Release In Ventral Hippocampus Research Articles

Adenosine A1 and A2A receptors differently control synaptic plasticity in the mouse dorsal and ventral hippocampus.

The hippocampus is a brain region involved in processing both memory and emotions, through a preferential involvement of the dorsal hippocampus (DH) and ventral hippocampus (VH), respectively. Adenosine A1 and A2A receptors (A1 R and A2A R) control both mood and memory, but it is not known if there is a different adenosine modulation of synaptic plasticity along the hippocampal axis. Using adult, C57BL/6 male mice, we show that both A1 R and A2A R were more abundant in DH compared with VH. However, recordings of field excitatory postsynaptic potentials at Schaffer collaterals-CA1 pyramidal synapses revealed that A1 R were equi-effective to inhibit basal excitatory synaptic transmission in DH and VH, but endogenous A1 R activation was more effective to depress the probability of release in VH. In contrast, the selective A2A R antagonist (SCH58261, 50nM) controlled both long-term potentiation (induced by a high frequency stimulation protocol) and long-term depression (induced by a low frequency stimulation protocol) selectively in DH rather than VH, whereas the selective A1 R antagonist (DPCPX, 100nM) revealed a similar tonic inhibition of long-term depression in DH and VH. These findings show a different control of synaptic plasticity by the adenosine modulation system in the dorsal and ventral poles of the hippocampus, which may underlie a different efficiency of the adenosine system to control mood and memory.

Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex

Novel fast-acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA-R) activation. We recently reported that the regionally-selective blockade of the glial glutamate transporter-1 (GLT-1) by dihydrokainic acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10 min) antidepressant-like responses, which involved AMPA-R activation and were associated to increased serotonin (5-hydroxytryptamine, 5-HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant-like responses of DHK microinfusion. First, we show that antidepressant-like responses evoked by IL application of DHK and citalopram are mediated by local 5-HT1A receptors (5-HT1A-R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5-HT release in DR and by a selective increase of c-Fos expression in DR 5-HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5-HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant-like responses evoked by IL DHK lasted for 2 h and could be prolonged for up to 24 h by attenuating self-inhibitory effects via 5-HT1A autoreceptors. In contrast, the antidepressant-like effects of S-AMPA microinfusion in IL were short-lasting. Together, our results further support a prominent role of the IL–DR pathway and of ascending 5-HT pathways in mediating antidepressant-like responses evoked by glutamatergic mechanisms.

Galanin differentially regulates acetylcholine release in ventral and dorsal hippocampus: a microdialysis study in awake rat

The purpose of the present study was to investigate, by use of in vivo microdialysis technique, the regulatory role of galanin on acetylcholine (ACh) release in the CA1, CA3, and dentate gyrus (DG) subregions of rat dorsal and ventral hippocampus. In the ventral hippocampus, local infusions of galanin (1.5 nmol) into CA1, and CA3, but not DG (3 nmol), decreased basal ACh release to 58.6% and 68.4%, respectively. In addition, local infusion of galanin (1.5 nmol) into the ventral DG, and CA3 areas decreased basal ACh levels in the CA1 to 51.2% and 84%, respectively. This observation implies that the effects of galanin are unlikely to be mediated via galanin autoreceptors on the cholinergic terminals, but rather via mechanisms involving galanin internalization and modulation of hippocampo-septo-hippocampal loops, attenuation of the excitability of the principal cells, or indirect modulation by galanin-containing vasopressin terminals to the ventral and/or dorsal hippocampus. In the dorsal hippocampus, galanin infusion (1.5 nmol) into the CA1 region increased ACh release to 128.2% of the control levels, but infusions of galanin had no effects in the CA3 and DG. In all cases, the ACh levels returned to basal values within 100 min after the galanin infusion. It is concluded that the attenuating effects of galanin on ACh release in the ventral hippocampus and increase in ACh release in the dorsal hippocampus are in line and support the current view on molecular and functional distinction between the ventral hippocampus being involved preferentially in motivational and emotional behavior, whereas the dorsal hippocampus is primarily implicated in cognitive processes of learning and memory.

Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies

The treatment of depression may be improved by using an augmentation approach involving selective serotonin reuptake inhibitors (SSRIs) in combination with compounds that focus on antagonism of inhibitory serotonin receptors. Using microdialysis coupled to HPLC, it has recently been shown that the systemic co-administration of 5-HT(2C) antagonists with SSRIs augmented the acute effect of SSRIs on extracellular 5-HT. In this paper, we have investigated the mechanism through which this augmentation occurs. The increase in extracellular 5-HT was not observed when both compounds were locally infused. However, varying the route of administration for both compounds differentially revealed that an augmentation took place when the 5-HT(2C) antagonist was locally infused into ventral hippocampus and the SSRI given systemically, but not when systemic 5-HT(2C) antagonist was co-administered with the local infusion of citalopram. This suggests that the release of extracellular serotonin in ventral hippocampus may be controlled by (an)other brain area(s). As 5-HT(2C) receptors are not considered to be autoreceptors, this would implicate that other neurotransmitter systems are involved in this process. To investigate which neurotransmitter systems were involved in the interaction, systemic citalopram was challenged with several glutamatergic, GABA-ergic, noradrenergic, and dopaminergic compounds to determine their effects on serotonin release in ventral hippocampus. It was determined that the involvement of glutamate, norepinephrine, and dopamine in the augmentation did not seem likely, whereas evidence implicated a role for the GABA-ergic system in the augmentation.

Anxiety but not arousal increases 5-HT release in the rat ventral hippocampus in vivo

Central serotonin (5-HT) is involved in the aetiology of depression and anxiety-disorders. Exposure of rats to tests of anxiety increases cortical and hippocampal 5-HT release determined by in vivo microdialysis. To discriminate whether this increase is caused by aversive conditions of a test for anxiety or by a unconditioned stressor evoking mainly arousal, we investigated the effects of an unconditioned acoustic stimulus and exposure to the elevated plus maze (X-maze), respectively, on 5 HT release in the ventral hippocampus compared to 5-HT release in the home cage and in a non-aversive unfamiliar environment in freely moving rats. Our results showed distinct pattern of 5-HT release in the ventral hippocampus depending on the stimulus used. Exposure to the X-maze for 20 minutes accompanied by an ‘anxious’ behaviour in the rats and increased extracellular 5-HT to 165% of basal release. Exposure to a less aversive ‘deactivated’ plus maze (115%) or to white noise for 20 minutes in the familiar surroundings of the home cage (98%) did not change hippocampal 5-HT release significantly, despite similar behavioural activation indicated by increased locomotor activity. While both, X-maze and white noise, may model anxiety and stress to a certain extent, it seems that the X-maze is more aversive. The results suggest a close relationship between anxiety-related behaviour, but not between arousal/non-specific behavioural activation, and 5-HT release in the ventral hippocampus.

Anxiety but not arousal increases 5‐hydroxytryptamine release in the rat ventral hippocampus in vivo

Central serotonin [5-hydroxytryptamine (5-HT)] is involved in the aetiology of numerous disease states, including depression and anxiety disorders. Studies have shown that exposure of rats to animal tests of anxiety increases extracellular 5-HT in the cortex or hippocampus determined by in vivo microdialysis. To discriminate whether this increase is caused by the aversive conditions of an animal test for anxiety or by an unconditioned stressor evoking mainly arousal, the present study investigates the effects of an unconditioned acoustic stimulus and exposure to the elevated plus maze (X-maze), respectively, on the release of 5-HT in the ventral hippocampus compared with hippocampal 5-HT release in the home cage and in a non-aversive unfamiliar environment in freely moving rats. Our results showed a distinct pattern of 5-HT release in the ventral hippocampus depending on the stimulus used. Exposure to the X-maze for 20 min was accompanied by an 'anxious' behaviour in the rats and increased extracellular 5-HT to 165% of basal release, whereas exposure to a less aversive 'deactivated' plus maze (115+/-6%) or to white noise for 20 min in the familiar surroundings of the home cage (98+/-6%) did not change hippocampal 5-HT release significantly, despite similar behavioural activation indicated by increased locomotor activity. While both the X-maze and white noise may model anxiety and stress to a certain extent, it seems that the X-maze is more aversive. The results suggest a close relationship between anxiety-related behaviour, but not arousal/non-specific behavioural activation, and 5-HT release in the ventral hippocampus.

Involvement of dopamine D(2) receptors in complex maze learning and acetylcholine release in ventral hippocampus of rats.

In the current study we focus on the involvement of dopamine D(2) receptors in the ventral hippocampus in memory performance and acetylcholine release. Using the aversively motivated 14-unit T-maze (Stone maze) the injection of raclopride, a D(2) receptor antagonist, into the ventral hippocampus (8 microg/kg) was found to impair memory performance. Co-injection of quinpirole, a D(2) receptor agonist (8 microg/kg), overcame the impairment in performance. Microdialysis study revealed that quinpirole infusion (10-500 microM) into the ventral hippocampus stimulated acetylcholine release in a dose-dependent manner, and systemic injection of quinpirole (0.5 mg/kg, i.p.) also stimulated acetylcholine release in the ventral hippocampus. Infusion of eticlopride, another D(2) receptor antagonist, into the ventral hippocampus suppressed acetylcholine release in the hippocampus induced by systemic injection of quinpirole. Taken together, we suggest that D(2) receptors in the ventral hippocampus are involved in memory performance, possibly through the regulation of acetylcholine.

Further investigation of the in vivo pharmacological properties of the putative 5-HT 1A antagonist, BMY 7378

The present study examined the actions of the putative 5-HT 1A antagonist BMY 7378 on central pre- and postsynaptic 5-HT 1A function in the rat in vivo. Unlike the direct acting 5-HT 1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), BMY 7378 (0.25–5 mg/kg s.c.) did not induce the full postsynaptically mediated 5-HT behavioural syndrome (forepaw treading, head weaving, flat body posture, hindlimb abduction). Indeed, the maximal 5-HT behavioural syndrome scores of BMY 7378 were about 10% of those for 8-OH-DPAT. Following pretreatment, however, BMY 7378 dose dependently (0.25–5 mg/kg s.c.) reduced to undetectable levels forepaw treading and head weaving induced by 8-OH-DPAT (0.75 mg/kg s.c.). BMY 7378 also inhibited stereotypy and locomotor activity induced by 0.5 mg/kg apomorphine although this effect was only statistically significant at the highest dose tested (5 mg/kg). In contrast to its apparent 5-HT 1A antagonist properties in the behavioural experiments, BMY 7378 caused a marked and dose-dependent (1.01-1.0 mg/kg s.c.) decrease of 5-HT release in ventral hippocampus of the anaesthetized rat as detected by brain microdialysis. This effect of BMY 7378 had a similar onset and duration of action but with slightly reduced efficacy compared to that previously described for 8-OH-DPAT. As with 8-OH-DPAT, the inhibitory effect of BMY 7378 on 5-HT release was attenuated by pretreatment with the 5-HT 1 receptor/β-adrenoceptor antagonist pindolol (8 mg/kg s.c.) but not its counterpart propranolol (20 mg/kg s.c.). Pretreatment with a combination of the β 1- and β 2-adrenoceptor antagonists metoprolol (4 mg/kg s.c.) and ICI 118 551 (4 mg/kg s.c.), respectively, did not alter the 5-HT response to BMY 7378. From these data we conclude that BMY 7378 is a mixed agonist/antagonist at central 5-HT 1A receptors.

5‐HT1 agonists reduce 5‐hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis

1. An intracerebral perfusion method, brain microdialysis, was used to assess changes of 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of the chloral hydrate-anaesthetized rat in response to systemic administration of a variety of 5-HT1 receptor agonists. 2. A stable output of reliably detectable endogenous 5-HT was measured in dialysates collected from ventral hippocampus with the 5-HT reuptake inhibitor, citalopram, present in the perfusion medium. 3. Under these conditions the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a dose-dependent (5-250 micrograms kg-1, s.c.) reduction of 5-HT in hippocampal dialysates. 4. Similarly, the putative 5-HT1A agonists gepirone (5 mg kg-1, s.c.), ipsapirone (5 mg kg-1, s.c.) and buspirone (5 mg kg-1, s.c.) markedly reduced levels of 5-HT in hippocampal perfusates whereas their common metabolite 1-(2-pyrimidinyl) piperazine (5 mg kg-1, s.c.), which does not bind to central 5-HT1A recognition sites, had no effect. 5. 5-Methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a drug with reported high affinity for brain 5-HT1B binding sites, also produced a dose-dependent (0.25-5 mg kg-1, s.c.) decrease of hippocampal 5-HT output. 6. These data are direct biochemical evidence that systemically administered putative 5-HT1A and 5-HT1B agonists markedly inhibit 5-HT release in rat ventral hippocampus in vivo.