Pre- and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task

Involvement of amygdaloid N-methyl-D-aspartate (NMDA) receptors in memory processes was investigated. Rats with cannulas implanted in the basolateral amygdala were trained on a 1 trial step-through inhibitory avoidance task and tested for 24-hr retention. Pretraining infusion of 2-amino-5-phosphonovaleric acid (APV) into the amygdala, but not striatum or hippocampus, produced a dose-dependent retention deficit, which was attenuated by immediate posttraining intra-amygdala infusion of NMDA. Posttraining APV infusion also caused a dose- and time-dependent retention deficit. Pretest APV infusion had no effect on performance in the retention test. Further, pre- or posttraining infusion of 5.0 micrograms APV failed to affect acquisition and retention in the Morris water maze task. These findings suggest that amygdala NMDA receptors are normally activated by aversive training and play a critical role in memory formation for affective experience.     

Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval). Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-microliter infusion containing 5.0 microgram of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5) or vehicle (phosphate-buffered saline, pH 7.4). Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean +/- SEM number of conditioned responses (CRs) during retention test session was 16.47 +/- 1.78 in the vehicle group and 9.93 +/- 1.59 in the AP5 group; P < 0.05). Post-training infusion of AP5 did not affect retention (mean +/- SEM number of conditioned responses during retention test session was 18.46 +/- 1.94 in the vehicle group and 20.42 +/- 2.38 in the AP5 group; P > 0.10). This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.     

Involvement of mechanisms dependent on NMDA receptors, nitric oxide and protein kinase A in the hippocampus but not in the caudate nucleus in memory

The effects of the NMDA receptor antagonist AP5, the nitric oxide synthase (NO) inhibitor NO-arg or the protein kinase A (PKA) inhibitor KT5720 on memory were evaluated. Rats bilaterally implanted in the CA1 region of the dorsal hippocampus were trained and tested in a step-down inhibitory avoidance task, and rats unilaterally implanted in the left posteroventral region of the caudate nucleus were trained and tested in a cued water maze task. Previous findings from this and other laboratories had found that lesions or pharmacological treatments of these sites significantly altered memory of these two tasks. Immediately after training, animals received intrahippocampal or intracaudate 0.5 microliter microinfusions of saline, AP5, NO-arg or KT5720. All three drugs impaired retention of inhibitory avoidance, but did not affect retention of the cued water maze. The findings suggest that NMDA receptor-, NO- and PKA-mediated processes in the dorsal hippocampus, but not in the caudate nucleus, are involved in memory.     

Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid.

Rats received an 8-trial training session on a spatial or cued task in a water maze, followed by a posttraining intracerebral injection of AP5 or saline. On a retention test 24 hr later, latency to mount the escape platform was used as a measure of memory. Intrahippocampal (10 μg), but not intra-dorsal striatal (2, 5, or 10 μg), injection of AP5 impaired memory in the spatial task. In contrast, intra dorsal striatal (2 μg), but not intrahippocampal (2, 5, or 10 μg) injection of AP5 impaired memory in the cued task. Intracerebral injections of AP5 delayed 2 hr posttraining were ineffective. The findings indicate a double dissociation of the roles of the hippocampus and dorsal striatum in memory, a role for N -methyl-{d}-aspartate receptor function in posttraining memory processes, and a glutamatergic modulation of both hippocampal and dorsal striatal memory processes, suggesting that different forms of memory may share a similar neurochemical basis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Local inhibition of hippocampal nitric oxide synthase does not impair place learning in the Morris water escape task in rats

Recent studies have provided evidence that nitric oxide (NO) has a role in certain forms of memory formation. Spatial learning is one of the cognitive abilities that has been found to be impaired after systemic administration of an NO-synthase inhibitor. As the hippocampus has a pivotal role in spatial orientation, the present study examined the role of hippocampal NO in spatial learning and reversal learning in a Morris task in adult rats. It was found that N omega-nitro-L-arginine infusions into the dorsal hippocampus affected the manner in which the rats were searching the submerged platform during training, but did not affect the efficiency to find the spatial location of the escape platform. Hippocampal NO-synthase inhibition did not affect the learning of a new platform position in the same water tank (i.e. reversal learning). Moreover, no treatment effects were observed in the probe trials (i.e. after acquisition and after reversal learning), indicating that the rats treated with N omega-nitro-L-arginine had learned the spatial location of the platform. These findings were obtained under conditions where the NO synthesis in the dorsal hippocampus was completely inhibited. On the basis of the present data it was concluded that hippocampal NO is not critically involved in place learning in rats.     

Pharmacological evidence of the role of dorsal striatum in spatial memory consolidation in mice.

This study investigated the role of dorsal striatum in spatial memory in mice. The mice were tested for their ability to detect a spatial displacement 24 hrs after training. In order to manipulate the dorsal striatum, focal administrations of the N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5 phosphonopentanoic acid (AP-5) were performed immediately after training. AP-5 impaired the mice's ability to detect the spatial change only if their initial position was constant during training and testing. These findings demonstrate that NMDA receptor blockade within the dorsal striatum impairs spatial memory consolidation in a task in which no explicit reward or procedural learning is involved. The results are discussed with reference to a possible selective involvement of this structure in processing spatial information acquired through an egocentric, but not an allocentric, frame of reference. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurotoxic damage to the dorsomedial striatum exaggerates the behavioral influence of a context-specific inhibitory association mediated by the ventral hippocampus.

This study investigated the role of the dorsomedial striatum (DMS) on the acquisition of a context-specific inhibitory association acquired during training on a simple visual discrimination task. The authors have previously shown that this inhibitory association depends on the circuitry of the ventral hippocampus. The authors were interested in the anatomical and functional relationship between the hippocampus and DMS and the potential contribution the DMS makes to this inhibitory behavior. Rats with neurotoxic lesions of the DMS, or shams, were assessed on the acquisition of a visual discrimination task. Following asymptotic performance, they were given reversal training in the same or different context from the original training. The results indicated that the rats with DMS damage showed an exaggerated context-specific inhibition effect. The rats with DMS damage were also impaired on a simultaneously trained tactile/spatial discrimination, a functional effect linked to a neural circuit that includes the dorsal hippocampus. A discussion of potential pathways and mechanisms for these different effects is presented. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA receptor antagonists impair memory for nonspatial, socially transmitted food preference.

Rats avoid unfamiliar foods and learn to prefer those that they smell on the breath of conspecifics. Hippocampal lesions produce rapid forgetting of this socially acquired memory. The authors report that NMDA receptor antagonists impair this memory. Rats given CPP were trained in the social transmission of food preference task. Normal rats showed robust memory 72 hr later. CPP-injected rats performed normally 24 hr, but randomly 72 hr, after training. Spatial context was irrelevant: Rats trained and tested in different rooms performed the same as rats trained and tested in 1 room. MK801 and intrahippocampal injections of APV produced amnestic effects similar to CPP. Thus, NMDA receptor activation is crucial for the persistence of socially acquired, hippocampus-dependent, nonspatial memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Liposomal amikacin: improved treatment of Mycobacterium avium complex infection in the beige mouse model

1. Binding of D,L-(E)-2-amino-4-[3H]-propyl-5-phosphono-3-pentenoic acid ([3H]-CGP 39653), a high affinity, selective antagonist at the glutamate site of the N-methyl-D-aspartate (NMDA) receptor, was investigated in rat brain by means of receptor binding and quantitative autoradiography techniques. 2. [3H]-CGP 39653 interacted with striatal and cerebellar membranes in a saturable manner and to a single binding site, with KD values of 15.5 nM and 10.0 nM and receptor binding densities (Bmax values) of 3.1 and 0.5 pmol mg-1 protein, respectively. These KD values were not significantly different from that previously reported in the cerebral cortex (10.7 nM). 3. Displacement analyses of [3H]-CGP 39653 in striatum and cerebellum, performed with L-glutamic acid, 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and glycine showed a pharmacological profile similar to that reported in the cerebral cortex. L-Glutamic acid and CPP produced complete displacement of specific binding with Ki values not significantly different from the cerebral cortex. Glycine inhibited [3H]CGP 39653 binding with shallow, biphasic curves, characterized by a high and a low affinity component. Furthermore, glycine discriminated between these regions (P < 0.005, one-way ANOVA), since the apparent Ki of the high affinity component of the glycine inhibition curve (KiH) was significantly lower (Fisher's protected LSD) in the striatum than the cortex (33 nM and 104 nM, respectively). 4. Regional binding of [3H]-CGP 39653 to horizontal sections of rat brain revealed a heterogeneous distribution of binding sites, similar to that reported for other radiolabelled antagonists at the NMDA site (D-2-[3H]-amino-5-phosphonopentanoic acid ([3H]-D-AP5) and [3H]-CPP). High values of binding were detected in the hippocampal formation, cerebral cortex and thalamus, with low levels in striatum and cerebellum. 5. [3H]-CGP 39653 binding was inhibited by increasing concentrations of L-glutamic acid, CPP and glycine. L-Glutamic acid and CPP completely displaced specific binding in all regions tested, with similar IC50 values throughout. Similarly, glycine was able to inhibit the binding in all areas considered: 10 microM and 1 mM glycine reduced the binding to 80% and 65% of control (average between areas) respectively. The percentage of specific [3H]-CGP 39653 binding inhibited by 1 mM glycine varied among regions (P < 0.05, two-ways ANOVA). Multiple comparison, performed by Fisher's protected LSD method, showed that the inhibition was lower in striatum (72% of control), with respect to cortex (66% of control) and hippocampal formation (58% of control). 6. The inhibitory action of 10 microM glycine was reversed by 100 microM 7-chloro-kynurenic acid (7-CKA), a competitive antagonist of the glycine site of the NMDA receptor channel complex, in all areas tested. Moreover, reversal by 7-CKA was not the same in all regions (P < 0.05, two-ways ANOVA). In fact, in the presence of 10 microM glycine and 100 microM 7-KCA, specific [3H]-CGP 39653 binding in the striatum was 131% of control, which was significantly greater (Fisher's protected LSD) than binding in the hippocampus and the thalamus (104% and 112% of control, respectively). 7. These results demonstrate that [3H]-CGP 39653 binding can be inhibited by glycine in rat brain regions containing NMDA receptors; moreover, they suggest the existence of regionally distinct NMDA receptor subtypes with a different allosteric mechanism of [3H]-CGP 39653 binding modulation through the associated glycine site.     

Cocaine-induced expression of striatal c-fos in the rat is inhibited by NMDA receptor antagonists

To assess the possible involvement of NMDA receptors in mediating the expression of striatal c-fos by cocaine injection, we investigated the effects of the noncompetitive NMDA receptor antagonists, ketamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), as well as the competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), in the perikarya of cocaine-treated rat brains. As previously shown by our group, administration of 20 mg/kg cocaine (IP) resulted in the immunocytochemical expression of the protooncogene in numerous cells of the caudate putamen (dorsal/sensorimotor striatum). A ketamine mixture anesthetic (2 mg/kg), however, administered 30 min prior to cocaine exposure completely blocked such genomic expression. Pretreatment with MK-801 (1 mg/kg) or CPP (5 mg/kg) also interfered, albeit to a lesser extent, with the expression of c-fos by cocaine in awake animals. These results indicate that cocaine induction of cellular c-fos in the caudate putamen is mediated at least in part by NMDA-sensitive receptors.     

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats.

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABAB receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six-day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2 mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABAB receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

The hippocampus and long-term object memory in the rat

Animal models of amnesia have yielded many insights into the neural substrates of different types of memories. Some very important aspects of memory, however, have been ignored in research using experimental animals. For example, to examine long-term memory investigators traditionally have relied on measures of information acquisition, which stand in contrast to the measures of retention commonly used in work with humans. We have recently developed a behavioral paradigm that measures both the acquisition and long-term retention of object discriminations, and found a selective retention impairment in rats with entorhinal-hippocampal disconnection (Vnek et al., 1995). The present study was designed to determine whether direct damage to the hippocampus likewise would lead to a selective deficit in the retention of visual discriminations. Rats with aspiration lesions of the dorsal hippocampus, rats with neocortical control lesions, and normal controls were trained on three object discrimination problems and then retrained 3 weeks later to measure retention. All animals showed the same level of performance during the training (acquisition) phase of testing, but the performance of animals with dorsal hippocampal injury fell below that of controls during retraining (retention). Taken together, these and our earlier results suggest that the hippocampus and anatomically related structures are particularly important for retaining visual discriminations over long delay intervals. These findings may clarify the role of the hippocampus in nonspatial memory.     

Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or in the amygdala were trained in one-trial step-down inhibitory (passive) avoidance using a 0.4 mA footshock. At various times after training (0, 1.5, 3, 6 or 9 h for animals implanted in the hippocampus; 0 or 3 h for those implanted in the amygdala), they received infusions of 8-Br-cAMP (cyclic adenosine monophosphate) (1.25 micrograms/side), SKF38393 (7.5 micrograms/side), SCH23390 (0.5 microgram/side), norepinephrine ClH (0.3 microgram/side), timolol ClH (0.3 microgram/side), 8-HO-DPAT (2.5 micrograms/side), NAN-190 (2.5 micrograms/side), forskolin (0.5 microgram/side) or KT5720 (0.5 microgram/side). Rats were tested for retention 24 h after training. SKF38393 is an agonist and SCH23390 an antagonist at dopamine D1 receptors, timolol is a beta-adrenoceptor antagonist, 8-HO-DPAT is an agonist and NAN-190 an antagonist at 5HT1A receptors, forskolin enhances adenylyl cyclase, and KT5720 inhibits protein kinase A. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory and KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF 38393, noradrenaline and NAN-190 caused memory facilitation, and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia. At 9 h from training, all treatments were again ineffective. When given into the amygdala 0 or 3 h post-training all treatments were ineffective, except for noradrenaline at 0 h, which caused retrograde facilitation. The data agree with the suggestion that in the hippocampus, but not the amygdala, a cAMP/protein kinase A pathway is involved in memory consolidation at 3 and 6 h from training, and that this is regulated by D1, beta, and 5HT1A receptors. This correlates with a previous report of increased cAMP levels, protein kinase A activity and P-CREB levels at 3-6 h from training in rat hippocampus in this task. This may be taken to suggest that the hippocampus, but not the amygdala, is involved in the long-term storage of step-down inhibitory avoidance in the rat.     

The contribution of NMDA receptors in the dorsolateral striatum to egocentric response learning.

The present study examined the effects of the N-methyl-D-aspartate (NMDA) competitive antagonist, 2-amino-5-phosphonopentanoic acid (AP-5), injected into the dorsolateral striatum on the acquisition and reversal learning of a response discrimination. Male Long-Evans rats were tested across 2 consecutive days in a modified cross-maze. An infusion of either saline or AP-5 (5 or 25 nM) occurred 5 min prior to testing. In acquisition rats learned to turn left or right. In reversal learning rats learned to turn in the opposite direction. An AP-5 infusion at 25 nmol, but not 5 nmol, impaired response acquisition. Neither AP-5 dose impaired response reversal learning. The results suggest that NMDA receptors in the dorsolateral striatum are critical for the initial learning of an egocentric response discrimination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice.

This study examined the role of dorsal hippocampal NMDA receptors and PKA activation in 17β-estradiol (E?)-induced enhancement of object memory consolidation. Mice explored two identical objects during training, after which they immediately received intraperitoneal injections of 0.2 mg/kg E?, and bilateral dorsal hippocampal infusions of Vehicle, the NMDA receptor antagonist APV (2.5 μg/side), or the cAMP inhibitor Rp-cAMPS (18.0 μg/side). Retention was tested 48 hours later. The enhanced object memory and increased ERK phosphorylation observed with E? alone was reduced by APV and Rp-cAMPS, suggesting that estrogenic enhancement of object memory involves NMDA receptors and PKA activation within the dorsal hippocampus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The CA3 subregion of the hippocampus is critical for episodic memory processing by means of relational encoding in rats.

This experiment tested the theory that the CA3 subregion of the hippocampus mediates episodic learning of arbitrary associations. The authors developed 2 tasks based on the episodic flavor-place paired-associate task described by M. Day, R. Langston, and R. G. Morris (2003): an object-cued spatial location recall task and a spatial location-cued object recall task. After rats were trained to a criterion of 80% correct on 1 of the 2 tasks, they received either a dorsal CA3 lesion or a vehicle control lesion. Control animals continued performing well on both tasks. Rats with lesions to dorsal CA3 were impaired on both tasks and performed at chance but were able to perform a nonepisodic version of the task as a control. These data suggest that CA3 mediates episodic learning of arbitrary associations as tested in the 1-trial object-cued spatial location recall and spatial location-cued object recall tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased training in an aversively motivated task attenuates the memory-impairing effects of posttraining N-methyl-D-aspartate-induced amygdala lesions.

Examined the effect of variations in the amount of preoperative training on the retention deficit produced by posttraining lesions of the amygdaloid complex (AC). Rats received 1, 10, or 20 training trials in a footshock-motivated retention escape task 7 days before receiving N-methyl-{d}-aspartate (NMDA) lesions of the AC. Inhibitory avoidance retention performance, which was measured 4 days postoperatively, indicated that increased training improved retention in AC-lesioned animals as well as in control animals. The retention performance of AC-lesioned animals was impaired when compared with that of controls; however, the impairment was partially attenuated by increased preoperative training. The finding that AC-lesioned animals displayed greater locomotor activity on the retention test compared with nonlesioned controls suggests that the increased activity may have contributed to the impaired inhibitory avoidance retention performance. Two days after the retention test, some of the AC-lesioned animals were subsequently trained on a continuous multiple-trial inhibitory avoidance response in the same apparatus. AC lesions did not block acquisition or retention of the task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Place learning strategy of substantia nigra pars compacta-lesioned rats.

The substantia nigra pars compacta (SNc) and the dorsal striatum are often considered to be necessary for stimulus-response (S-R) habit learning, whereas the dorsal hippocampus is considered to be necessary for relational (declarative) memory. Spatial learning is a kind of relational learning that occurs when a rat is released from different locations (variable start) in a water maze to find a submerged platform that is kept in a constant location. However, when the rat is always released from the same starting position (constant start), it can learn to find the platform oriented by a fixed configuration of cues, that is, by S-R learning. To test the critical role of the SNc in S-R and relational learning, the authors tested adult male Wistar rats, sham-operated or with a lesion in the SNc, in these 2 versions of the water maze task. The SNc lesion was induced by bilateral intranigral infusion of 0.5 μmol 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine. Although the SNc-lesioned rats learned the variable-start version as effectively as sham rats did, they were significantly impaired in learning the constant-start version of the task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Optimized release of dexamethasone and gentamicin from a soluble ocular insert for the treatment of external ophthalmic infections

The aziridinium ion of ethylcholine (AF64A), a cholinergic neurotoxin, was injected into the right striatum of a rat. The unilateral injection of 10 nmol AF64A reduced the activity of choline acetyltransferase (CAT) and the tissue content of acetylcholine (ACh) in the striatum. The striatal contents of dopamine (DA), norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA) and gamma-aminobutyric acid (GABA) were unchanged. These results suggest that the cholinospecificity in the striatal lesion was induced by the 10 nmol dose of AF64A. The number of N-methyl-D-aspartic acid (NMDA) receptors in the striatum treated with 10 nmol AF64A was determined by a specific binding assay using [3H](+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP), a selective ligand for NMDA receptors. The number of the NMDA receptors decreased significantly in the injected area. On the other hand, in a microdialysis using normal rats, the perfusion of 50 microM NMDA into the striatum increased ACh release. The perfusion of 100 microM MK801 which is the specific and non-competitive NMDA receptor antagonist, decreased the basal levels of ACh release and blocked NMDA-elicited ACh release. Taken together, the present results strongly suggest that a population of NMDA receptors exists on cholinergic interneurons within the striatum, and it directly regulates ACh release.     

Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway: role of somatodendritic autoreceptors

5-HT1A autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5-HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5-HT (5-HT(ext)) induced by the 5-HT uptake inhibitor paroxetine in forebrain were potentiated by the 5-HT1A antagonist WAY-100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5-HT(ext) during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY-100635. The perfusion of 50 micromol/L citalopram in the dorsal or median raphe nucleus reduced 5-HT(ext) in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5-HT(ext) induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY-100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self-inhibition mediated by 5-HT1A autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5-HT1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.