Functional imbalance of the dopamine neurotransmitter system in the brain is thought to be a key component underlying both schizophrenia and substance use disorders, and their comorbidity is increasingly being recognized in human populations (Negrete, 2003) and investigated using animal models (Chambers and Taylor, 2004). Data obtained from rats utilizing either the neonatal hippocampal lesion (schizophrenia) or self-administration (substance use) animal models have suggested that the hippocampus is likely to be involved in both schizophrenia (Harrison, 2004), and drug relapse (Vorel et al., 2001; Sun and Rebec, 2003). It is therefore important to determine the role of the endogenous dopamine transmitter system in normal and pathological hippocampal function.

The understanding of the actions of dopamine as a neurotransmitter in the hippocampal formation has evolved over the past 3 decades, from the presumption that dopamine had no significant role (except as a precursor to norepinephrine), to the current appreciation that dopamine can act via multiple signaling pathways in the hippocampus. For example, in the CA1 region, potential physiological actions include the modulation of a calcium-activated K⁺ current (Benardo and Prince, 1982; Pockett, 1985; Malenka and Nicoll, 1986; Berretta et al., 1990; Pedarzani and Storm, 1995), excitatory neurotransmission (Hsu, 1996; Otmakhova and Lisman, 1998; Yang, 2000; Kotecha et al., 2002), voltage-gated ion channels (Cantrell et al., 1997; Hoffman and Johnston, 1999), and inhibitory neurotransmission (Gribkoff and Ashe, 1984a,b). The observations concerning effects on the calcium-activated K⁺ current and on evoked EPSPs are somewhat controversial because both enhancements and inhibitions of each of these measures by dopamine agonists are reported.

In addition, several reports have also described the effects of dopamine on long-term potentiation (LTP) at the Schaffer collateral synapse in the CA1 region. D_1/5 dopamine antagonists inhibit both late LTP (Frey et al., 1991; Swanson-Park et al., 1999) and early LTP (Otmakhova and Lisman, 1996), as well as long-term depression (Chen et al., 1995), suggesting that endogenous dopamine facilitates synaptic plasticity in the CA1 region of the hippocampus. We have reported recently that LTP is significantly enhanced in the presence of the monoamine transporter blockers, and this action is prevented by a dopamine D₂-like receptor antagonist (Thompson et al., 2005). Since GABAergic synaptic transmission exerts a powerful influence over LTP induction at Schaffer collateral synapses (Davies et al., 1991), we have tested the hypothesis that dopamine might modulate GABAergic IPSCs in the CA1 region of the hippocampus.

In this report, we show that the application of either cocaine or a selective D₃ dopamine receptor agonist can inhibit the monosynaptic IPSCs evoked from stratum radiatum and recorded in CA1 pyramidal neurons and that a selective D₃ dopamine receptor antagonist was effective in preventing these actions. Our findings point to a newly appreciated role for the D₃ dopamine receptor subtype in mediating a disinhibition in CA1 that can lead to a net excitation of pyramidal neurons in this region of the hippocampus (a preliminary description of this work has appeared previously, Hammad and Wagner, 2004).

Materials and Methods

In Vitro Hippocampal Slices. Hippocampal slices were obtained from freshly dissected brains of male Sprague-Dawley rats, 4 to 6 weeks old (Zivic-Miller Laboratories (Zelienople, PA), anesthetized with halothane prior to decapitation, in compliance with protocols approved under North Dakota State University and the University of Georgia Animal Care and Use guidelines. The brain was removed from the cranium, chilled for ∼30 sec in ice-cold, oxygenated (95/5% O₂/CO₂) artificial cerebrospinal fluid (ACSF; composition: 125 mM NaCl, 3 mM KCl, 1 mM NaH₂PO4, 1.5 mM MgCl₂, 2.5 mM CaCl₂, 26 mM NaHCO₃, and 10 mM glucose, pH 7.4), and then 400 or 500 μM sections were cut on a Vibraslice microtome. Hippocampal slices were dissected free, and the CA3 region was surgically removed. The slices were transferred to a holding chamber containing oxygenated ACSF and allowed to recover at room temperature for at least 1 h. The slices were then transferred to a heated, submersion-type recording chamber where they were perfused at a flow rate of 1.5 to 2 ml/min of oxygenated ACSF and warmed to 30°C during an additional recovery hour.

Whole-Cell Electrophysiology. Whole-cell recording electrodes (3–5 MΩ) were pulled on a Sutter P-97 horizontal micropipette puller using 1.5-mm thin-wall borosilicate glass tubing (WPI, Sarasota, FL). Blind recordings from the pyramidal layer of the CA1 region were done using a motorized micromanipulator with the aid of a dissecting microscope. Passive properties (holding current, input resistance) as well as synaptic currents were monitored in voltage-clamp using an Axopatch 200B amplifier, and the data were acquired and analyzed using pCLAMP 9 software (Molecular Devices, Sunnyvale, CA). A holding potential of –60 mV was used for all recordings. A bipolar stimulating electrode (Kopf Instruments, Tujunga, CA) was connected to constant current stimulus isolation unit (WPI) and used to evoke synaptic currents.

The following intracellular recording solution was used: 145 mM KMeSO₃, 2 mM MgCl₂, 2 mM EGTA, 0.2 mM CaCl₂, 2 mM Mg-ATP, and 2 mM HEPES, pH 7.2, with KOH. Pharmacologically isolated IPSCs were evoked in the presence of 2,3-dihydroxy-6,7-dinitroquinoxaline (10 μM) and 2-amino-5-phosphonovalerate (50 μM). The peak amplitude of this monosynaptic IPSC response was used for comparative analysis (paired Student's t test before/after drug application). Pharmacologically isolated EPSCs were evoked in the presence of picrotoxin (100 μM) and intracellular QX314 (5 mM). The peak amplitude of the EPSC response was used for comparative analysis (paired Student's t test before/after drug application).

Extracellular Electrophysiology. Population spike (PS) responses were measured from recording electrodes placed in the CA1 pyramidal cell body layer following stimulation of the stratum radiatum. The baseline stimulus intensity was set at a level evoking a PS of 40 to 60% of maximal amplitude. A pair of responses (PS1 and PS2) was evoked at an interstimulus interval of 10 ms. For each response, the peak negative amplitude was subtracted from the peak positive amplitude to obtain the amplitudes of PS1 and PS2. The PS2/PS1 ratio was then calculated for a 5-min period both immediately before and 15 to 20 min following drug application. This paired-pulse ratio was used for comparative analysis (paired Student's t test before/after drug application).

Drugs and Chemicals. For drug application, all drugs were applied via bath perfusion, using a three-way valve. The dead volume of the tubing and chamber was <2 ml, allowing rapid onset (<5 min) for most compounds at the typical perfusion rate. Cocaine hydrochloride was obtained from the National Institute on Drug Abuse (RTI, Research Triangle Park, NC), and both PD 128907 and U 99194 maleate were obtained from Tocris Cookson Inc. (Ellisville, MO). All other drugs/chemicals were obtained from Sigma Diagnostics (St. Louis, MO).

Results

Inhibitory Postsynaptic Currents Evoked from Stratum Radiatum Are Selectively Inhibited by Cocaine. Monosynaptic IPSCs (see Materials and Methods) were evoked by stimulating different hippocampal strata, stratum radiatum, stratum pyramidale, or stratum oriens in the CA1 region of hippocampal slices. Bath application of cocaine (10 μM) significantly inhibited the amplitude of IPSCs evoked by stimulating in the stratum radiatum (Fig. 1, B and C, 72 ± 8%, n = 7), whereas the IPSCs evoked by stimulating in the stratum oriens were not significantly affected (Fig. 1, A and C, 92 ± 8%, n = 8). Cocaine had intermediate effects on the IPSCs evoked following stimulation in the stratum pyramidale (data not shown). The differential sensitivity observed between these stimulation sites suggested that different subsets of interneurons were being activated, with the monosynaptic IPSCs evoked from the stratum radiatum layer being the most sensitive to cocaine. All subsequent experiments were carried out using responses evoked from stratum radiatum.

Pretreatment with D₃ Receptor Antagonists Prevents the Cocaine-Induced Inhibition of the IPSC. We have recently described the dose-response relationship for the actions of cocaine using the field excitatory postsynaptic potential recording technique to assess drug effects on baseline synaptic transmission and the magnitude of LTP in CA1 (Thompson et al., 2005). Those results demonstrate that cocaine at the concentration that we have chosen for the present studies (i.e., 10 μM) acts primarily by blocking monoamine transporters and by the subsequent activation of dopamine receptors. In our experimental preparation, cocaine does not have significant effects as a local anesthetic at concentrations lower than 30 μM (see also Dunwiddie et al., 1988). Thus, we have tested the hypothesis that cocaine inhibited the monosynaptic IPSC by increasing endogenous monoamine transmitter levels and activating dopamine receptors. A series of dopamine receptor antagonists were tested to determine if there is a receptor subtype-selective effect of cocaine on the evoked IPSC. Preincubation (15+ min prior to cocaine application) with the D_1/5 antagonist SCH 23390 (3 μM) did not significantly affect the ability of cocaine to inhibit the IPSC (Fig. 2A, 75 ± 2%, n = 7). In contrast, pretreatment with the D₂-like antagonist eticlopride (3 μM) completely prevented the inhibitory effects of cocaine on the IPSC (Fig. 2B, 98 ± 7%, n = 5). Attempts to reverse the actions of cocaine with eticlopride application following the 20-min exposure to cocaine were not successful (data not shown). The D₂-like dopamine receptor class consists of three subtypes, D₂, D₃, and D₄ receptors. As observed with eticlopride, preincubation with either the potent D_2/3 receptor antagonist raclopride (30 nM, Fig. 2C, 96 ± 9%, n = 5) or the D₃-selective receptor antagonist U 99194 maleate (1 μM, Fig. 2D, 104 ± 7%, n = 5) prevented the inhibitory effects of cocaine on the IPSC, suggesting that activation of the D₃ subtype of dopamine receptor is mediating these effects.

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Fig. 1.

Cocaine inhibits IPSCs evoked in stratum radiatum. A and B, summary plots of normalized IPSP measurements recorded from pyramidal cells in the CA1 region of the hippocampus. Bars, mean ± S.E.M. from n = 8 (A) or n = 7 (B) recordings. Insets, 250-ms sweeps from representative experiments illustrating relative IPSC amplitudes 0 to 5 min prior to (left sweep) and 15 to 20 min postcocaine (10 μM) application (right sweep; for clarity, stimulus artifacts are truncated). Vertical scale bar, 150 pA in A and 100 pA in B. The stimulating electrode was placed in either the stratum oriens (A) or the stratum radiatum layer (B) in CA1. C, summary quantification demonstrating no significant difference in IPSC peak amplitude in the presence of cocaine when monosynaptic IPSCs are evoked from stratum oriens, whereas IPSCs evoked from stratum radiatum were significantly reduced relative to the predrug time period (*, p < 0.05). Bars, mean ± S.E.M.

A D₃-Selective Agonist Can Mimic the Effects of Cocaine on the IPSC. To further test the hypothesis that D₃ receptors mediate the effects of cocaine, the selective D₃ receptor agonist PD 128907 (1 μM) was bath applied to the slice. As was the case with cocaine, PD 128907 had an inhibitory effect on the monosynaptic IPSC amplitude (Fig. 3, A and C, 76 ± 6%, n = 9). The input resistance of these neurons was 97 ± 11 MΩ prior to drug exposure and did not change significantly in the presence of the D₃ receptor agonist (108 ± 12 MΩ, p > 0.25). Preincubation with the selective D₃ receptor antagonist U 99194 (1 μM, Fig. 3, B and C, 91 ± 7%, n = 7) prevented any significant inhibition of the IPSC amplitude by PD 128907. Thus, both in terms of the magnitude of IPSC decrease (–28% w/cocaine versus –24% w/PD 128907), as well as the sensitivity to the selective D₃ receptor antagonist U 99194, the actions of cocaine on the monosynaptic IPSC evoked following stimulation in the stratum radiatum can be fully accounted for via actions at the D₃ receptor.

D₃ Receptor Activation Disinhibits Pyramidal Cells. We next assessed the effects of the D₃ receptor agonist on paired-pulse depression (PPD) of the CA1 population spike response, which is thought to assay inhibitory influence on synchronous CA1 pyramidal cell firing. Dopamine can attenuate PPD, suggesting a disinhibitory effect (Gribkoff and Ashe, 1984b). Similarly, we found that application of D₃ receptor agonist significantly increased the ratio of the paired population spike responses (Fig. 4, A and B). PPD of the population spike prior to drug application (0.76 ± 0.07, n = 4) was converted to paired-pulse facilitation in the presence of PD 128907 at 0.3 (1.14 ± 0.06, n = 4) and 3 (1.39 ± 0.07, n = 4) μM. Interestingly, in addition to the persistent effect of dopamine on PPD that was blocked by pretreatment with the dopamine receptor antagonist spiroperidol, Gribkoff and Ashe (1984a) also reported an acute suppression of the initial population spike amplitude that was reversible and not prevented by spiroperidol. We did not observe any significant decrease in the amplitude of PS1 in the presence of PD 128907 (Fig. 4A). These findings suggests that one of these two previously reported actions of dopamine on the CA1 population spike can be attributed to the activation of D₃ receptors (i.e., the persistent disinhibition), whereas the acute decrease of excitatory transmission is likely to be mediated by a different dopamine receptor subtype (Hsu, 1996; Otmakhova and Lisman, 1998).

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Fig. 2.

Pretreatment with D₃ dopamine receptor antagonists block the cocaine-mediated inhibition of the IPSC. A to D, summary plots of normalized stratum radiatum IPSP measurements recorded from pyramidal cells in the CA1 region of the hippocampus. Bars, mean ± S.E.M. from n = 7 (A) or n = 5 (B–D) recordings. Insets, 250-msec sweeps from representative experiments illustrating relative IPSC amplitudes 0 to 5 min prior to (left sweep) and 15 to 20 min postcocaine (10 μM) application (right sweep; for clarity, stimulus artifacts are truncated). Vertical scale bar, 200 pA in A, B, and D and 100 pA in C. A, pretreatment with the D_1/5 selective antagonist SCH 23390 (3 μM) was not effective in preventing a significant cocaine-induced reduction in the IPSC (p < 0.05). In contrast, pretreatment with three different D₂-like antagonists was effective in blocking the actions of cocaine (B–D), including the D₃-selective antagonist U 99194 (1 μM).

Cocaine Enhances Synaptic Excitation of Pyramidal Cells. If cocaine acts via D₃ receptor activation and causes disinhibition, then it should enhance synaptic excitation of pyramidal neurons. To investigate this possibility, mixed EPSC-IPSC responses were evoked by stimulating in the stratum radiatum (Fig. 5C) in the absence of either glutamatergic or GABA-ergic antagonists. Following the application of cocaine (10 μM), the EPSC component was significantly enhanced (+30 ± 10%, p < 0.02), whereas the IPSC component of the mixed response was concomitantly decreased (-24 ± 10%) in these same cells (n = 6). Notably, the magnitude of the decrease in the IPSC component of the mixed EPSC-IPSC response observed under these conditions compares quite favorably with the decrease observed in the monosynaptic IPSC following either cocaine (–28%, Fig. 1B) or PD 128907 (–24%, Fig. 3A) application, suggesting that the modulation of ionotropic glutamatergic drive of GABA-ergic neurons is not a significant contributing factor to D₃ receptor-mediated actions in this circuit. Additional evidence consistent with this inference is that cocaine does not significantly affect pharmacologically isolated EPSCs (+13 ± 12%, n = 7). Thus, both the population spike measure (Fig. 4A) and the intracellular measures (Figs. 1B and 5) are consistent with the conclusion that D₃ receptor activation directly affects inhibitory circuitry in the CA1 and, as a result, indirectly modulates excitatory synaptic transmission.

Discussion

We conclude that cocaine selectively reduced the magnitude of monosynaptic IPSCs evoked by stimulation in the stratum radiatum of the CA1 region of the hippocampus and that this was mediated by activation of D₃ dopamine receptors. D₃ receptor antagonists blocked cocaine's effects, and a D₃ agonist mimicked them. The resulting disinhibition can increase excitability at Schaffer collateral synapses of CA1 pyramidal neurons. We suggest that these D₃ receptors are presynaptic because application of the selective D₃ receptor agonist PD 128907 elicited no significant change in the passive membrane properties of CA1 pyramidal cells. In addition, in the presence of cocaine, the IPSCs evoked from stratum radiatum were significantly inhibited, whereas those evoked from stratum oriens were not, indicating that a general inhibition of postsynaptic GABA responsiveness did not occur. The observation that the EPSC component of the mixed synaptic response increased concomitantly with the decrease in the IPSC component argues against a general local anesthetic action for cocaine under these conditions. In summary, the results are consistent with the possibility that a subpopulation of interneurons in the CA1 region express D₃ dopamine receptors and that inhibition of this group of GABAergic neurons by either endogenously released dopamine (facilitated by cocaine) or, by application of selective D₃ receptor agonists, promotes enhanced excitability in this region of the hippocampus. These findings have implications for the potential contribution of the hippocampal dopaminergic system to the neuroadaptations occurring following exposure to drugs of abuse and the hippocampal pathology related to schizophrenia.

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Fig. 3.

A D₃ agonist also inhibits IPSCs evoked in stratum radiatum. A and B, summary plots of normalized stratum radiatum IPSP measurements recorded from pyramidal cells in the CA1 region of the hippocampus. Bars, mean ± S.E.M. from n = 9 (A) or n = 7 (B) recordings. Insets, 250-msec sweeps from representative experiments illustrating relative IPSC amplitudes 0 to 5 min prior to (left sweep) and 15 to 20 min post-PD 128907 application (right sweep; for clarity, stimulus artifacts are truncated). Vertical scale bar, 150 pA in A and B. C, summary quantification demonstrating a significant decrease in the stratum radiatum IPSC peak amplitude in the presence of the D₃ agonist PD 128907 (1 μM) relative to the predrug time period (*, p < 0.05). Pretreatment with the D₃-selective antagonist U 99194 (1 μM) was effective in preventing this action of PD 128907. Bars, mean ± S.E.M.

Our initial studies were motivated by our recently reported findings that acutely applied cocaine can act through dopamine transporter blockade to enhance neurotransmitter activation of D₂-like dopaminergic receptors and significantly enhance the magnitude of LTP evoked in the CA1 region of hippocampal slices (Thompson et al., 2005). We also noted that Gribkoff and Ashe (1984a, using paired stimuli while recording population spike responses) had previously concluded that exogenously applied dopamine could elicit a long-lasting attenuation of inhibition in the CA1. As outlined in the previous paragraph, we have found strong support for such a disinhibitory mechanism of cocaine actions using whole-cell voltage-clamp recordings of monosynaptic IPSCs evoked following stimulation of the stratum radiatum in the CA1 region. Activation of the D₃ subtype of dopamine receptor appeared to mediate this effect because a D₃-selective agonist could mimic the actions of cocaine, and pretreatment with a selective D₃ antagonist prevented significant effects of either cocaine or PD 128907.

The potential relevance of the endogenous dopamine transmitter system to hippocampal function is increasingly being recognized and incorporated into models for novelty detection and long-term memory (Lisman and Grace, 2005), and a significant amount of anatomical evidence has accumulated in support of an endogenous dopaminergic projection from mesencephalic structures such as the ventral tegmental area and the substantia nigra to the hippocampal formation (for review, see Gasbarri et al., 1997). Despite this, it remains the case that the absolute level of dopamine present in hippocampal tissue is quite low relative to the other monoamine transmitters. For example, one report of the levels of DA, norepinephrine, and 5-hydroxytryptamine in the CA1 region of ventral hippocampus indicates approximately 20-fold less DA than norepinephrine or 5-hydroxytryptamine (Hortnagl et al., 1991). Therefore, it is potentially significant that the dopamine receptor type we have identified as being likely to mediate the actions of cocaine on the IPSC is the D₃ receptor because it has the highest affinity for dopamine among all of the five members of the DA receptor family (at a K_i of 25 nM, it has approximately 20-fold higher affinity than for the D₂ receptor type; Sokoloff et al., 1990). This would potentially allow for significant activation of D₃ receptors by endogenous dopamine during enhanced release or inhibited reuptake, despite the aforementioned relatively low absolute amount of DA known to be present in the tissue.

We propose that the D₃ type of receptor is the most likely to mediate the observed effects of cocaine for the following reasons. First, the highly selective D1/5 antagonist SCH 23390 was ineffective when used at a concentration at least 1000-fold higher than its K_i for these sites. Second, the most selective antagonist tested for the D₂-like family was U 99194, which has a 14-fold higher affinity for D₃ sites compared with D₂ sites, and the concentration used was approximately 6 times greater than its affinity for D₃ sites and 13 times lower than its affinity for D₂ sites. In addition, U 99194 exhibits a >60-fold preference for the D₃ site as compared with D₄ binding site (Audinot et al., 1998). Third, the D₃-selective agonist PD 128907 was fully capable of mimicking the actions of cocaine, and this compound has been reported to have >300-fold preference for the D₃ site as compared with D₂ binding site (Audinot et al., 1998). The effectiveness of three different dopamine receptor antagonists to block cocaine's effects, along with the ability of a selective dopamine receptor agonist to mimic cocaine's effect on the IPSC, strongly suggests that the common property of these four distinct compounds is their actions at the D₃ type of dopamine receptor and is not consistent with effects at a non specific (i.e., a nondopaminergic) site. Finally, Hsu (1996) reported that the evoked EPSP in CA1 was inhibited via activation of a D₂ type of dopamine receptor, an effect that we also did not observe when PD 128907 was applied to the population response (Fig. 4) or when cocaine was applied to the evoked EPSC (Fig. 5). This suggests that neither cocaine nor PD 128907 was acting via D₂ receptor activation under the conditions we have described.

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Fig. 4.

D₃ receptor activation disinhibits CA1. A, pairs of PS responses evoked at an interstimulus interval of 10 msec are illustrated (for clarity, stimulus artifacts are truncated). Arrows indicate an example of the peak negative- and peak positive-going components of PS2 that were used for the quantification of PS amplitudes in general. The sweeps are 60 msec in duration. Vertical scale bar, 7 mV. Left inset, predrug PS1-PS2 sequence; center and right insets, relative increase in the amplitude of PS2 as compared with PS1 in the presence of increasing concentrations of the D₃ agonist PD 128907 (each sweep is the average of eight responses from a representative experiment). B, summary quantification of effects of D₃ agonist application on the PS2/PS1 ratio. Application of both 0.3 and 3 μM PD 128907 resulted in a significant increase in the PS2/PS1 ratio (*, p < 0.05; **, p < 0.01, respectively). Bars, mean ± S.E.M.

Assuming activation of the D₃ type of dopamine receptor is occurring following either cocaine or PD 128907 application, the mechanisms underlying the subsequent inhibition of the evoked IPSC is a topic of considerable interest. This dopamine receptor type has been localized in the CA1 to the neuropil of the stratum radiatum and stratum oriens (but not stratum lacunosum-moleculare; Khan et al., 1998), where several classes of GABA-ergic interneurons are located and where some tyrosine hydroxylase-like immunoreactivity has been reported (Milner and Bacon, 1989). This distribution contrasts with that of the D₄ dopamine receptor type, which is most densely associated with the CA1 pyramidal cell body layer and also was found in all the strata containing the pyramidal cell dendritic processes (stratum oriens, stratum radiatum, and stratum lacunosum-moleculare). In comparison, the density of D₂ immunostaining is relatively sparse in the CA1 (Khan, et al., 1998). The activation of D₃ dopamine receptors has been shown to interact with multiple signal transduction pathways, including acting to inhibit adenylate cyclase, inhibit calcium currents, and enhance potassium currents (for review, see Missale et al., 1998). Assuming that D₃ receptors are associated with nonpyramidal neurons in the CA1 region of the hippocampus, any of these generally inhibitory consequences could underlie the disinhibition we have described at the level of pyramidal cell activation. Our inability to reverse the cocaine-induced decrease in the IPSC with antagonist is consistent with prior observations describing the long-lived nature of some of the effects of dopamine in the CA1 (Gribkoff and Ashe, 1984a,b) and also indicates that the activation of a signaling cascade has occurred that persists beyond receptor occupancy by agonist. More definitive characterization of this signaling mechanism will require additional experiments that include recording from the D₃ receptor-bearing cell and observing the direct effects of D₃ receptor activation.

In conclusion, in this report, we have described a novel, specific role for the D₃ subtype of dopamine receptor in modulating synaptic function in the CA1 region of the hippocampus. The D₃ receptor-mediated inhibition of GABAergic influence in the CA1 could facilitate the limbic hyperactivity previously associated with schizophrenic symptoms (Krieckhaus et al., 1992; Heckers, 2001) and may also contribute to the persisting alterations in behavioral responses that occur following exposure to drugs of abuse (Caine and Koob, 1993; Vorel et al., 2002). D₃ receptor-mediated disinhibition is likely to be a key mechanism by which dopamine can impact the processing of neuronal signals through hippocampal circuitry and thereby potentially contribute to the maladaptive states associated with drug addiction and schizophrenia.

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Fig. 5.

Cocaine enhances synaptic excitability in stratum radiatum. A and B, summary plots of normalized EPSC (A) or IPSP (B) components of mixed EPSC/IPSC synaptic responses recorded from CA1 pyramidal cells following stimulation of the stratum radiatum. Bars, mean ± S.E.M. from n = 6 recordings. C, averaged sweeps of 300-msec duration illustrating relative amplitudes 0 to 5 min prior to (presweep) and 15 to 20 min postcocaine (10 μM) application (postsweep; for clarity, stimulus artifacts are truncated). Vertical scale bar, 400 pA. D, summary quantification demonstrating a significant enhancement in the amplitude of the inward component of the mixed EPSC/IPSC synaptic response (EPSC) in the presence of cocaine (*, p < 0.05). Although consistently decreased (six of six cells), the outward (IPSC) component of the mixed EPSC/IPSC synaptic response was not significantly affected by cocaine due to the large variance in the baseline amplitude of this measure (range, 14–216 pA). Bars, mean ± S.E.M.