enhances cocaine-induced decreases in VTA GABA efflux, thereby disinhibiting the mesolimbic DA projection and potentiating the ability of peripherally administered cocaine to increase NAcc DA levels. Because of the importance of increased NAcc DA levels in the mediation of the reinforcing effects of cocaine, these findings suggest that 5-HT1B receptors in the VTA contribute to the facilitation of cocaine reward produced by the peripheral administration of 5-HT1B receptor agonists.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: DA, dopamine; VTA, ventral tegmental area; NAcc, nucleus accumbens; 5-HT, 5-hydroxytryptamine (serotonin); GLU, glutamatel; aCSF, artificial cerebral spinal fluid; 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin; CP 93,129, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo [3,2-b]pyridin-5-one dihydrochloride; GR 55562, 3-[3-(dimethylamine)propyl]-4-hydroxy-N-[4-(4-pyridinyl] phenyl] benzamide dihydrochloride.
Address correspondence to: Dr. Loren H. Parsons, The Scripps Research Institute, Department of Neuropharmacology, CVN-7, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: lparsons{at}scripps.edu
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