Interfering with Fos expression in rat perirhinal cortex impairs recognition memory

Previous work has shown that immunohistochemical imaging of Fos protein is a reliable marker for changes in activity related to recognition memory in the perirhinal (PRH) cortex of the medial temporal lobe; however, whether PRH Fos expression is necessary for recognition memory had not been established. To investigate this potential requirement, antisense Fos oligodeoxynucleotide (ODN) was infused locally into PRH cortex to interfere with Fos production. As in previous studies, differential Fos expression produced by viewing novel or familiar visual stimuli was measured by immunohistochemistry: antisense Fos ODN infusion into PRH cortex disrupted the normal pattern of differential Fos expression in PRH cortex. The effect of antisense Fos ODN infusion into PRH cortex was therefore sought on recognition memory. Infusion before or immediately after acquisition impaired recognition memory for objects when the memory delay was 3 or 24 h, but not when the delay was 20 min, or when the ODN was infused before retrieval after a 24‐h delay. The findings indicate a role for Fos in consolidation processes underlying long‐term recognition memory for objects and establish that interfering with its expression impairs recognition memory. Antisense Fos ODN infusion also impaired object‐in‐place recognition memory. The results demonstrate that Fos is necessary for neuronal mechanisms in PRH cortex essential to recognition memory. © 2012 Wiley Periodicals, Inc.     

Activation of dopamine D1 receptors in the medial septum improves scopolamine-induced amnesia in the dorsal hippocampus

In the present study, we investigated the influence of intra-medial septum (intra-MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post-training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2 μg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3 μg/rat had no effect, but at dose of 0.5 μg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5 μg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1 μg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75 μg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75 μg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5 μg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5 μg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine.     

Interfering with perirhinal brain‐derived neurotrophic factor expression impairs recognition memory in rats

The role of brain‐derived neurotrophic factor (BDNF) in recognition memory was investigated by locally infusing oligodeoxynucleotides (ODNs) into perirhinal cortex, a region of the temporal lobe essential for familiarity discrimination. Antisense but not sense BDNF ODN impaired consolidation of long‐term (24h) but not shorter‐term (20min) recognition memory. © 2010 Wiley‐Liss, Inc.     

Involvement of dopamine D1 receptors of the central amygdala on the acquisition and expression of morphine-induced place preference in rat

In the present study, the effects of intra-central amygdala (CeA) injection of dopamine D1 receptor agonist and antagonist on morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-CeA administration of the dopamine D1 receptor agonist, SKF 38393 (2 and 4 micro g/rat) with an ineffective dose of morphine (0.5 mg/kg), elicited a significant conditioned place preference. On the other hand, a single dose of SKF 38393 (2 micro g/rat, intra-CeA) in combination with the lower doses (0.5 and 2.5 mg/kg), but not with the higher doses of morphine potentiated morphine-induced CPP. Furthermore, intra-CeA administration of the dopamine D1 receptor antagonist, SCH 23390 (0.5-1 micro g/rat) decreased the acquisition of conditioned place preference induced by morphine (7.5 mg/kg). The response of SKF 38393 was decreased by SCH 23390 (0.75 micro g/rat). SKF 38393 or SCH 23390 by themselves did not elicit any effect on place conditioning. On the other hand, intra-CeA administration of SKF 38393 or SCH 23390 significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. SKF 38393 or SCH 23390 injections into the CeA had no effects on the locomotor activity on the test sessions. The results indicate that the dopamine D1 receptors in the CeA may be involved in the acquisition and expression of morphine-induced place preference.     

Attenuation of morphine withdrawal signs by a D1 receptor agonist in the locus coeruleus of rats

In the present study, the effects of intra-locus coeruleus injection of a dopamine D(1) receptor agonist (SKF38393) on naloxone-induced withdrawal signs of morphine-dependent rats were examined. Twenty different withdrawal signs were assessed. The total withdrawal score was calculated and used as an index of withdrawal intensity for comparison. The D(1) agonist and antagonist were injected 15 and 30 min prior to expression of naloxone-induced withdrawal signs, respectively. SKF38393 (2 and 4 microg/site) decreased while SCH23390 (a D(1) antagonist) had no effect on the total withdrawal score. On the other hand, SCH23390 (25 ng/site) reversed the SKF38393 effect. It may be concluded that activation of dopamine D(1) receptors in the locus coeruleus attenuates naloxone-induced withdrawal.     

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses

Hippocampus is importantly involved in dopamine‐dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta‐burst stimulation‐induced long‐term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral‐CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 μM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50‐150 μM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 μM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor‐mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.     

Modulation of acetylcholine release by D1, D2 dopamine receptors in rat striatum under freely moving conditions

Using in vivo brain dialysis under freely moving conditions, we have studied the effects of dopamine (DA) agonists and antagonists on acetylcholine (ACh) and DA release in rat striatum. The striatal infusion of the D1 DA receptor specific agonist, SKF38393, increased striatal ACh release in a dose-dependent manner (10(-6) to 10(-4) M), and 3 x 10(-5) M SKF38393 elicited a 60% augmentation in the level of ACh release. The level of ACh was increased with perfusion of 10(-4) M SCH23390, a D1 specific antagonist, but decreased with 10(-3) M SCH23390. The D2 specific agonist, LY171555, and the antagonist, sulpiride, slightly altered the level of ACh in the striatum. On the other hand the level of DA dramatically increased in a dose-dependent manner with SKF38393 or SCH23390 and decreased with LY171555. LY171555 inhibited the effect of 10(-4) M SKF38393 on ACh release, and enhanced the effect of SKF38393 on DA release. These results suggest that the D1 DA receptor mainly mediates ACh release and the D2 DA receptor modifies the effects of the D1 receptor.     

Dopaminergic neuromodulation of high gamma stimulus phase‐locking in gerbil primary auditory cortex mediated by D1/D5‐receptors

Cortical release of the neurotransmitter dopamine has been implied in adapting cortical processing with respect to various functions including coding of stimulus salience, expectancy, error prediction, behavioral relevance and learning. Dopamine agonists have been shown to modulate recurrent cortico‐thalamic feedback, and should therefore also affect synchronization and amplitude of thalamo‐cortical oscillations. In this study, we have used multitaper spectral and time–frequency analysis of stimulus‐evoked and spontaneous current source density patterns in primary auditory cortex of Mongolian gerbils to characterize dopaminergic neuromodulation of the oscillatory structure of current sources and sinks. We systemically applied D1/D5‐receptor agonist SKF‐38393 followed by competitive D1/D5‐receptor antagonist SCH‐23390. Our results reveal an increase in stimulus phase‐locking in the high gamma‐band (88–97 Hz) by SKF‐38393, specifically in layers III/IV at the best frequency, which occurred at 20 ms after tone onset, and was reversed by SCH‐23390. However, changes in induced oscillatory power after SKF‐38393 treatment occurred stimulus‐independently in the background activity in different layers than phase‐locking effects and were not reversed by SCH‐23390. These effects might either reflect longer‐lasting changes in neural background noise, non‐specific changes due to ketamine anesthesia, or an interaction of both. Without concomitant stimulus‐induced power increase, increased stimulus phase‐locking in layers III/IV indicates enhanced phase‐resetting of neural oscillations by the stimulus after D1/D5‐receptor activation. The frequency characteristics, together with the demonstrated stimulus specificity and layer specificity, suggest that changes in phase‐resetting originate from dopaminergic neuromodulation of thalamo‐cortical interactions. Enhanced phase‐resetting might be a key step in the recruitment of cortical activity modes interpreting sensory input.     

Differential BDNF signaling in dentate gyrus and perirhinal cortex during consolidation of recognition memory in the rat

Consolidation of long‐term memory is dependent on synthesis of new proteins in the hippocampus and associated cortical regions. The neurotrophin brain‐derived neurotrophic factor (BDNF) is tightly regulated by activity‐dependent cellular processes and is strongly linked with mechanisms underlying learning and memory. BDNF activation of tyrosine receptor kinase (TrkB) stimulates intracellular signaling cascades implicated in plasticity, including the extracellular‐signal related kinase (ERK)/mitogen‐activated protein kinase (MAPK) pathway and the phosphatidylinositide‐3‐kinase (PI3K)/Akt pathway. Here, we investigate the role of BDNF, ERK/MAPK, and PI3K/AKT signaling cascade in recognition memory in the rat. We report that recognition memory was associated with increased release of BDNF in the dentate gyrus and perirhinal cortex. This was associated with significant increases in p44ERK activation and c‐fos expression in the dentate gyrus and PI3K activation and c‐fos expression in the perirhinal cortex. Furthermore, both recognition memory and the associated cell signaling events in dentate gyrus and perirhinal cortex were blocked by intraperitoneal injection of the Trk receptor inhibitor tyrphostin AG879. These data are consistent with the hypothesis that BDNF‐stimulated intracellular signaling plays a role in consolidation of recognition memory in the rat. © 2012 Wiley Periodicals, Inc.     

D1 receptor modulation of memory retrieval performance is associated with changes in pCREB and pDARPP-32 in rat prefrontal cortex

We have recently shown a significant role of dopamine D(1) receptors in recognition and temporal order memory retrieval for objects in rodents [Hotte M, Naudon L, Jay TM. Modulation of recognition and temporal order memory retrieval by dopamine D(1) receptor in rats. Neurobiol Learn Mem 2005;84:85-92]. The present study investigates the signal transduction pathways underlying dopamine D(1) receptor modulation of retrieval performance in these memory tasks at different delays. We analyzed the level of phosphorylation of both CREB (cAMP response element binding protein) and DARPP-32 (dopamine and cAMP-regulated phosphoprotein, 32 kDa) in (1) the prefrontal cortex of rats that had performed the object recognition task, (2) the prefrontal and perirhinal cortices of rats that had performed the temporal order memory task for objects. For comparison, we explored the phosphorylation state of CREB and DARPP-32 in the prefrontal cortex, nucleus accumbens and hippocampus of rats having performed badly on the delayed spatial win-shift task after D(1) blockade. The improvement in recognition and temporal order memory performance at a 4h-delay was associated with an increased phosphorylation of both CREB and DARPP-32 in the prefrontal cortex of rats treated with the D(1) agonist SKF 81297. By contrast, the significant impairment of delayed spatial memory retrieval after administration of the selective D(1) antagonist SCH 23390 was associated with decreased phosphorylation of CREB and DARPP-32 in the prefrontal cortex. These results provide insight into molecular mechanisms involved in D(1) receptor-dependent modulation of short- versus long-term memory in prefrontal cortex where DARPP-32 in synergy with CREB may represent a pivotal role.     

Inhibition of low calcium induced epileptiform discharges in the hippocampus by dopamine D1 receptor agonist, SKF 38393

The influence of dopamine D1 receptor agonist, SKF 38393 has been studied in vitro in the model of low calcium spontaneous epileptiform discharges. Application of SKF 38393 (3 microM) to the perfusing medium evoked a decrease in neuronal firing rate of hippocampal CA1 neurons. The effect of SKF 38393 was blocked by pretreatment with SCH 23390. It is concluded that simulation of hippocampal D1 dopamine receptors by SKF 38393 inhibits epilepsy-like events induced by low calcium concentration in the perfusing fluid.     

Activation of D1 and D2 dopamine receptors increases the activity of the somatostatin receptor-effector system in the rat frontoparietal cortex

The role of dopamine D1 and D2 receptor subtypes in the regulation, in vivo, of the somatostatin (SRIF) receptor-effector system in rat frontoparietal cortex was investigated. The D1-receptor agonist SKF 38393 (4 mg/kg) or the D2-receptor agonist bromocriptine (2 mg/kg), administered intraperitoneally to rats, increased the number of SRIF receptors without altering the affinity constant, an effect antagonized by both SCH 23390 (0.25 mg/kg) and raclopride (5 mg/kg), D1 and D2 receptor antagonists, respectively. These antagonists alone had no effect on [(125)I]Tyr(3) octreotide binding to its receptors. No change in binding was detected when the dopamine agonists were added in vitro. Basal adenylyl cyclase (AC) activity was increased by SKF 38393 treatment and decreased by bromocriptine. Octreotide (SMS 201-995)-mediated inhibition of basal and forskolin-stimulated AC was increased by SKF 38393 or bromocriptine treatment. In frontoparietal cortical slices, basal inositol-1,4, 5-triphosphate (IP(3)) levels were decreased by bromocriptine treatment but were unaffected by SKF 38393. SMS 201-995 increased the IP(3) accumulation in control, SKF 38393-, and bromocriptine-treated rats. Insofar as SRIF and dopamine appear to be involved in motor regulation and could well modulate somatosensory functions in frontal and parietal cortex, respectively, heterologous receptor regulation may have important repercussions regarding the control exerted by these neurotransmitters on frontal and parietal cortical function in the intact animal.     

Simultaneous modulation of retrieval by dopaminergic D(1), beta-noradrenergic, serotonergic-1A and cholinergic muscarinic receptors in cortical structures of the rat.

Retrieval of inhibitory avoidance has been recently shown to require intact glutamate receptors, protein kinases A and C and mitogen-activated protein kinase in the CA1 region of the rat hippocampus and in the entorhinal, posterior parietal and anterior cingulate cortex. These enzymatic activities are known to be modulated by dopamine D(1), beta-noradrenergic, 5HT1A and cholinergic muscarinic receptors. Here we study the effect on retrieval of this task of well-known agonists and antagonists of these receptors infused in the same brain cortical regions and into the basolateral amygdala, in rats. The drugs used were SKF38393 (D(1) agonist), noradrenaline, 8-HO-DPAT (5HT1A agonist), oxotremorine (muscarinic agonist), SCH23390 (D(1) antagonist), timolol (beta antagonist), NAN-190 (5HT1A antagonist) and scopolamine (muscarinic antagonist). All were studied at two different dose levels. The localised infusion of SKF38393, noradrenaline, NAN-190 and oxotremorine into any of the cortical structures mentioned 10 min prior to a 24-h retention test session of one-trial step-down inhibitory avoidance enhanced retention test performance. SCH2330, timolol, 8-HO-DPAT and scopolamine hindered retention test performance. In the basolateral amygdala only an enhancing effect of noradrenaline and an inhibitory effect of timolol were seen. Three hours after the infusions, retention test performance returned to normal in all cases. None of the treatments affected locomotion or rearing in an open field or behaviour in the elevated plus maze. Therefore, their effects on retention testing can be attributed to an influence on retrieval. In conclusion, memory retrieval of this apparently simple task requires the participation of CA1, entorhinal, posterior parietal and anterior cingulate cortex, and is strongly modulated by, dopaminergic D(1), beta-noradrenergic, muscarinic cholinergic and 5HT1A receptors in the four areas. The first three types of receptor enhance, and the latter inhibits, retrieval. Only beta-adrenoceptors appears to be involved in the modulation of retrieval of this task by the amygdala. The results bear on the well-known influence of emotion and mood on retrieval, and indicate that this involves many areas of the brain simultaneously. In addition, the results point to similarities and differences between the modulatory mechanisms that affect retrieval and those involved in the consolidation of the same task.     

A role for calcium-calmodulin-dependent protein kinase II in the consolidation of visual object recognition memory

The aim was to investigate the role of calcium-calmodulin-dependent protein kinase (CAMK)II in object recognition memory. The performance of rats in a preferential object recognition test was examined after local infusion of the CAMKII inhibitors KN-62 or autocamtide-2-related inhibitory peptide (AIP) into the perirhinal cortex. KN-62 or AIP infused after acquisition impaired memory tested at 24 h, indicating an involvement of CAMKII in the consolidation of recognition memory. Memory was impaired when KN-62 was infused at 20 min after acquisition or when AIP was infused at 20, 40, 60 or 100 min after acquisition. The time-course of CAMKII activation in rats was further examined by immunohistochemical staining for phospho-CAMKII^Thre286α at 10, 40, 70 and 100 min following the viewing of novel and familiar images. At 70 min, processing novel images resulted in more phospho-CAMKII^Thre286α-stained neurons in the perirhinal cortex than did the processing of familiar images, consistent with the viewing of novel images increasing the activity of CAMKII at this time. This difference was eliminated by prior infusion of AIP. These findings establish that CAMKII is active within the perirhinal region between ∼20 and 100 min following learning and then returns to baseline. Thus, increased CAMKII activity is essential for the consolidation of long-term object recognition memory but continuation of that increased activity throughout the 24 h memory delay is not necessary for maintenance of the memory.     

Modulation of the extinction of two different fear-motivated tasks in three distinct brain areas

The hippocampus, basolateral amygdala and ventromedial prefrontal cortex participate in the extinction of inhibitory avoidance and contextual fear conditioning. We studied the effect of drugs acting on receptors involved in synaptic modulation on extinction of both tasks. The drugs were given bilaterally right after the first of two sessions of extinction in each task through cannulae implanted into the mentioned areas. The doses used are known to influence memory consolidation of the original tasks. Their effects were evaluated on a second extinction session 24h later, and assumed to result from influences on the consolidation of extinction. The glutamate NMDA receptor stimulant d-serine (50 μg/side) and the histamine methyl-transferase inhibitor SKF9188 (12.5 μg/side) enhanced, and the NMDA antagonist amino-phosphonopentanoate (5 μg/side) and the H2 histamine receptor antagonist ranitidine (17.5 μg/side) inhibited, extinction of both tasks regardless of the region into which they were administered. Thus, glutamate NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Norepinephrine (1 μg/side), the β-adrenoceptor antagonist timolol (1 μg/side), the D1 dopamine receptor agonist SKF38393 (12.5 μg/side) and the D1 antagonist SCH23390 (1.5 μg/side) also affected extinction of both tasks, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by β- and D1 receptors is more complex. In conclusion, extinction of two different aversive tasks is modulatable by various systems, which bears upon the behavioral and pharmacological treatment of fear-motivated brain disorders.     

Basolateral amygdala modulation of the nucleus accumbens dopamine response to stress: role of the medial prefrontal cortex

The basolateral amygdala (BLA) is involved in modulating affective responses to stress and, along with the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), receives a stress-responsive dopamine (DA) projection from the ventral tegmental area. The present study was undertaken to characterize the role of BLA DA D1 and D2/D3 receptor subtypes in modulating the NAc and mPFC DA responses to stress. Voltammetry was used to monitor, in freely behaving rats, stress-induced DA release in NAc or mPFC after injection of D1 (SCH 23390) or D2/D3 (raclopride) receptor antagonist into BLA. Intra-BLA SCH 23390 injection potentiated stress-induced NAc DA release but attenuated the mPFC DA stress response; raclopride had no effect on either the NAc or mPFC DA responses to stress. Based on these results, we also examined the possibility that BLA can indirectly modulate the NAc DA stress response via its projection to mPFC. To do so we studied the effects of intra-mPFC co-administration of D1 (SKF 38393) and D2/D3 (quinpirole) receptor agonists on the potentiated NAc DA stress response resulting from intra-BLA SCH 23390 injection. Alone, mPFC D1 and D2/D3 receptor co-activation had no effect on stress-induced NAc DA release, but did prevent the potentiated NAc DA stress response produced by BLA D1 receptor blockade. These findings indicate that BLA DA modulates the NAc and mPFC DA stress responses via activation of the D1 receptor subtype. They also suggest that BLA DA modulates stress-induced NAc DA release indirectly by modulating the mPFC DA response to stress.     

Recognition memory for faces and scenes in amnesia: dissociable roles of medial temporal lobe structures

The relative contributions of the hippocampus and the perirhinal cortex to recognition memory are currently the subject of intense debate. Whereas some authors propose that both structures play a similar role in recognition memory, others suggest that the hippocampus might mediate recollective and/or associative aspects of recognition memory, whereas the perirhinal cortex may mediate item memory. Here we investigate an alternative functional demarcation between these structures, following reports of stimulus-specific perceptual deficits in amnesics with medial temporal lobe (MTL) lesions. Using a novel recognition memory test for faces and scenes, participants with broad damage to MTL structures, which included the hippocampus and the perirhinal cortex, were impaired on both face and scene memory. By contrast, participants with damage limited to the hippocampus showed deficits only in memory for scenes. These findings imply that although both the hippocampus and surrounding cortex contribute to recognition memory, their respective roles can be distinguished according to the type of material to be remembered. This interaction between lesion site and stimulus category may explain some of the inconsistencies present in the literature.     

D1 dopamine receptor activation reduces extracellular glutamate and GABA concentrations in the medial prefrontal cortex

The present study examined effect of administration of a selective D1 dopamine receptor agonist, SKF38393 on extracellular concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in mPFC, by using in vivo microdialysis. Perfusion with SKF38393 via a dialysis probe reduced concentrations of both Glu and GABA dose-relatedly, and these effects were prevented by co-perfusion with a D1 dopamine receptor antagonist, SCH23390 (40 microM). These results suggested that the dopaminergic hyperactivity may lead to the hypofunction of glutamatergic and GABAergic systems in mPFC via D1 dopamine receptor stimulation.     

Limbic pallidal adaptations following long-term cessation of dopaminergic transmission: lack of upregulation of dopamine receptor function

Neurons in the ventral pallidum (VP) exhibit robust responding to activation of dopamine (DA) receptors of the D1 class. To determine if the VP adapts to chronic cessation of DA transmission, the present studies examined D1 receptor-mediated responses in the VP recorded extracellularly in chloral-hydrate anesthetized rats following destruction of DA neurons with 6-hydroxydopamine (6-OHDA) or long-term treatment with the D1 antagonist SCH23390. Indices of basal spiking (i.e., spontaneous firing rate and pattern) recorded 10-21 days after unilateral 6-OHDA treatment did not differ from controls. Moreover, DA depletion did not alter the proportion of VP neurons whose rate was enhanced with i.v. injections of the D1 agonist SKF38393, and the functional efficacy (Emax) and potency (ED50) were similar to controls. There also was no change in the direction of responses, the Emax or the ED50 measure of sensitivity (ECur50) to iontophoretic application of DA or SKF38393 in VP neurons. Forty-eight hours after 21 once-daily treatments with SCH23390, the number of [3H]SCH23390-labeled D1 receptors was increased in the striatum, but unchanged in the VP, globus pallidus, or septum. Accordingly, there was no functional upregulation of VP responses to i.v. SKF38393. Indeed, the proportion of SKF38393-sensitive neurons was decreased after chronic SCH23390. Distinguishing the VP from other forebrain regions, these findings indicate that basal spiking is not altered in the VP following chronic DA depletion, and that no upregulation of VP DA receptor function occurs following either dopaminergic lesions or chronic antagonism of D1 receptors.