Inhibitory effects of glycine on morphine-induced hyperactivity,reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice

The effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice was examined. A single administration of morphine (10 mg/kg, s.c.) induced hyperactivity as measured in mice. The morphine-induced hyperactivity was inhibited by pretreatment with glycine (100, 200 and 400 mg/kg, i.p.). In addition, it was found repeated administration of morphine (10 mg/kg, s.c.) to mice daily for 6 days caused an increase in motor activity which could be induced by a subsequent morphine dose, an effect known as reverse tolerance or sensitization. Glycine (100, 200 and 400 mg/kg, i.p.) also inhibited morphine-induced reverse tolerance. Mice that had received 7 daily repeated administrations of morphine also developed postsynaptic dopamine receptor supersensitivity, as shown by enhanced ambulatory activity after administration of apomorphine (2 mg/kg, s.c.). Glycine inhibited the development of postsynaptic dopamine receptor supersensitivity induced by repeated administration of morphine. It is suggested that the inhibitory effects of glycine might be mediated by dopaminergic (DAergic) transmission. Accordingly, the inhibition by glycine of the morphine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity suggests that glycine might be useful for the treatment of morphine addiction.     

Inhibition of diazepam on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity

The effects of diazepam on the development of reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine were examined in mice. A single administration of morphine induced hyperactivity and the morphine-induced hyperactivity was inhibited dose-dependently by the administration of diazepam (1, 2 and 4 mg x kg(-1), i.p.), an agonist for benzodiazepine receptor linked to the GABA(A) receptor. Daily repeated administration of morphine developed reverse tolerance to the hyperactivity of morphine. The concomitant administration of diazepam inhibited the morphine-induced hyperactivity and the diazepam administration prior to and during the chronic administration of morphine in mice inhibited the development of reverse tolerance to the hyperactivity of morphine (10 mg x kg(-1), s.c.). Postsynaptic dopamine receptor supersensitivity was also developed in reverse tolerant mice that had received the same morphine. The development of postsynaptic dopamine receptor supersensitivity was evidenced by the enhanced ambulatory activity of apomorphine (2 mg x kg(-1), s.c.). Diazepam also inhibited the development of postsynaptic dopamine receptor supersensitivity induced by the chronic administration of morphine. These results suggest that the hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine may be modulated via the activation of the GABA(A) receptor induced by diazepam.     

Inhibition of muscimol on morphine-induced hyperactivity,reverse tolerance and postsynaptic dopamine receptor supersensitivity

This study was performed to investigate the effect of muscimol on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice. A single administration of morphine induced hyperactivity as measured in mice, and the morphine-induced hyperactivity was inhibited dose-dependently by the administration of the GABA(A) agonist, muscimol (0.3, 0.5 and 1.0 mg kg(-1) i.p.). However, daily repeated administration of morphine caused the development of reverse tolerance against morphine hyperactivity (10 mg kg(-1) s.c.). The administration of muscimol inhibited the development of reverse tolerance against morphine hyperactivity (10 mg kg(-1) s.c.) in mice that had received chronic administration of morphine. Postsynaptic dopamine receptor supersensitivity, as shown by the enhanced ambulatory activity after administration of apomorphine (2 mg kg(-1) s.c.), also developed in reverse-tolerant mice. Muscimol also inhibited the development of postsynaptic dopamine receptor supersensitivity induced by the chronic administration of morphine. These results suggest that the hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine can be inhibited via the activation of GABA(A) receptors.     

Inhibition of baclofen on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity.

The effects of baclofen on the development of reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine were examined in mice. A single administration of morphine induced hyperactivity and the morphine-induced hyperactivity was inhibited dose dependently by the administration of a GABA(B)receptor agonist, baclofen (1.25, 2.5 and 5 mg kg(-1), i.p.). Daily repeated administration of morphine developed reverse tolerance to the hyperactivity of morphine. The concomitant administration of baclofen inhibited the morphine-induced hyperactivity and the baclofen administration prior to and during the chronic administration of morphine in mice inhibited the development of reverse tolerance to the hyperactivity of morphine (10 mg kg(-1), s.c.). Postsynaptic dopamine receptor supersensitivity was also developed in reverse-tolerant mice that had received the same morphine. The development of postsynaptic dopamine receptor supersensitivity was evidenced by the enhanced ambulatory activity of apomorphine (2 mg kg(-1), s.c.). Baclofen also inhibited the development of postsynaptic dopamine receptor supersensitivity induced by the chronic administration of morphine. These results suggest that the hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity induced by morphine may be modulated via the activation of GABA(B)receptors induced by baclofen.     

Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats

Rationale  While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. Objectives  To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT^−/−) rat and the involvement of compensatory changes in 5-HT_1A receptor function are the objectives of the study. Materials and methods  The SERT^−/− rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine self-administration. In addition, the function and expression of 5-HT_1A receptors was assessed using telemetry and autoradiography, respectively, and the effect of 5-HT_1A receptor ligands on cocaine’s psychomotor effects were studied. Results  Cocaine-induced hyperactivity and conditioned place preference, as well as intravenous cocaine self-administration were enhanced in SERT^−/− rats. Furthermore, SERT^−/− rats displayed a reduced hypothermic response to the 5-HT_1A receptor agonist 8-OHDPAT. S-15535, a selective somatodendritic 5-HT_1A receptor agonist, reduced stress-induced hyperthermia (SIH) in wild-type controls (SERT^+/+), while it increased SIH in SERT^−/− rats. As 5-HT_1A receptor binding was reduced in selective brain regions, these thermal responses may be indicative for desensitized 5-HT_1A receptors. We further found that both 8-OHDPAT and S-15535 pretreatment increased low-dose cocaine-induced locomotor activity in SERT^−/− rats, but not SERT^+/+ rats. At a high cocaine dose, only SERT^+/+ animals responded to 8-OHDPAT and S-15535. Conclusion  These data indicate that SERT^−/−-associated 5-HT_1A receptor adaptations facilitate low-dose cocaine effects and attenuate high-dose cocaine effects in cocaine supersensitive animals. The role of postsynaptic and somatodendritic 5-HT_1A receptors is discussed.     

delta-Subunit containing GABAA receptor knockout mice are less sensitive to the actions of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol

The pharmacological profile of a gamma-aminobutyric acid A (GABA(A)) receptor depends upon subunit composition. Studies using recombinant expression systems suggest that delta-subunit containing GABA(A) receptors are particularly sensitive to the actions of the GABA(A) partial agonist, 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP, gaboxadol). Here we investigated the actions of THIP in mutant mice lacking the GABA(A) receptor delta-subunit gene. Using the chloride flux assay, we determined that the actions of THIP were reduced by 21% in the cortical, but not cerebellar, membranes of knockout mice. Similar results were seen with another GABA(A) agonist, muscimol. Moreover, delta-subunit knockout mice exhibited a 54% reduction in sensitivity to the hypnotic actions of THIP as assessed by the loss of righting reflex test. These data support the notion that delta-containing GABA(A) receptors are at least partially responsible for the actions of THIP, and contribute to the growing literature suggesting that the pharmacological specificity of GABA(A) receptors depends on which subunits are present or absent.     

Opiate receptor supersensitivity produced by chronic naloxone treatment: dissociation of morphine-induced antinociception and conditioned taste aversion

In three separate experiments, rats were used to assess the effects of chronic administration of naloxone on specific binding of 3H-naloxone in various regions of the central nervous system (CNS) and on the efficacy of morphine to produce antinociception and a conditioned taste aversion. Chronic naloxone treatment increased opiate binding in medulla-pons, midbrain, hypothalamus, hippocampus, striatum, and prefrontal cortex, but not in either spinal cord or cerebellum. In those CNS regions exhibiting increased opiate binding, the duration of increased binding following termination of the naloxone treatment differed between regions. In conjunction with the increase in opiate binding, the efficacy of morphine to produce antinociception was potentiated, while the efficacy to produce a conditioned taste aversion was unchanged. Moreover, the administration of naloxone during behavioral testing blocked completely the antinociceptive effect, but not the aversive effect, of morphine. These results indicate that morphine-induced antinociception and conditioned taste aversion may be dissociated neuropharmacologically.     

Short-term steroid treatment increases delta GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects

In this study, 48 h administration of 3alpha-OH-5beta-pregnan-20-one (3alpha,5beta-THP) or 17beta-estradiol (E2)+progesterone (P) to female rats increased expression of the delta subunit of the GABA(A) receptor (GABAR) in CA1 hippocampus. Coexpression of alpha4 and delta subunits was suggested by an increased response of isolated pyramidal cells to the GABA agonist 4,5,6,7- tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), following 48 h steroid treatment, and nearly complete blockade by 300 microM lanthanum (La3+). Because alpha4betadelta GABAR are extrasynaptic, we also recorded pharmacologically isolated GABAergic holding current from CA1 hippocampal pyramidal cells in the slice. The La3+-sensitive THIP current, representative of current gated by alpha4betadelta GABAR, was measurable only following 48 h steroid treatment. In contrast, the bicuculline-sensitive current was not altered by steroid treatment, assessed with or without 200 nM gabazine to block synaptic current. However, 48 h steroid treatment resulted in a tonic current insensitive to the benzodiazepine agonists lorazepam (10 microM) and zolpidem (100 nM). These results suggest that 48 h steroid treatment increases expression of alpha4betadelta GABAR which replace the ambient receptor population. Increased anxiolytic effects of THIP were also observed following 48 h steroid treatment. The findings from the present study may be relevant for alterations in mood and benzodiazepine sensitivity reported across the menstrual cycle.     

Differential effects of dopamine D2 and GABAA receptor antagonists on dopamine neurons between the anterior and posterior ventral tegmental area of female Wistar rats

Previous findings indicated differences in neuronal circuitries mediating drug reinforcement between the anterior and posterior ventral tegmental area (VTA). The objective of the present study was to examine the effects of the dopamine D₂ antagonist sulpiride and the GABA_A antagonist picrotoxin administered in the anterior and posterior VTA on the activity of mesoaccumbal dopamine neurons in female Wistar rats. Sulpiride and picrotoxin were administered in the anterior and posterior VTA. Extracellular dopamine levels were measured in sub-regions of the VTA and nucleus accumbens (ACB). Reverse-microdialysis of sulpiride (100 µM) into the posterior VTA increased extracellular dopamine levels locally (80% above baseline) and in the ACB shell and core (70% above baseline), whereas reverse-microdialysis into the anterior VTA produced a much smaller effect locally (30% above baseline) and in the ACB shell and core. In contrast, microinjection of picrotoxin (80 and 160 µM) into the anterior, but not posterior VTA, increased dopamine release in the ACB shell. The results suggest that dopamine neurons in the posterior VTA, compared to the anterior VTA, may be under greater D₂ receptor-mediated tonic inhibition, whereas dopamine neurons in the anterior VTA, compared to the posterior VTA, may be under greater GABA_A receptor-mediated tonic inhibition.     

Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids

Effects of common monoterpenoid alcohols and ketones were investigated on recombinant human gamma-aminobutyric acid A (GABAA; alpha1beta2gamma2s) and glycine (alpha1 homomers) receptors expressed in Xenopus oocytes. GABA currents were enhanced by coapplications of 10-300 microM: (+)-menthol>(-)-menthol>(-)-borneol>(-)-menthone=camphor enantiomers>carvone enantiomers, with menthol acting stereoselectively. By contrast, thujone diastereomers inhibited GABAA receptor currents while glycine currents were only markedly potentiated by menthol. Positive modulation by (+)-menthol was explored given its pronounced effects (e.g., at 100 microM, GABA and glycine EC20 responses increased by 496+/-113% and 135+/-56%, respectively). (+)-Menthol, 100 microM, reduced EC50 values for GABA and glycine from 82.8+/-9.9 to 25.0+/-1.8 microM, and from 98.7+/-8.6 to 75.7+/-9.4 microM respectively, with negligible effects on maximal currents. This study reveals a novel neuroactive role for menthol as a stereoselective modulator of inhibitory ligand-gated channels.     

Additive inhibition of lordosis by simultaneous treatments with GABA(A) and GABA(B) receptor agonists, muscimol and baclofen, in female rats

In order to investigate the relationship between GABA_A and GABA_B receptors in the induction of lordosis behavior, agonists of these receptor subtypes were injected simultaneously to estrogen-treated ovariectomized rats and lordosis behavior was observed before and after the injections. The GABA_A receptor agonist, muscimol (MUS), at a dose in the range from 1.0 to 1.4 mg/kg body weight (bw) or the GABA_B receptor agonist, baclofen (BAC) at a dose in the range from 1 to 10 mg/kg bw, was injected intraperitoneally. The lordosis quotient (LQ) decreased after treatments with MUS or BAC and a dose-dependent decrease of LQ was observed in MUS or BAC-treated rats. When 1.2 mg/kg bw MUS and 5 mg/kg bw BAC were injected simultaneously, the mean LQ decreased strongly and was significantly lower than the values obtained after single injections of the agonists at these doses (P < 0.05). In addition, to ascertain the time-course of changes, a behavioral test was carried out 7 times from 15 to 180 min after the injection of agonists. The low LQ in the rats injected with both MUS and BAC continued longer than in rats given single injections. These results indicate that both GABA_A and GABA_B receptors are involved in lordosis-inhibiting mechanisms by the GABA neuron and operate independently.     

Chronic progesterone treatment augments while dehydroepiandrosterone sulphate prevents tolerance to ethanol anxiolysis and withdrawal anxiety in rats

We have recently shown that the neurosteroid allopregnanolone modulates anxiolytic effect of ethanol. In the present report, we attempted to examine whether neurosteroids progesterone and dehydroepiandrosterone sulphate (DHEAS), which modulate gamma-aminobutyric acid (GABA(A)) receptor function, affects development of tolerance to ethanol anxiolysis and withdrawal anxiety. Rats on ethanol (6% v/v in nutritionally balanced liquid diet) for prolong period (10 days) were injected twice daily either with vehicle, progesterone (a precursor of allopregnanolone, positive GABA(A) receptor modulator), finasteride (5alpha-reductase inhibitor) or DHEAS (negative GABA(A) receptor modulator). During this period, rats were acutely challenged periodically with ethanol (2 g/kg, i.p., 8% w/v) and subjected to the elevated plus maze test. For withdrawal studies, similar treatment protocols (except ethanol challenge) were employed and on day 11, rats were subjected to the elevated plus maze test at different time intervals post-ethanol withdrawal. While progesterone significantly advanced the development of tolerance to ethanol anxiolysis and enhanced withdrawal anxiety, DHEAS and finasteride prevented such behavioral alterations. These data highlight the important role played by GABAergic neurosteroids progesterone and DHEAS in the development of tolerance to ethanol anxiolysis and withdrawal anxiety in rats. Moreover, it points to the potential usefulness of specific neurosteroids as targets in the treatment of alcoholism.     

Pharmacology of structural changes at the GABA(A) receptor transmitter binding site

BACKGROUND AND PURPOSE

The binding of transmitter to specialized binding pockets leads to rearrangements in the structure of the receptor eventually resulting in channel opening. We used voltage-clamp fluorometry to investigate the pharmacological basis and biophysical processes that underlie structural changes at the transmitter binding site of the rat α1β2γ2L GABA_A receptor.

EXPERIMENTAL APPROACH

Simultaneous electrophysiological and site-specific fluorescence measurements were conducted on receptors expressed in Xenopus oocytes and labelled with an environmentally-sensitive fluorophore, Alexa 546 maleimide, at the α1L127C site.

KEY RESULTS

Receptors activated by GABA demonstrate a concentration-dependent increase in fluorescence intensity, indicating that the environment surrounding the fluorophore becomes less polar upon activation. Qualitatively similar responses were observed with other GABA site ligands such as piperidine-4-sulphonic acid, muscimol, β-alanine and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. Fluorescence changes were not affected by the direction of current flow. During long applications of GABA significant desensitization developed, which was not accompanied by additional changes in fluorescence. Pentobarbital was an efficacious agonist of the labelled mutant receptor but did not cause changes in fluorescence. Direct activation by etomidate or the steroid allopregnanolone also did not result in fluorescence changes. Functional potentiation of GABA-activated receptors by allopregnanolone or etomidate enhanced both the GABA-elicited functional response and the fluorescence change. In contrast, potentiation by pentobarbital was not accompanied by an enhanced fluorescence response.

CONCLUSIONS AND IMPLICATIONS

The data indicate that there is no direct correlation between current flow or position of the activation gate and the structural changes as detected by Alexa 546-labelled α1L127Cβ2γ2L GABA_A receptors. Channel potentiation by pentobarbital qualitatively differs from potentiation by etomidate or allopregnanolone.     

Adenosine A2A receptor-induced inhibition of NMDA and GABAA receptor-mediated synaptic currents in a subpopulation of rat striatal neurons

The function of adenosine A(2A) receptors, localized at the enkephalin-containing GABAergic medium spiny neurons of the striatum, has been discussed controversially. Here we show that, in the absence of external Mg(2+), the adenosine A(2A) receptor agonist CGS 21680 postsynaptically depressed the NMDA, but not the non-NMDA (AMPA/kainate) receptor-mediated fraction of the electrically evoked EPSCs in a subpopulation of striatal neurons. Current responses to locally applied NMDA but not AMPA were also inhibited by CGS 21680. However, in the presence of external Mg(2+), the inhibition by CGS 21680 of the GABA(A) receptor-mediated IPSCs led to a depression of the EPSC/IPSC complexes. The current response to the locally applied GABA(A) receptor agonist muscimol was unaltered by CGS 21680. Whereas, the frequency of spontaneous (s)IPSCs was inhibited by CGS 21680, their amplitude was not changed. Hence, it is suggested that under these conditions the release rather than the postsynaptic effect of GABA was affected by CGS 21680. In conclusion, under Mg(2+)-free conditions, CGS 21680 appeared to postsynaptically inhibit the NMDA receptor-mediated component of the EPSC, while in the presence of external Mg(2+) this effect turned into a presynaptic inhibition of the GABA(A) receptor-mediated IPSC.     

Inhibition by ginsenosides Rb1 and Rg1 of cocaine-induced hyperactivity, conditioned place preference, and postsynaptic dopamine receptor supersensitivity in mice.

A single or repeated administration of cocaine (15 mg/kg) in mice produced hyperactivity and conditioned place preference (CPP). Ginsenoside Rb1 (Rb1) and ginsenoside Rg1 (Rg1), prior to and during the cocaine treatment in mice, inhibited cocaine-induced hyperactivity and CPP. The development of enhanced postsynaptic dopamine (DA) receptor sensitivity in mice displaying a cocaine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg). Rb1 and Rg1 inhibited the development of postsynaptic DA receptor supersensitivity. However, Rb1 and Rg1 did not show any antidopaminergic activity at the postsynaptic DA receptors, because the apomorphine-induced climbing behavior was not inhibited by Rb1 and Rg1. Therefore, it is presumed that Rb1 and Rg1 modulate DA activity induced by cocaine at the presynaptic DA receptors, and this modulation results in the inhibition of postsynaptic dopaminergic activation. These results suggest that the cocaine-induced CPP may be associated with enhanced DA receptor sensitivity. The inhibition by Rb1 and Rg1 of cocaine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by cocaine at the presynaptic DA receptors.     

Determinants of amentoflavone interaction at the GABA(A) receptor

We investigated the recognition properties of different GABA(A) receptor subtypes and mutant receptors for the biflavonoid amentoflavone, a constituent of St. John's Wort. Radioligand binding studies showed that amentoflavone recognition paralleled that of the classical benzodiazepine diazepam in that it had little or no affinity for alpha4- or alpha6-containing receptors. Lysine and alanine substitutions at position 101 of the rat alpha1 subunit resulted in a complete loss of competitive amentoflavone binding, but functional analysis of the alanine mutant expressed with beta2 and gamma2 subunits in Xenopus oocytes revealed no significant difference in the negative modulation of GABA-induced currents brought about by amentoflavone. Furthermore, elimination of the gamma subunit had no effect on the negative modulation of these currents. This negative modulation was also observed at alpha1beta1gamma2 GABA(A) receptors and is therefore not likely mediated by the loreclezole site. These results suggest a complex mechanism of amentoflavone interaction at GABA(A) receptors.     

Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice

• 1.1. Ginseng total saponin (GTS), 200 mg/kg i.p. 3 hr prior to morphine, inhibited the development of reverse tolerance to the ambulatory-accelerating effect of morphine.
• 2.2. GTS, 200 mg/kg, also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of morphine, 10 mg/kg a day for 7 days.
• 3.3. These results suggest that GTS may be useful for the prevention and therapy of the adverse action of morphine.

     

Failure of apomorphine to induce dopamine receptor hypersensitivity

A pomorphine, a direct dopamine agonist, failed to induce the so called dopamine receptor supersensitivity. Furthermore, a review of the evidence strongly suggests that the mechanisms involved in this phenomenon are not purely dopaminergic. This phenomenon is more complex than one of simple changes in the sensitivity or number of a particular type of receptor. Also sexual differences were observed and the literature suggest an involvement of serotoninergic mechanisms in stereotyped behavior.     

Abnormal synaptic plasticity in basolateral amygdala may account for hyperactivity and attention-deficit in male rat exposed perinatally to low-dose bisphenol-A

If the pregnant and lactating female rats are exposed to environmental levels of bisphenol-A (BPA), their male offspring will display hyperactivity and attention-deficit. In patients with attention-deficit/hyperactivity disorder (ADHD), the size of the amygdala is reported to be reduced. This study examined functional alterations in the basolateral amygdala (BLA) of the postnatal 28-day-old male offspring exposed perinatally to BPA (BPA-rats). We specifically focused on the synaptic properties of GABAergic/dopaminergic systems in the BLA. A single electrical stimulation of the capsule fibers evoked multispike responses with an enhanced primary population spikes (1st-PS) in the BPA-rats. A single train of high-frequency stimulation of the fibers induced NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in BPA-rats, but not in control rats. Also, paired-pulse inhibition (PPI, GABA-dependent) in control rats was reversed to paired-pulse facilitation (PPF) in BPA-rats. Perfusion of slices obtained from BPA-rats with the GABA_A receptor (GABA_AR) agonist muscimol blocked the multispike responses and LTP, and recovered PPI. By contrast, the dopamine D1 receptor antagonist SCH23390 abolished LTP and attenuated the increased amplitude of 1st-PS in BPA-rats. Conversely, blockade of GABA_AR by bicuculline could produce the multispike responses and PPF in BLA in control rats. Furthermore, in BLA the infusion of SCH23390, muscimol or the NMDAR blocker MK801 ameliorated the hyperactivity and improved the deficits in attention. These findings suggest that the perinatal exposure to BPA causes GABAergic disinhibition and dopaminergic enhancement, leading to an abnormal cortical-BLA synaptic transmission and plasticity, which may be responsible for the hyperactivity and attention-deficit in BPA-rats.This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’.     

Roles of BDNF, dopamine D3 receptors, and their interactions in the expression of morphine-induced context-specific locomotor sensitization

Drug seeking, craving, and relapse can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. Previous studies indicated that the dopamine D₃ receptor (Drd3) might be involved in the expression of drug-conditioned responses in rats, and brain-derived neurotrophic factor (BDNF) could modulate Drd3 expression in the nucleus accumbens (NAc). However, the involvement of neural regions with Drd3 activation and the underlying interaction between BDNF and Drd3 in the expression of behavioral responses controlled by a drug-associated environment have remained poorly understood. The present study used a conditioning procedure to assess the roles of BDNF, Drd3, and their interactions in the NAc in the expression of morphine-induced context-specific locomotor sensitization. We showed that the expression of locomotor sensitization in the morphine-paired environment was accompanied by significantly increased expression of Drd3 mRNA and BDNF mRNA and protein levels. Both sensitized locomotion in morphine-paired rats and enhanced Drd3 mRNA were suppressed by intra-NAc infusion of anti-tyrosine kinase receptor B (TrkB) IgG. Furthermore, intra-NAc infusion of the Drd3-selective antagonist SB-277011A significantly decreased the expression of context-specific locomotor sensitization and upregulated BDNF mRNA. Altogether, these results suggest that BDNF/TrkB signaling and activation of Drd3 in the NAc are required for the expression of morphine-induced context-specific locomotor sensitization.