Cocaine diminishes consolidation of cued fear memory in female rats through interactions with ventral hippocampal D2 receptors.

In addition to cocaine's addictive properties, cocaine use may lead to heightened risk-taking behavior. The disruptive effects of cocaine on aversive memory formation may underlie this behavior. The present study investigated the effects of cocaine on fear memory using a cued fear conditioning paradigm in female Sprague Dawley rats, and further determined the role of D2 receptors in modulating the effect of cocaine on cued fear expression. Animals received six evenly spaced shocks preceded by a tone. The following day, rats were returned to the fear chamber where tones, but no shocks, were delivered. In Experiment 1, separate or concurrent administrations of cocaine (15 mg/kg; i.p.) and the D2 receptor antagonist eticlopride (0.1 mg/kg; i.p.) were given immediately after conditioning trials. It was determined that cocaine administration during the consolidation period diminished the expression of cued fear during the subsequent test day. Concurrent eticlopride administration attenuated this effect, indicating the involvement of D2 receptors in the deleterious effects of cocaine on fear memory consolidation. In Experiment 2, eticlopride (0.05 µg) was infused directly into the ventral hippocampus (VH) after fear conditioning and before cocaine administration. Cocaine continued to disrupt consolidation of cued and contextual fear memory, and concurrent intra-VH eticlopride blocked this effect, thereby demonstrating that VH D2 receptors mediate cocaine-induced impairment of fear memory consolidation. Overall, the present study provides evidence that acute cocaine administration impairs aversive memory formation and establishes a potential circuit through which cocaine induces its detrimental effects on fear memory consolidation.

Effect of positive allosteric modulation and orthosteric agonism of dopamine D2-like receptors on respiration in mouse models of Rett syndrome.

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2Bird and Mecp2R168X mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2-like receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2-like receptor positive allosteric modulator, and quinpirole, a dopamine D2-like receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2-like receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2Bird/+ and Mecp2R168X/+ mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7 % CO2). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2R168X/+ and Mecp2Bird/+ mice, while also reducing respiratory rate. These results suggest that D2-like receptors could contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of D2-like receptors alone was not sufficient to evoke these effects.

Carotid body plastic behavior: evidence for D2-H3 receptor-receptor interactions.

Dopamine and histamine receptors D2R and H3R are G protein-coupled receptors (GPCRs) which can establish physical receptor-receptor interactions (RRIs), leading to homo/hetero-complexes in a dynamic equilibrium. Although D2R and H3R expression has been detected within the carotid body (CB), their possible heterodimerization has never been demonstrated. The aim of this work was to verify D2R and H3R colocalization in the CB, thus suggesting a possible interplay that, in turn, may be responsible of specific D2R-H3R antagonistic functional implications. The CBs of both Sprague-Dawley rats (n = 5) and human donors (n = 5) were dissected, and immunolocalization of D2R and H3R was performed; thereafter, in situ proximity ligation assay (PLA) was developed. According to experimental evidence (immunohistochemistry and double immunofluorescence), all the samples displayed positive D2R/H3R elements; hence, PLA assay followed by confocal microscopy analysis was positive for D2R-H3R RRIs. Additionally, D2R-H3R heterodimers were mainly detected in type I cells (ßIII-tubulin-positive cells), but type II cells' involvement cannot be excluded. RRIs may play a role in functional modulation of CB cells; investigating RRIs in the CB may guide toward the comprehension of its plastic changes and fine regulatory role while also unveiling their possible clinical implications.

Dopamine D2-like receptors on conditioned and unconditioned fear: A systematic review of rodent pharmacological studies.

Growing evidence supports dopamine's role in aversive states, yet systematic reviews focusing on dopamine receptors in defensive behaviors are lacking. This study presents a systematic review of the literature examining the influence of drugs acting on dopamine D2-like receptors on unconditioned and conditioned fear in rodents. The review reveals a predominant use of adult male rats in the studies, with limited inclusion of female rodents. Commonly employed tests include the elevated plus maze and auditory-cued fear conditioning. The findings indicate that systemic administration of D2-like drugs has a notable impact on both innate and learned aversive states. Generally, antagonists tend to increase unconditioned fear, while agonists decrease it. Moreover, both agonists and antagonists typically reduce conditioned fear. These effects are attributed to the involvement of distinct neural circuits in these states. The observed increase in unconditioned fear induced by D2-like antagonists aligns with dopamine's role in suppressing midbrain-mediated responses. Conversely, the reduction in conditioned fear is likely a result of blocking dopamine activity in the mesolimbic pathway. The study highlights the need for future research to delve into sex differences, explore alternative testing paradigms, and identify specific neural substrates. Such investigations have the potential to advance our understanding of the neurobiology of aversive states and enhance the therapeutic application of dopaminergic agents.

Single-dose methamphetamine administration impairs ORM retrieval in mice via excessive DA-mediated inhibition of PrLGlu activity.

Methamphetamine (METH), an abused psychostimulant, impairs cognition through prolonged or even single-dose exposure, but animal experiments have shown contradictory effects on memory deficits. In this study we investigated the effects and underlying mechanisms of single-dose METH administration on the retrieval of object recognition memory (ORM) in mice. We showed that single-dose METH administration (2 mg/kg, i.p.) significantly impaired ORM retrieval in mice. Fiber photometry recording in METH-treated mice revealed that the activity of prelimbic cortex glutamatergic neurons (PrLGlu) was significantly reduced during ORM retrieval. Chemogenetic activation of PrLGlu or glutamatergic projections from ventral CA1 to PrL (vCA1Glu-PrL) rescued ORM retrieval impairment. Fiber photometry recording revealed that dopamine (DA) levels in PrL of METH-treated mice were significantly increased, and micro-infusion of the D2 receptor (D2R) antagonist sulpiride (0.25 µg/side) into PrL rescued ORM retrieval impairment. Whole-cell recordings in brain slices containing the PrL revealed that PrLGlu intrinsic excitability and basal glutamatergic synaptic transmission were significantly reduced in METH-treated mice, and the decrease in intrinsic excitability was reversed by micro-infusion of Sulpiride into PrL in METH-treated mice. Thus, the impaired ORM retrieval caused by single-dose METH administration may be attributed to reduced PrLGlu activity, possibly due to excessive DA activity on D2R. Selective activation of PrLGlu or vCA1Glu-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.

The influence of hippocampal dopamine D2 receptor losses on episodic-memory decline across 5 years is moderated by BDNF and KIBRA polymorphisms.

Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation. Previously, we reported that higher DA D2 receptor (D2DR) availability in hippocampus is beneficial for episodic memory only in older carriers of more advantageous genotypes of well-established plasticity-related genetic variations, the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. Extending our observations to the longitudinal level, the current data show that individuals with one or no beneficial BDNF and KIBRA genotype (n = 80) decline more in episodic memory across five years, without any contribution of losses in hippocampal D2DR availability to memory decline. Although carriers of two beneficial genotypes (n = 39) did not decline overall in episodic memory, losses of hippocampal D2DR availability were predictive of episodic-memory decline among these individuals. Our findings have implications for interventions targeting DA modulation to enhance episodic memory in aging, which may not benefit all older individuals.

Stimulation of VTA dopamine inputs to LH upregulates orexin neuronal activity in a DRD2-dependent manner.

Dopamine and orexins (hypocretins) play important roles in regulating reward-seeking behaviors. It is known that hypothalamic orexinergic neurons project to dopamine neurons in the ventral tegmental area (VTA), where they can stimulate dopaminergic neuronal activity. Although there are reciprocal connections between dopaminergic and orexinergic systems, whether and how dopamine regulates the activity of orexin neurons is currently not known. Here we implemented an opto-Pavlovian task in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation to investigate the relationship between dopamine release and orexin neuron activity in the lateral hypothalamus (LH). We found that dopamine release can be evoked in LH upon optogenetic stimulation of VTA dopamine neurons and is also naturally evoked by cue presentation after opto-Pavlovian learning. Furthermore, orexin neuron activity could also be upregulated by local stimulation of dopaminergic terminals in the LH in a way that is partially dependent on dopamine D2 receptors (DRD2). Our results reveal previously unknown orexinergic coding of reward expectation and unveil an orexin-regulatory axis mediated by local dopamine inputs in the LH.

Nucleus accumbens core dopamine D2 receptors are required for performance of the odor span task in male rats.

RATIONALE: The nucleus accumbens (NAc) core gates motivationally relevant behavioral action sequences through afferents from cortical and subcortical brain regions. While the role of the NAc core in reward and effort-based decision making is well established, its role in working memory (WM) processes is incompletely understood. The odor span task (OST) has been proposed as a measure of non-spatial working memory capacity (WMC) as it requires rodents to select a novel odor from an increasing number of familiar odors to obtain a food reward. OBJECTIVE: To assess the role of the NAc core in the OST using (1) reversible chemical inactivation and (2) selective blockade of dopamine D1 and D2 receptors in the area. METHODS: Well-trained male rats were tested on the OST following intra-NAc core infusions of muscimol/baclofen, the D1 receptor antagonist SCH-23390 (1 µg/hemisphere) and the D2 receptor antagonist eticlopride (1 µg/hemisphere). Behavioral measurements included the average odor span, maximum odor span, choice latency, searching vigor, and patterns of responding during foraging that may relate to impulsivity. RESULTS: Chemical inactivation of the NAc core significantly decreased odor span relative to sham and vehicle conditions. Selective antagonism of D2, but not D1, receptors in the NAc core also produced deficits in odor span. We found that secondary behavioral measures of choice latency, searching vigor, and responding to the first odor stimulus encountered were largely unaffected by treatment. CONCLUSIONS: These findings suggest that D2 receptors in the NAc core are required for OST performance.

Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats.

Background: Dopamine receptors have been reported to be involved in pain, while the exact effects and mechanism in bone cancer pain have not been fully explored. Methods: Bone cancer pain model was created by implanting walker 256 mammary gland carcinoma into right tibia bone cavity. Primary cultured spinal neurons were used for in vitro evaluation. FLIPR, western-blot, immunofluorescence, and Co-IP were used to detect cell signaling pathway. Results: Our results indicated that spinal dopamine D1 receptor (D1DR) and spinal dopamine D2 receptor (D2DR) could form heteromers in TCI rats, and antagonizing spinal D1DR and D2DR reduced heteromers formation and alleviated TCI-induced bone cancer pain. Further results indicated that D1DR or D2DR antagonist induced antinociception in TCI rats could be reversed by D1DR, D2DR, and D1/D2DR heteromer agonists. And Gq, IP3, and PLC inhibitors also attenuated TCI-induced bone cancer pain. In vitro results indicated that D1DR or D2DR antagonist decreased the Ca2+ oscillations upregulated by D1DR, D2DR, and D1/D2DR heteromer agonists in activated primary cultured spinal neurons. Moreover, inhibition of D1/D2DR heteromers induced antinociception in TCI rats was partially mediated by the CaMKII and MAPKs pathway. In addition, a natural compound levo-Corydalmine (l-CDL), could inhibit D1/D2DR heteromers and attenuate bone cancer pain. Results: Inhibition of spinal D1/D2DR heteromers via l-CDL decreases excitability in spinal neurons, which might present new therapeutic strategy for bone cancer pain.

Dopaminergic D2 receptor modulation of striatal cholinergic interneurons contributes to sequence learning.

Learning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability, dopamine and glutamate release, and synaptic plasticity. Cholinergic neurons in dStr pause their tonic firing during the performance of learned action sequences. Activation of dopamine type-2 receptors (D2Rs) on ChIs is one mechanism of ChI pausing. In this study we show that deleting D2Rs from ChIs by crossing D2-floxed with ChAT-Cre mice (D2Flox-ChATCre), which inhibits dopamine-mediated ChI pausing and leads to deficits in an operant action sequence task and lower breakpoints in a progressive ratio task. These data suggest that D2Flox-ChATCre mice have reduced motivation to work for sucrose reward, but show no generalized motor skill deficits. D2Flox-ChATCre mice perform similarly to controls in a simple reversal learning task, indicating normal behavioral flexibility, a cognitive function associated with ChIs. In vivo electrophysiological recordings show that D2Flox-ChatCre mice have deficits in sequence encoding, with fewer dStr MSNs encoding entire action sequences compared to controls. Thus, ChI D2R deletion appears to impair a neural substrate of action chunking. Virally replacing D2Rs in dStr ChIs in adult mice improves action sequence learning, but not the lower breakpoints, further suggesting that D2Rs on ChIs in the dStr are critical for sequence learning, but not for driving the motivational aspects of the task.

Regulation of plasma glucose levels by central dopamine D2 receptors is impaired in type 1 but not type 2 diabetic mouse models.

Glucose metabolism is reported to be regulated by the central nervous system, but it is unclear whether this regulation is altered in diabetes. We investigated whether regulation of glucose metabolism by central dopamine D2 receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride induced hyperglycemia in control mice, but not in streptozotocin (STZ)-induced diabetic mice, a type 1 diabetic model. Hyperglycemia induced by quinpirole or l-sulpiride was diminished following fasting and these drugs did not affect hyperglycemia in the pyruvate tolerance test. In addition, both quinpirole and l-sulpiride increased hepatic glucose-6-phosphatase (G6Pase) mRNA. In STZ-induced diabetic mice, dopamine and dopamine D2 receptor mRNA in the hypothalamus, which regulates glucose homeostasis, were decreased. Hepatic glycogen and G6Pase mRNA were also decreased in STZ-induced diabetic mice. Neither quinpirole nor l-sulpiride increased hepatic G6Pase mRNA in STZ-induced diabetic mice. In diet-induced obesity mice, a type 2 diabetic model, both quinpirole and l-sulpiride induced hyperglycemia, and hypothalamic dopamine and dopamine D2 receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D2 receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D2 receptors does not affect glucose levels in type 1 but does so in type 2 diabetic models. Moreover, hypothalamic dopaminergic function and hepatic glycogenolysis are decreased in the type 1 diabetic model, which reduces hyperglycemia induced by stimulation or blockade of dopamine D2 receptors.

Dopamine agonists in Parkinson's disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment.

Dopamine agonists (DAs) have demonstrated efficacy for the treatment of Parkinson's disease (PD) but are limited by adverse effects (AEs). DAs can vary considerably in their receptor subtype selectivity and affinity, chemical composition, receptor occupancy, and intrinsic activity on the receptor. Most currently approved DAs for PD treatment primarily target D2/D3 (D2-like) dopamine receptors. However, selective activation of D1/D5 (D1-like) dopamine receptors may enable robust activation of motor function while avoiding AEs related to D2/D3 receptor agonism. Full D1/D5 receptor-selective agonists have been explored in small, early-phase clinical studies, and although their efficacy for motor symptoms was robust, challenges with pharmacokinetics, bioavailability, cardiovascular AEs, and dyskinesia rates similar to levodopa prevented clinical advancement. Generally, repeated dopaminergic stimulation with full DAs is associated with frontostriatal dysfunction and sensitization that may induce plastic changes in the motor system, and neuroadaptations that produce long-term motor and nonmotor complications, respectively. Recent preclinical and clinical studies suggest that a D1/D5 receptor-selective partial agonist may hold promise for providing sustained, predictable, and robust motor control, while reducing risk for motor complications (e.g., levodopa-induced dyskinesia) and nonmotor AEs (e.g., impulse control disorders and excessive daytime sleepiness). Clinical trials are ongoing to evaluate this hypothesis. The potential emerging availability of novel dopamine receptor agonists with selective dopamine receptor pharmacology suggests that the older terminology "dopamine agonist" may need revision to distinguish older-generation D2/D3-selective agonists from D1/D5-selective agonists with distinct efficacy and tolerability characteristics.

Spatiomolecular Characterization of Dopamine D2 Receptors Cells in the Mouse External Globus Pallidus.

The external globus pallidus (GPe) is part of the basal ganglia circuit and plays a key role in controlling the actions. Although, many evidence indicate that dopamine through its activation of D2 receptors (D2Rs) modulates the GPe neuronal activity, the precise spatiomolecular characterization of cell populations expressing D2Rs in the mouse GPe is still lacking. By combining single molecule in situ hybridization, cell type-specific imaging analyses, and electrophysiology slice recordings, we found that GPe D2R cells are neurons preferentially localized in the caudal portion of GPe. These neu- rons comprising pallido-striatal, pallido-nigral, and pallido-cortical neurons segregate into two distinct populations displaying molecular and electrophysiological features of GPe GABAergic PV/NKX2.1 and cholinergic neurons respectively. By clarifying the spatial molecular identity of GPe D2R neurons in the mouse, this work provides the basis for future studies aiming at disentangling the action of do- pamine within the GPe.

Immunohistochemical Expression of Ki-67, Dopamine D1 and Dopamine D2 Receptors in Meningiomas in a Tertiary Institution in Mexico.

Objectives Meningiomas (MNGs) are the most common intracranial tumors found in the adult population. While most intracranial MNGs may be surgically removed, a subset of patients remains ineligible for conventional treatment. This is either because of a lack of surgical access or due to atypical, anaplastic or invasive characteristics of the tumors. These patients may benefit from targeted therapies that focus on cell receptor expression. The aim of this study was to assess dopamine receptor (DR) and Ki-67 expression in the MGNs of patients treated with surgery in the Instituto Nacional de Neurología y Neurocirugía, Mexico. Materials and methods This study analyzed 23 patients with confirmed MNG diagnoses (10 female and 13 male (mean age: 44.5 years)) who had undergone surgical resection between 2010 and 2014 at our institution. In the collected samples, we performed analyses for Ki-67, Dopamine 1 and Dopamine 2 receptors' expression. Results For the markers Ki-67, DR-D1 and DR-D2, the mean percentual expressions were 18.9%, 23.02% and 8.33%. No significant correlation was found between the expressions of these receptors and the studied MNG characteristics. The expression index of Ki-67 showed a significant relation with mean age (p = 0.03) and prolactin levels (p = 0.02). Conclusions Samples showed varied expressions of the studied receptors. Despite the difference in expressions between the markers, more studies are needed to confirm the findings. In contrast to previous studies, we could not find any relationship between D2-R and tumor characteristics.

Dopamine receptor-mediated roles on retinal ganglion cell hyperexcitability and injury in experimental glaucoma.

Extraordinary excitability (hyperexcitability) is closely related to retinal ganglion cell (RGC) injury in glaucoma. Dopamine (DA) and its receptors are involved in modulating RGC excitability. We investigated how DA system affects RGC injury in chronic ocular hypertension (COH) experimental glaucoma model. Western blotting and immunohistochemistry results revealed that expression of DA D2-like receptor (D2R) in RGCs was increased in COH retinas. Patch-clamp recordings showed that outward K+ currents were downregulated, while Na+ currents and NaV1.6 expression were upregulated in RGCs of COH retinas, which could be reversed by intravitreal pre-injection of the D2R antagonist sulpiride, but not by the D1-like receptor (D1R) antagonist SCH23390. However, pre-injection of the D1R agonist SKF81297 could partially reverse the increased expression of NaV1.6 proteins. Consistently, the numbers of evoked action potentials induced by current injections were increased in RGCs of COH retinas, indicating that RGCs may be in a condition of hyperexcitability. The increased frequency of evoked action potentials could be partially block by pre-injection of sulpiride, SKF81297 or DA, respectively. Furthermore, the increased number of TUNEL-positive RGCs in COH retinas could be partially reduced by intravitreal pre-injection of sulpiride, but not by pre-injection of SCH23390. Moreover, pre-injection of SKF81297 or DA could reduce the number of TUNEL-positive RGCs in COH retinas. All these results indicate that in COH retina, activation of D2R enhances RGC hyperexcitability and injury, while activation of D1R results in the opposite effects. Selective inhibition of D2R or activation of D1R may be an effective strategy for treatment of glaucoma.

Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring.

BACKGROUND: Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions. METHODS: In vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring. RESULTS: MIA-treated offspring showed disrupted recognition memory in the novel object recognition task (t = 2.30, p = 0.031). This poly(I:C)-based group displayed decreased extracellular dopamine (DA) concentrations compared to controls (t = 3.17, p = 0.0068). Potassium-evoked release of DA and noradrenaline (NA) were impaired in the poly(I:C) group (DA: Ft[10,90] = 43.33, p < 0.0001; Ftr[1,90] = 1.224, p = 0.2972; Fi[10,90] = 5.916, p < 0.0001; n = 11); (NA: Ft[10,90] = 36.27, p < 0.0001; Ftr[1,90] = 1.841, p = 0.208; Fi[10,90] = 8.686, p < 0.0001; n = 11). In the same way, amphetamine-evoked release of DA and NA were also impaired in the poly(I:C) group (DA: Ft[8,328] = 22.01, p < 0.0001; Ftr[1,328] = 4.507, p = 0.040; Fi[8,328] = 2.319, p = 0.020; n = 43); (NA: Ft[8,328] = 52.07; p < 0.0001; Ftr[1,328] = 4.322; p = 0.044; Fi[8,398] = 5.727; p < 0.0001; n = 43). This catecholamine imbalance was accompanied by increased dopamine D1 and D2 receptor expression (t = 2.64, p = 0.011 and t = 3.55, p = 0.0009; respectively), whereas tyrosine hydroxylase, DA and NA tissue content, DA and NA transporter (DAT/NET) expression and function were unaltered. CONCLUSIONS: MIA induces in offspring a presynaptic catecholaminergic hypofunction in PFC with cognitive impairment. This poly(I:C)-based model reproduces catecholamine phenotypes reported in schizophrenia and represents an opportunity for the study of cognitive impairment associated to this disorder.

Double dissociation of perirhinal nicotinic acetylcholine receptors and dopamine D2 receptors in modulation of object memory consolidation by nicotine, cocaine and their conditioned stimuli.

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l-741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS-, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS- pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l-741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves.

Corrigendum: Intra-accumbens raclopride administration prevents behavioral changes induced by intermittent access to sucrose solution.

[This corrects the article DOI: 10.3389/fnins.2018.00074.].

The effects of the recurrent social isolation stress on fear extinction and dopamine D2 receptors in the amygdala and the hippocampus.

BACKGROUND: The present study assessed the influence of recurrent social isolation stress on the aversive memory extinction and dopamine D2 receptors (D2R) expression in the amygdala and the hippocampus subnuclei. We also analyzed the expression of epigenetic factors potentially associated with fear extinction: miRNA-128 and miRNA-142 in the amygdala. METHODS: Male adult fear-conditioned rats had three episodes of 48 h social isolation stress before each fear extinction session in weeks intervals. Ninety minutes after the last extinction session, the D2R expression in the nuclei of the amygdala and the hippocampus (immunocytochemical technique), and mRNA levels for D2R in the amygdala were assessed (PCR). Moreover, we evaluated the levels of miRNA-128 and miRNA-142 in the amygdala. RESULTS: It was found that recurrent social isolation stress decreased the fear extinction rate. The extinguished isolated rats were characterized by higher expression of D2R in the CA1 area of the hippocampus compared to the extinguished and the control rats. In turn, the isolated group presented higher D2R immunoreactivity in the CA1 area compared to the extinguished, the control, and the extinguished isolated animals. Moreover, the extinguished animals had higher expression of D2R in the central amygdala than the control and the extinguished isolated rats. These changes were accompanied by the increase in miRNA-128 level in the amygdala in the extinguished isolated rats compared to the control, the extinguished, and the isolated rats. Moreover, the extinguished rats had lower expression of miRNA-128 compared to the control and the isolated animals. CONCLUSIONS: Our results suggest that social isolation stress impairs aversive memory extinction and coexists with changes in the D2R expression in the amygdala and hippocampus and increased expression of miRNA-128 in the amygdala.

Limbic System Response to Psilocybin and Ketamine Administration in Rats: A Neurochemical and Behavioral Study.

The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well understood; however, clinical studies have shown that the administration of the fast-acting antidepressant ketamine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction in depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus were observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in the acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin's effect on stress, anxiety and structural changes in the limbic system and translate into the antidepressant effect of psilocybin in depressed patients.