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The prefrontal cortex, particularly its medial subregions (mPFC), mediates critical functions such as executive control, behavioral inhibition, and memory formation, with relevance for everyday functioning and psychopathology. Despite broad characterization of the mPFC in multiple model organisms, the extent to which mPFC structure and function vary according to an individual's sex is unclear – a knowledge gap that can be attributed to a historical bias for male subjects in neuroscience research. Recent efforts to consider sex as a biological variable in basic science highlight the great need to close this gap. Here we review the knowns and unknowns about how rodents categorized as male or female compare in mPFC neuroanatomy, pharmacology, as well as in aversive, appetitive, and goal- or habit-directed behaviors that recruit the mPFC. We propose that long-standing dogmatic concepts of mPFC structure and function may not remain supported when we move beyond male-only studies, and that empirical challenges to these dogmas are warranted. Additionally, we note some common pitfalls in this work. Most preclinical studies operationalize sex as a binary categorization, and while this approach has furthered the inclusion of non-male rodents it is not as such generalizable to what we know of sex as a multidimensional, dynamic variable. Exploration of sex variability may uncover both sex differences and sex similarities, but care must be taken in their interpretation. Including females in preclinical research needs to go beyond the investigation of sex differences, improving our knowledge of how this brain region and its subregions mediate behavior and health. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models". • This review highlights a significant gap in understanding sex variability in the mPFC. • Current reference atlases for the rat mPFC are largely based on male subjects, emphasizing the need for a systematic investigation into potential sex differences in brain anatomy. • Theories on mPFC function lack consensus, with limited female-inclusive studies questioning generalizability of findings. • Recognizing sex as a multimodal and multidimensional variable is vital to understanding the scope of possible sex variance in mPFC. [ABSTRACT FROM AUTHOR]

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30–45 with vehicle or THC (escalating doses, 3–20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3–4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABA A receptor function or inhibit glycogen synthase kinase 3β (GSK3β), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3β signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC. • Daily THC injection reduced body weight gains, intake of saccharin and ethanol. • Adolescent exposure to ethanol and THC impaired plasticity in prelimbic cortex. • This plasticity was restored with perfusion of GABA PAM and GSK3β inhibitor. [ABSTRACT FROM AUTHOR]

Craving often precedes relapse into cocaine addiction. This explains why considerable research effort is being expended to try to develop anti-craving strategies for relapse prevention. Recently, we discovered using the classic reinstatement model of cocaine craving that the reinstating or priming effect of cocaine can be extinguished with repeated priming in rats – a phenomenon dubbed extinction of cocaine priming because it is thought to involve extinction of the conditioned interoceptive cues of the drug. Here we measured the effect of this extinction strategy on subsequent relapse-like behavior in rats (i.e., return to the pre-extinction pattern of cocaine self-administration once the drug is made again available after extinction). We found that extensive extinction of the conditioned priming effects of cocaine had no major impact on relapse-like behavior. This lack of effect occurred despite evidence for post-extinction loss of neuronal responses to cocaine priming in brain regions causally involved in cocaine reinstatement (i.e., the dorsomedial prefrontal cortex and the core of the nucleus accumbens). These findings suggest that the conditioned priming effects of cocaine can be dissociated from and are thus not essential for relapse-like behavior, and that extinction of these effects is unlikely to represent a viable approach to relapse prevention. Overall, these findings are in general agreement with previous neurobiological dissociation studies and with research on extinction of exteroceptive drug cues. • Cocaine craving can be triggered by drug priming. • Behavioral and neuronal responses to cocaine priming can be extinguished. • Extensive extinction of cocaine-primed craving has no impact on subsequent relapse. • This dissociation stresses the necessity of developing interventions that directly target relapse. [ABSTRACT FROM AUTHOR]

Abstract Ketamine is a fast acting experimental antidepressant with significant therapeutic potential for emotional disorders such as major depressive disorder and alcohol use disorders. Of particular interest is binge alcohol use, which during intermittent withdrawal from drinking involves depressive-like symptoms reminiscent of major depressive disorder. Binge drinking has been successfully modeled in mice with the Drinking in the Dark (DID) paradigm, which involves daily access to 20% ethanol, for a limited duration and selectively during the dark phase of the circadian light cycle. Here we demonstrate that DID exposure reduces the cell surface expression of NMDA- and AMPA-type glutamate receptors in the prelimbic cortex (PLC) of female but not male mice, along with reduced activity of the mammalian target of rapamycin (mTOR) signaling pathway. Pretreatment with an acute subanesthetic dose of ketamine suppresses binge-like ethanol consumption in female but not male mice. Lastly, DID-exposure reduces spontaneous glutamatergic synaptic transmission in the PLC of both sexes, but synaptic transmission is rescued by ketamine selectively in female mice. Thus, ketamine may have therapeutic potential as an ethanol binge suppressing agent selectively in female subjects. Highlights • Drinking in the Dark reduces glutamatergic synaptic transmission and mTOR signaling in the medial prefrontal cortex. • Ketamine prophylactically reduces binge-like ethanol consumption in female, but not male mice. • Ketamine-induced normalization of glutamatergic synaptic transmission reverses excessive alcohol drinking. [ABSTRACT FROM AUTHOR]

Abstract Nicotine enhances the conditioned reinforcing properties of reward-paired cues. We investigated the role of the ventral tegmental area (VTA), nucleus accumbens (NAcc), and prelimbic (PrL) and infralimbic (IL) cortices in mediating this enhancement. Male Long-Evans rats were implanted with bilateral guide cannulae aimed at either the VTA, NAcc, PrL or IL cortex. Next, rats underwent 12 sessions of Pavlovian conditioning. Each session consisted of 30 trials wherein a 5 s conditioned stimulus (CS) was paired with water (0.05 ml). Tests of responding for conditioned reinforcement were conducted during which presentation of the CS, now acting as a conditioned reinforcer (CRf), was contingent upon pressing one of two levers (CRf lever). Pressing the other lever had no consequences (NCRf lever). To determine if nicotinic acetylcholine receptors (nAChRs) in the VTA, NAcc, PrL cortex, or IL cortex mediate nicotine-enhanced responding for a CRf, the α4β2 nAChR antagonist Dihydro-Beta-Erythroidine (DHβE; 10 nmol/0.5 μL) was infused into the respective areas prior to a systemic nicotine injection (0.2 mg/kg; SC). DHβE infused into the VTA, NAcc, or IL cortex, but not PrL cortex, attenuated nicotine-enhanced responding for a CRf. Next, to confirm that nAChRs in the VTA, NAcc, or IL cortex mediate this enhancement, nicotine (8, 16, or 32 nmol/0.5 μL) was infused into the respective areas. Nicotine infused into the VTA, but not NAcc or IL cortex, enhanced responding for a CRf. These findings suggest that nicotine primarily acts on α4β2 nAChRs in the VTA to potentiate the conditioned reinforcing properties of reward-related cues. Highlights • Systemic administration of nicotine enhanced responding for conditioned reinforcement. • This effect of systemic nicotine was attenuated by infusion of DHβE into the VTA, NAcc, and IL cortex, but not PrL cortex. • Infusion of nicotine into the VTA, but not NAcc or IL cortex, enhanced responding for conditioned reinforcement. [ABSTRACT FROM AUTHOR]

Binge drinking during adolescence can have behavioral and neurobiological consequences. We have previously found that adolescent intermittent ethanol (AIE) exposure produces sex-specific social alterations indexed via decreases of social investigation and/or social preference in rats. The prelimbic cortex (PrL) regulates social interaction, and alterations within the PrL resulting from AIE may contribute to social alterations. The current study sought to determine whether AIE-induced PrL dysfunction underlies decreases in social interaction evident in adulthood. We first examined social interaction-induced neuronal activation of the PrL and several other regions of interest (ROIs) implicated in social interaction. Adolescent male and female cFos-LacZ rats were exposed to water (control) or ethanol (4 g/kg, 25% v/v) via intragastric gavage every other day between postnatal day (P) 25 and 45 (total 11 exposures). Since cFos-LacZ rats express β-galactosidase (β-gal) as a proxy for Fos, activated cells that express of β-gal can be inactivated by Daun02. In most ROIs, expression of β-gal was elevated in socially tested adult rats relative to home cage controls, regardless of sex. However, decreased social interaction-induced β-gal expression in AIE-exposed rats relative to controls was evident only in the PrL of males. A separate cohort underwent PrL cannulation surgery in adulthood and was subjected to Daun02-induced inactivation. Inactivation of PrL ensembles previously activated by social interaction reduced social investigation in control males, with no changes evident in AIE-exposed males or females. These findings highlight the role of the PrL in male social investigation and suggest an AIE-associated dysfunction of the PrL that may contribute to reduced social investigation following adolescent ethanol exposure. • Adolescent intermittent ethanol (AIE) causes social impairments in males, but not females, and reduces prelimbic cortical activity. • Chemical inactivating prelimbic neuronal ensembles following a social stimulus reduces future social interaction in control, but not AIE exposed males. • Social interaction in females was not impacted by inactivation of prelimbic cortex neuronal ensembles. [ABSTRACT FROM AUTHOR]

Abstract Epigenetic remodeling contributes to synaptic plasticity via modification of gene expression, which underlies cocaine-induced long-term memory. A prevailing hypothesis in drug addiction is that drugs of abuse rejuvenate developmental machinery to render reward circuitry highly plastic and thus engender drug memories to be highly stable. Identification and reversal of these pathological pathways are therefore critical for cocaine abuse treatment. Previous studies revealed an interesting finding in which the mRNA of histone lysine demethylase, KDM6B, is upregulated in the medial prefrontal cortex (mPFC) during early cocaine withdrawal. However, whether and how it contributes to drug-seeking behavior remain unknown. Here we used a conditioned place preference paradigm to investigate the potential role of KDM6B in drug-associated memory. We found that KDM6B protein levels selectively increased in the mPFC during cocaine withdrawal. Notably, systemic injection of KDM6B inhibitor, GSK-J4, disrupted both reconsolidation of cocaine-conditioned memory and cocaine-primed reinstatement, suggesting dual effects of KDM6B in cocaine reward memory. In addition, we found that NMDAR expression and function were both enhanced during early cocaine withdrawal in mPFC. Injection of GSK-J4 selectively reversed this cocaine-induced increase of NR2A expression and synaptic function, suggesting that mal-adaptation of cocaine-induced synaptic plasticity in mPFC largely underlies KDM6B-mediated cocaine-associated memory. Altogether, these data suggest that KDM6B plays an essential role in cocaine-associated memory, which mainly acts through enhancing cocaine-induced synaptic plasticity in the mPFC. Our findings revealed a novel role of KDM6B in cocaine-associated memory and inhibition of KDM6B is a potential strategy to alleviate drug-seeking behavior. Highlights • KDM6B protein is selectively increased in the mPFC during cocaine withdrawal. • Inhibiting KDM6B decreases cocaine-conditioned memory reconsolidation. • Inhibiting KDM6B attenuates cocaine-primed reinstatement. • Inhibiting KDM6B specifically blocks the NR2A expression and function. [ABSTRACT FROM AUTHOR]

Drug addiction is a brain disorder characterized by chronic, compulsive use of drugs. Previous studies have found a number of chronic morphine-induced changes in the brain at molecular levels. A study from our lab showed that chronic morphine-induced increase in the expression of presynaptic D1 receptors in basolateral amygdala (BLA) neurons played an important role in environmental cue-induced retrieval of morphine withdrawal memory. However, the downstream neurocircuitry of chronic morphine-induced increase presynaptic D1 receptors in the BLA remains to be elucidated. Using retrogradely labelling technique combined with whole-cell patch-clamp methods, our results showed that (1) chronic morphine sensitized the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that projected to the prelimbic cortex (PrL), but had no influence on that in BLA neurons that projected to the nucleus accumbens (NAc) or the CA1 of the hippocampus; (2) chronic morphine sensitized the effect of D1 receptor agonist on action potential firing in BLA neurons that projected to the PrL, but without affecting the intrinsic excitability and the sensitivity of postsynaptic glutamate receptors to glutamate in BLA neurons that projected to the PrL. These results suggest that chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that project to PrL and induces a sensitization of the effect of D1 receptor agonist on action potential firing in BLA neurons that project to the PrL. [ABSTRACT FROM AUTHOR]

The incubation of cue-reinforced cocaine-seeking coincides with increased extracellular glutamate within the ventromedial prefrontal cortex (vmPFC). The vmPFC is comprised of two subregions that oppositely regulate drug-seeking, with infralimbic (IL) activity inhibiting, and prelimibic (PL) activity facilitating, drug-seeking. Thus, we hypothesized that increasing and decreasing endogenous glutamate within the IL would attenuate and potentiate, respectively, cue-reinforced drug-seeking behavior, with the converse effects observed upon manipulations of endogenous glutamate within the PL. Male Sprague-Dawley rats were trained to self-administer cocaine (0.25 mg/infusion; 6 h/day X 10 days), the delivery of which was signaled by a tone-light cue. Rats were then subdivided into 3 or 30 day withdrawal groups. For testing, rats were microinjected with vehicle, 20 mM of the mGlu2/3 agonist LY379268 (to lower endogenous glutamate), or 300 μM of the excitatory amino acid transporter inhibitor threo -β-benzyloxyaspartate (TBOA; to raise endogenous glutamate) into either the IL or PL (0.5 μl/side) and then given a 30-min test for cue-reinforced drug-seeking. Vehicle-infused rats exhibited incubated responding on the cocaine-associated lever. Neither LY379268 nor TBOA altered behavior at 3 days withdrawal, indicating that glutamate within neither subregion regulates cue-reinforced drug-seeking during early withdrawal. At 30 days withdrawal, intra-PL LY379268 microinjection significantly decreased drug-seeking behavior, while the effect was more modest when infused intra-IL. Interestingly, intra-IL TBOA attenuated incubated drug-seeking during protracted withdrawal, but did not affect behavior when infused intra-PL. These results argue that glutamate release within the PL in response to drug-seeking likely drives the manifestation of incubated cocaine-seeking during protracted withdrawal. [ABSTRACT FROM AUTHOR]

Cocaine and other drugs of abuse trigger long-lasting adaptations in excitatory and inhibitory neurotransmission in the mesocorticolimbic system, and this plasticity has been implicated in several key facets of drug addiction. For example, glutamatergic neurotransmission mediated by AMPA receptors (AMPAR) is strengthened in medium spiny neurons (MSNs) in the NAc core and shell during withdrawal following repeated in vivo cocaine administration. Repeated cocaine administration also suppresses inhibitory signaling mediated by G protein-gated inwardly rectifying K + (GIRK) channels in pyramidal neurons of the prelimbic cortex, an important source of glutamatergic input to the NAc core that has been implicated in cocaine-seeking and behavioral sensitization. Here, we tested the hypothesis that suppression of GIRK channel activity in forebrain pyramidal neurons can promote plasticity of glutamatergic signaling in MSNs. Using novel conditional knockout mouse lines, we report that GIRK channel ablation in forebrain pyramidal neurons is sufficient to enhance AMPAR-dependent neurotransmission in D 1 R-expressing MSNs in the NAc core, while also increasing motor-stimulatory responses to cocaine administration. A similar increase in AMPAR-dependent signaling was seen in both D 1 R- and D 2 R-expressing MSNs in the NAc core during withdrawal from repeated cocaine administration in normal mice. Collectively, these data are consistent with the premise that the cocaine-induced suppression of GIRK-dependent signaling in glutamatergic inputs to the NAc core contributes to some of the electrophysiological and behavioral hallmarks associated with repeated cocaine administration. [ABSTRACT FROM AUTHOR]

The role of prelimbic (PrL) 5-HT 6 receptors in depression is poorly understood, particularly in Parkinson's disease-related depression. Here we reported that 6-hydroxydopamine lesions in rats decreased sucrose preference and increased immobility time as measured by the sucrose preference and forced swim tests when compared to sham-operated rats, indicating the induction of depressive-like behaviors. Intra-PrL injection of 5-HT 6 receptor agonist WAY208466 induced depressive-like responses in sham-operated rats, and produced antidepressant-like effects in the lesioned rats. However, 5-HT 6 receptor antagonist SB258585 produced antidepressant-like effects in sham-operated rats, and increased the expression of depressive-like behaviors in the lesioned rats. Neurochemical results showed that intra-PrL injection of WAY208466 and SB258585 decreased or increased dopamine (DA) and noradrenaline (NA) levels in the medial prefrontal cortex, amygdala, habenula and ventral hippocampus in sham-operated and the lesioned rats, respectively. WAY208466 increased the firing rate of PrL glutamate neurons in the two groups of rats, while SB258585 decreased the firing rate of the neurons. Compared to sham-operated rats, the duration of WAY208466 and SB258585 action on the firing rate of glutamate neurons was markedly prolonged in the lesioned rats. The lesion did not change the co-localization of 5-HT 6 receptor and glutamate neurons in the PrL. These findings indicate that 5-HT 6 receptors in the PrL are involved in the regulation of depressive-like behaviors, which attribute to changes in DA and NA levels in the limbic and limbic-related brain regions. Additionally, the results suggest that the lesion leads to a supersensitization of 5-HT 6 receptors on glutamate neurons in the PrL. [ABSTRACT FROM AUTHOR]

Cognitive and attentional processes governed by the prefrontal cortex (PFC) are influenced by cholinergic innervation. Here we have explored the role of α7 nicotinic acetylcholine receptors (nAChRs) as mediators of cholinergic signalling in the dorsomedial (prelimbic) PFC, using mouse brain slice electrophysiology. Activation of α7 nAChRs located on glutamatergic terminals and cell soma of GABAergic interneurons increased excitation and inhibition, respectively, in layer V of the prelimbic cortex. These actions were distinguished by their differential dependence on local acetylcholine (ACh): potentiation of endogenous cholinergic signalling with the positive allosteric modulator, PNU-120596, enhanced spontaneous excitatory events, an effect that was further increased by inhibition of acetylcholinesterase. In contrast, α7 nicotinic modulation of inhibitory signalling required addition of exogenous agonist (PNU-282987) as well as PNU-120596, and was unaffected by acetylcholinesterase inhibition. Thus α7 nAChRs can bi-directionally regulate network activity in the prelimbic cortex, depending on the magnitude and localisation of cholinergic signalling. This bidirectional influence is manifest in dual effects of α7 nAChRs on theta-burst-induced long-term potentiation (LTP) in layer V of the prelimbic cortex. Antagonism of α7 nAChRs significantly decreased LTP implicating a contribution from endogenous ACh, consistent with the ability of local ACh to enhance glutamatergic signalling. Exogenous agonist plus potentiator also decreased LTP, indicative of the influence of this drug combination on inhibitory signalling. Thus α7 nAChRs make a complex contribution to network activity and synaptic plasticity in the prelimbic cortex. [ABSTRACT FROM AUTHOR]

Recent studies indicated that epigenetic modification, especially DNA methylation, play an important role in the persistence of addiction-related memory. 5-aza-2-deoxycytidine (5-aza), an inhibitor of DNA methyltransferases, was approved for clinical treatment. However, it is not clear whether 5-aza is involved in opiate addiction. In this study, using the morphine-induced conditioned place preference (mCPP) model in rats, we injected 5-aza into hippocampus (CA1) and prelimbic cortex (PL), and tested the behavioral consequences at various stages of consolidation, acquisition and retrieval. Moreover, to test whether protein phosphatase regulates the effects of 5-aza, protein phosphatase (PP) 1/2A inhibitor okadaic acid (OA) was infused before 5-aza injection. We found that 5-aza injection into CA1 but not into PL significantly attenuated the consolidation and acquisition of mCPP, however, the inhibition of DNA methylation in PL but not in CA1 enhanced the retrieval of mCPP. All these behavioral effects were absent when OA was infused before 5-aza injection. These findings suggest that 5-aza interfere opiate-related memory, and protein phosphatase plays an important role in this process. [ABSTRACT FROM AUTHOR]

The prelimbic cortex (PL) is involved in the control of behavioral and autonomic responses to stress. The present study aimed to investigate whether opioid neurotransmission in the PL modulates autonomic responses evoked by restraint stress (RS). Bilateral microinjection of 0.03, 0.3 and 3 nmol/100 nL of the nonselective opioid antagonist naloxone into the PL reduced pressure and tachycardiac responses evoked by RS. However, no effects were observed after its injection at doses of 0.003 and 30 nmol/100 nL, thus resulting in an inverted U-shaped dose-inhibition curve. Similar to naloxone, the selective μ-opioid antagonist CTAP, and the selective κ-opioid antagonist nor-BNI, also reduced MAP and HR increases induced by RS when injected into the PL, whereas treatment with the selective δ-opioid antagonist naltrindole did not affect the pressor and tachycardiac response caused by RS. Blockade of opioid neurotransmission in the PL did not affect the fall in tail temperature and increase in body temperature induced by RS. The present results confirm the involvement of PL opioid neurotransmission in the modulation of cardiovascular responses evoked during the exposure to an aversive situation, and suggest that responses observed after the blockade of local opioid receptors is due to alterations in PL neuronal activity. Furthermore, these results suggest that a distinct circuitry is involved in modulation of the sympathetic output to different vascular territories. [ABSTRACT FROM AUTHOR]

The ketamine metabolite (2 R ,6 R)-hydroxynorketamine (HNK) has recently been suggested to exert fast-acting antidepressant-relevant actions and was proposed as an ideal next-generation antidepressant. However, the microRNA-mediated mechanism underlying its effects is still unknown. In the present study, we investigated the role of miR-34a in the prelimbic (PL) cortex during (2 R ,6 R)-HNK-mediated antidepressant-like effects. Male (8–10 weeks old) C57BL/6J mice and primary hippocampal cultured neurons were employed. The tests of forced swimming, tail suspension, sucrose preference, and female urine sniffing were used as indices of depressive-like behaviors. (2 R ,6 R)-HNK enhanced miR-34a levels in a time-dependent manner at 1, 24 h, and 3 days in vitro , in a time-dependent manner at 1 and 24 h, and in a dose-dependent manner at 10 and 30 mg/kg in PL. Pretreatment with NBQX or verapamil blocked (2 R ,6 R)-HNK-enhanced miR-34a expression and NBQX pretreatment blocked AMPA-elevated miR-34a levels in vitro. AAV-miR-34a in PL produced antidepression-behavioral effects and rescued stress-induced depressive-like behaviors. Moreover, PL AAV-miR-34a increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) and potentiated evoked excitatory postsynaptic currents (EPSCs). Slices incubated with miR-34a mimic acutely enhanced the frequency and amplitude of mEPSCs in the PL. Intra-PL application of miR-34a rapidly produced antidepression-like effects and reversed stress-evoked depressive-like behaviors. Furthermore, intra-PL application of anti-miR-34a attenuated both systemic and local (2 R ,6 R)-HNK-mediated antidepressant-like actions. Collectively, these results suggest that miR-34a in PL plays an antidepression-like role and contributes to the fast-acting antidepressant-relevant actions of (2 R ,6 R)-HNK. The present study provides evidence for a miR-34a-dependent mechanism underlying the fast-acting antidepressant-like actions of (2 R ,6 R)-HNK, indicating a novel role of PL miR-34a in antidepression. • (2 R ,6 R)-HNK enhanced miR-34a expression in vitro and in vivo. • AAV-miR-34a and miR-34a mimic in PL produced antidepressant-related behavioral and synaptic effects. • Anti-miR-34a in PL attenuated the antidepressant-like actions of (2 R ,6 R)-HNK. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine (DA) receptor transmission through either D1 or D2-like subtypes is involved critically in the processing of emotional information within the medial prefrontal cortex (mPFC). However the functional role of specific DA D1-like receptor transmission in the expression of emotionally salient associative memories (either aversive or rewarding) is not currently understood. Here we demonstrate that specific activation of DA D1 receptors in the prelimbic (PLC) division of the mPFC causes a transient block in the behavioral expression of both aversive and rewarding associative memories. We report that intra-PLC microinfusions of a selective D1 receptor agonist block the spontaneous expression of an associative olfactory fear memory, without altering the stability of the original memory trace. Furthermore, using an unbiased place conditioning procedure (CPP), intra-PLC D1 receptor activation blocks the spontaneous expression of an associative morphine (5 mg/kg; i.p.) reward memory, while leaving morphine-primed memory expression intact. Interestingly, both intra-PLC D1-receptor mediated block of either fear-related or reward-related associative memories were dependent upon downstream cyclic-AMP (cAMP) signaling as both effects were rescued by co-administration of a cAMP signaling inhibitor. The blockade of both rewarding and aversive associative memories is mediated through a D1-specific signaling pathway, as neither forms of spontaneous memory expression were blocked by intra-PLC microinfusions of a D2-like receptor agonist. Our results demonstrate that the spontaneous expression of either rewarding or aversive emotionally salient memories shares a common, D1-receptor mediated substrate within the mPFC. [Copyright &y& Elsevier]

Abstract: This paper studied the effect of neurosteroid dehydroepiandrosterone sulfate on spontaneous glutamate release in the prelimbic cortex by using electrophysiological and biochemical methods combined with a pharmacological approach and made some comparisons with those in the hippocampus. The results showed that dehydroepiandrosterone sulfate increased the frequency of miniature excitatory postsynaptic currents in the prelimbic cortex and hippocampus; sigma-1 receptor antagonist partially blocked the effect of dehydroepiandrosterone sulfate in the prelimbic cortex, but completely blocked it in the hippocampus; D1 receptor antagonist, adenylyl cyclase inhibitor and protein kinase A inhibitor completely blocked the effect of dehydroepiandrosterone sulfate in the prelimbic cortex; dehydroepiandrosterone sulfate increased the activity of protein kinase A in the prelimbic cortex and hippocampus; the effect of dehydroepiandrosterone sulfate on protein kinase A was completely blocked by sigma-1 receptor antagonist in the hippocampus, but was partially blocked in the prelimbic cortex; interestingly, here again, the effect of dehydroepiandrosterone sulfate on protein kinase A was completely blocked by D1 receptor antagonist in the prelimbic cortex. These results suggest that dehydroepiandrosterone sulfate promotes presynaptic glutamate release in the prelimbic cortex via activation of D1 and sigma-1 receptors. [Copyright &y& Elsevier]

Abstract: Pregnenolone sulfate is one of the most abundantly produced neurosteroids in the brain. The present paper studies the effect of pregnenolone sulfate on excitatory synaptic transmission in the pyramidal cells of the layer V–VI of the prelimbic cortex using whole-cell patch-clamp in slices. We found that pregnenolone sulfate inhibited stimulus-evoked excitatory postsynaptic currents (EPSC); the effect of pregnenolone sulfate was significant at concentration of 1 μM and increased with an increase in concentrations; pregnenolone sulfate had no effect on the amplitude and frequency of miniature excitatory spontaneous postsynaptic currents; pregnenolone sulfate significantly enhanced the paired-pulse facilitation (PPF) and inhibited dopamine and 5-HT-evoked increase in the frequency of spontaneous excitatory postsynaptic currents; the protein kinase A inhibitor H89 and Rp-cAMPS enhanced PPF and canceled the effect of pregnenolone sulfate on PPF; pregnenolone sulfate inhibited the protein kinase A agonist forskolin-evoked increase in the frequency of spontaneous excitatory postsynaptic currents; the Gi protein inhibitor N-ethylmaleimide canceled the effect of pregnenolone sulfate on PPF. These results suggest that pregnenolone sulfate inhibits stimulus-evoked EPSC via presynaptic inhibition of protein kinase A in rat prelimbic cortical neurons. [Copyright &y& Elsevier]

We examined the effects of progesterone on frequency of miniature excitatory postsynaptic currents (mEPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs), and dopamine-induced increase in the frequency of sEPSCs in pyramidal cells of layers V–VI of the rat prelimbic cortex using whole-cell patch-clamp techniques in slices. The results showed that progesterone 100 μM had no effects on the frequency of mEPSCs and sEPSCs, but significantly inhibited dopamine-induced increase in frequency of sEPSCs. This was in contrast to the effect of progesterone on the effect of 5-HT, which showed no changes after progesterone. When studying the mechanism of the progesterone effect, we observed that GABAA receptor antagonist and progesterone receptor antagonist did not influence the effect of progesterone; progesterone had no effects on D1 receptor agonist, protein kinase A and protein kinase C activator-induced increase in the frequency of sEPSCs. Interestingly, σ1 receptor antagonist could inhibit the effect of dopamine and σ1 receptor agonist had a synergistic effect on the effect of D1 receptor agonist. These results suggest that progesterone may inhibit dopamine-induced increase in frequency of sEPSCs in rat prelimbic cortical neurons via inhibition of σ1/D1 receptor synergism because progesterone has been known to be an antagonist of σ1 receptor. [Copyright &y& Elsevier]