[show abstract][hide abstract] ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.
PLoS ONE 01/2013; 8(5):e64541. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Endocannabinoids serve as retrograde signaling molecules at many synapses within the CNS, particularly GABAergic and glutamatergic synapses. Synapses onto midbrain dopamine (DA) neurons in the ventral tegmental area (VTA) make no exception to this rule. In fact, the effects of cannabinoids on dopamine transmission as well as DA-related behaviors are generally exerted through the modulation of inhibitory and excitatory afferents impinging onto DA neurons. Endocannabinoids, by regulating different forms of synaptic plasticity in the VTA, provide a critical modulation of the DA neuron output and, ultimately, of the systems driving and regulating motivated behaviors. Because DA cells exhibit diverse states of activity, which crucially depend on their intrinsic properties and afferent drive, the understanding of the role played by endocannabinoids in synaptic modulations is critical for their overall functions. Particularly, endocannabinoids by selectively inhibiting afferent activity may alter the functional states of DA neurons and potentiate the responsiveness of the reward system to phasic DA.
[show abstract][hide abstract] ABSTRACT: The rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area (VTA), is an important site involved in aversion processes. The RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding dopamine (DA) neurons in the VTA. Here, we studied how RMTg neurons regulate both spontaneous firing of DA cells and their response to the cannabinoid agonist WIN55212-2 (WIN), morphine, cocaine, and nicotine. We utilized single-unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to study RMTg-induced inhibition of DA cells and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of caudal afferents, respectively. The electrical stimulation of the RMTg elicited a complete suppression of spontaneous activity in approximately half of the DA neurons examined. RMTg-induced inhibition correlated with firing rate and pattern of DA neurons and with their response to a noxious stimulus, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA cells. Both morphine and WIN depressed RMTg-induced inhibition of DA neurons in vivo and IPSCs evoked by RMTg stimulation in brain slices with presynaptic mechanisms. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results further support the role of the RMTg as one of the main inhibitory afferents to DA cells and suggest that cannabinoids and opioids might disinhibit DA neurons by profoundly influencing synaptic responses evoked by RMTg activation.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2011; 37(5):1164-76. · 6.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by α7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2010; 36(3):589-602. · 6.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme that degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single-unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptor. URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system.
[show abstract][hide abstract] ABSTRACT: Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.
Journal of Neuroscience 01/2009; 28(51):13985-94. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sardinian alcohol-preferring (sP) or -nonpreferring (sNP) rats are one of the few pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, respectively. Ventral tegmental area (VTA) dopamine (DA) neurons have long been implicated in many drug-related behaviors, including alcohol self-administration. However, the electrophysiological properties of these cells in sP and sNP rats remain unknown.
This study was designed to examine the properties of posterior VTA DA neurons and to unveil functional differences between sP and sNP rats.
The electrophysiological properties of DA cells were examined performing either single-cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices.
Extracellular single-unit recordings revealed an increased spontaneous activity in sP rats. However, a corresponding difference was not found in vitro. Moreover, DA cells of sP and sNP rats showed similar intrinsic properties, suggesting changes at synaptic level. Therefore, inhibitory- and excitatory-mediated currents were studied. A decreased probability of GABA release was found in sP rats. Additionally, sP rats showed a reduced depolarization-induced suppression of inhibition, which is an endocannabinoid-mediated form of short-term plasticity. Additionally, the effect of cannabinoid-type 1 (CB1) receptor agonist WIN55,212-2 on GABAA IPSCs was smaller in sP rats, suggesting either a reduced number or functionality of CB1 receptors in the VTA.
Our findings suggest that both decreased GABA release and endocannabinoid transmission in the VTA play a role in the increased impulse activity of DA cells and, ultimately, in alcohol preference displayed by sP rats.
[show abstract][hide abstract] ABSTRACT: Endocannabinoid-mediated forms of transient synaptic depression have been described in several brain structures, including the dopaminergic ventral tegmental area (VTA). However, their functional and/or behavioural correlates are yet to be determined.
The present study was designed to investigate whether back-propagating action potentials in dopamine (DA) neurons, evoked by the stimulation of the medial forebrain bundle (MFB), could trigger endocannabinoid-mediated forms of synaptic modulation. The MFB contains axons ascending from DA neurons to the nucleus accumbens and other forebrain structures, and its stimulation is rewarding because it elicits intra-cranial self-stimulation.
Single cell extracellular recordings were carried out from anti-dromically identified VTA DA neurons in chloral hydrate anesthetized rats.
DA neurons responded to MFB stimulation (1 s, 20-80 Hz) with a frequency-dependent increase in spontaneous firing rate, which was enhanced by the cannabinoid type-1 receptor antagonist SR141716A (1 mg/kg) and depressed by the agonist WIN55212-2 (0.125 mg/kg). Increasing brain levels of the endocannabinoid anandamide by blocking its major hydrolysing enzyme, fatty-acid amide hydrolase, with URB597 (0.1 mg/kg) was ineffective, whereas blockade of the endocannabinoid membrane transporter with UCM707 (1 mg/kg) enhanced post-stimulus firing rate.
Our study indicates that stimulation of the MFB evokes an endocannabinoid-mediated short-term modulation of DA neuron activity. Thus, endocannabinoids might play an important role in the mechanisms underlying the rewarding properties of MFB stimulation.
[show abstract][hide abstract] ABSTRACT: Endocannabinoids act as neuroprotective molecules promptly released in response to pathological stimuli. Hence, they may represent one component of protection and/or repair mechanisms mobilized by dopamine (DA) neurons under ischemia. Here, we show that the endocannabinoid 2-arachidonoyl-glycerol (2-AG) plays a key role in protecting DA neurons from ischemia-induced altered spontaneous activity both in vitro and in vivo. Accordingly, neuroprotection can be elicited through moderate cannabinoid receptor type-1 (CB1) activation. Conversely, blockade of endocannabinoid actions through CB1 receptor antagonism worsens the outcome of transient ischemia on DA neuronal activity. These findings indicate that 2-AG mediates neuroprotective actions by delaying damage and/or restoring function of DA cells through activation of presynaptic CB1 receptors. Lastly, they point to CB1 receptors as valuable targets in protection of DA neurons against ischemic injury and emphasize the need for a better understanding of endocannabinoid actions in the fine control of DA transmission.
Neurobiology of Disease 11/2006; 24(1):15-27. · 5.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: The noradrenergic pathway arising from the locus coeruleus (LC) is involved in the regulation of attention, arousal, cognitive processes and sleep. These physiological activities are affected by Cannabis exposure - both in humans and laboratory animals. In addition, exogenous cannabinoids, as well as pharmacological and genetic manipulation of the endocannabinoid system, are known to influence emotional states (e.g. anxiety) for which a contributory role of the LC-noradrenergic system has long been postulated. However, whether cannabinoid administration would affect the LC neuronal activity in vivo is still unknown. To this end, single-unit extracellular recordings were performed from LC noradrenergic cells in anaesthetized rats. Intravenous injection of both the synthetic cannabinoid agonist, WIN55212-2, and the main psychoactive principle of Cannabis, Delta9-tetrahydrocannabinol, dose-dependently increased the firing rate of LC noradrenergic neurons, with WIN55212-2 being the most efficacious. Similar results were obtained by the administration of these drugs into a lateral ventricle. Cannabinoid-induced stimulation of LC noradrenergic neuronal activity was counteracted by SR141716A, a cannabinoid receptor antagonist/reverse agonist, which by itself slightly reduced LC discharge rate. Moreover, WIN55212-2 suppressed the inhibition of noradrenergic cells produced by stimulation of the major gamma-aminobutyric acid (GABA)ergic afferent to the LC, the nucleus prepositus hypoglossi. Altogether, these findings suggest the involvement of noradrenergic pathways in some consequences of Cannabis intake (e.g. cognitive and attention deficits, anxiety reactions), as well as a role for cannabinoid receptors in basic brain activities sustaining arousal and emotional states.
European Journal of Neuroscience 06/2006; 23(9):2385-94. · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several lines of evidence indicate that the endogenous cannabinoid system is involved in the pharmacological and behavioural effects of alcohol. The mesolimbic dopaminergic (DA) system and the nucleus accumbens (NAc) process rewarding properties of drugs of abuse, including alcohol and cannabinoids, whereas endocannabinoids in these regions modulate synaptic function and mediate short- and long-term forms of synaptic plasticity.
The present study was designed to investigate the contribution of the endogenous cannabinoid system in alcohol electrophysiological effects in the mesolimbic reward circuit.
We utilized extracellular single cell recordings from ventral tegmental area (VTA) DA and NAc neurons in anesthetized rats. DA neurons were antidromically identified as projecting to the shell of NAc, whereas NAc putative medium spiny neurons were identified by their evoked responses to basolateral amygdala (BLA) stimulation.
Alcohol stimulated firing rate of VTA DA neurons and inhibited BLA-evoked NAc neuron spiking responses. The cannabinoid type-1 receptor (CB1) antagonist rimonabant (SR141716A) fully antagonized alcohol effect in both regions. In the NAc, either inhibition of the major catabolic enzyme of the endocannabinoid anandamide, the fatty-acid amyd hydrolase, with URB597 or a pretreatment with the CB1 receptor agonist WIN55212-2 significantly depressed alcohol-induced effects in the NAc.
These results corroborate the notion of the involvement of endocannabinoids and their receptors in the actions of alcohol and highlight the endocannabinoid system as a valuable target in the therapy for alcoholism.
[show abstract][hide abstract] ABSTRACT: Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid naturally occurring in the mammalian brain, which recently emerged as a major recreational drug of abuse. GHB has multiple neuronal mechanisms including activation of both the GABA(B) receptor, and a distinct GHB-specific receptor. This complex GHB-GABA(B) receptor interaction is probably responsible for the multifaceted pharmacological, behavioral and toxicological profile of GHB. Drugs of abuse exert remarkably similar effects upon reward-related circuits, in particular the mesolimbic dopaminergic system and the nucleus accumbens (NAc). We used single unit recordings in vivo from urethane-anesthetized rats to characterize the effects of GHB on evoked firing in NAc "shell" neurons and on spontaneous activity of antidromically identified dopamine (DA) cells located in the ventral tegmental area. GHB was studied in comparison with the GABA(B) receptor agonist baclofen and antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911). Additionally, we utilized a GHB analog, gamma-(p-methoxybenzil)-gamma-hydroxybutyric acid (NCS-435), devoid of GABA(B) binding properties, but with high affinity for specific GHB binding sites. In common with other drugs of abuse, GHB depressed firing in NAc neurons evoked by the stimulation of the basolateral amygdala. On DA neurons, GHB exerted heterogeneous effects, which were correlated to the baseline firing rate of the cells but led to a moderate stimulation of the DA system. All GHB actions were mediated by GABA(B) receptors, since they were blocked by SCH50911 and were not mimicked by NCS-435. Our study indicates that the electrophysiological profile of GHB is close to typical drugs of abuse: both inhibition of NAc neurons and moderate to strong stimulation of DA transmission are distinctive features of diverse classes of abused drugs. Moreover, it is concluded that addictive and rewarding properties of GHB do not necessarily involve a putative high affinity GHB receptor.
[show abstract][hide abstract] ABSTRACT: Endocannabinoids form a novel class of retrograde messengers that modulate short- and long-term synaptic plasticity. Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) are the best characterized transient forms of endocannabinoid-mediated synaptic modulation. Stimulation protocols consisting of long-lasting voltage steps to the postsynaptic cell are routinely used to evoke DSE-DSI. Little is known, however, about more physiological conditions under which these molecules are released in vitro. Moreover, the occurrence in vivo of such forms of endocannabinoid-mediated modulation is still controversial. Here we show that physiologically relevant patterns of synaptic activity induce a transient suppression of excitatory transmission onto dopamine neurons in vitro. Accordingly, in vivo endocannabinoids depress the increase in firing and bursting activity evoked in dopamine neurons by prefrontal cortex stimulation. This phenomenon is selectively mediated by the endocannabinoid 2-arachidonoyl-glycerol (2-AG), which activates presynaptic cannabinoid type 1 receptors. 2-AG synthesis involves activation of metabotropic glutamate receptors and Ca2+ mobilization from intracellular stores. These findings indicate that dopamine neurons release 2-AG to shape afferent activity and ultimately their own firing pattern. This novel endocannabinoid-mediated self-regulatory role of dopamine neurons may bear relevance in the pathogenesis of neuropsychiatric disorders such as schizophrenia and addiction.
Journal of Neuroscience 12/2004; 24(47):10707-15. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent studies have raised concerns about subtle long-lasting neurobiological changes that might be triggered by exposure to Cannabis derivatives, especially in a critical phase of brain maturation, such as puberty. The mesolimbic dopamine (DA) system, involved in the processing of drug-induced reward, is a locus of action of cannabinoids and endocannabinoids. Thus, we compared the effects of repeated cannabinoid administration in adolescent and adult rats on DA neuronal functions and responses to drugs of abuse.
Single-unit extracellular recordings from antidromically identified mesoaccumbens DA neurons and from their target cells in the nucleus accumbens were carried out in urethane-anesthetized rats. Animals were pretreated during adolescence or adulthood, for 3 days, with the cannabinoid agonist WIN55212.2 (WIN) or vehicle and allowed a 2-week interval.
In cannabinoid-administered rats, DA neurons were significantly less responsive to the stimulating action of WIN, regardless of the age of pretreatment; however, in the adolescent group, but not in the adult, long-lasting cross-tolerance developed to morphine, cocaine, and amphetamine.
Our study suggests that an enduring form of neuronal adaptation occurs in DA neurons after subchronic cannabinoid intake at a young age, affecting subsequent responses to drugs of abuse.
[show abstract][hide abstract] ABSTRACT: The endogenous cannabinoid system has been shown to play a crucial role in controlling neuronal excitability and synaptic transmission. In this study we investigated the effects of a cannabinoid receptor (CB-R) agonist WIN 55,212-2 (WIN) on excitatory synaptic transmission in the rat ventral tegmental area (VTA). Whole-cell patch clamp recordings were performed from VTA dopamine (DA) neurons in an in vitro slice preparation. WIN reduced both NMDA and AMPA EPSCs, as well as miniature EPSCs (mEPSCs), and increased the paired-pulse ratio, indicating a presynaptic locus of its action. We also found that WIN-induced effects were dose-dependent and mimicked by the CB1-R agonist HU210. Furthermore, two CB1-R antagonists, AM281 and SR141716A, blocked WIN-induced effects, suggesting that WIN modulates excitatory synaptic transmission via activation of CB1-Rs. Our additional finding that both AM281 and SR141716A per se increased NMDA EPSCs suggests that endogenous cannabinoids, released from depolarized postsynaptic neurons, might act retrogradely on presynaptic CB1-Rs to suppress glutamate release. Hence, we report that a type of synaptic modulation, previously termed depolarization-induced suppression of excitation (DSE), is present also in the VTA as a calcium-dependent phenomenon, blocked by both AM281 and SR141716A, and occluded by WIN. Importantly, DSE was partially blocked by the D2DA antagonist eticlopride and enhanced by the D2DA agonist quinpirole without changing the presynaptic cannabinoid sensitivity. These results indicate that the two pathways work in a cooperative manner to release endocannabinoids in the VTA, where they play a role as retrograde messengers for DSE via CB1-Rs.
Journal of Neuroscience 02/2004; 24(1):53-62. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent evidence indicates that the basolateral amygdala (BLA) may be involved in behavioural effects induced by cannabinoids. High levels of CB1 cannabinoid receptors have been shown in this region, where they modulate excitatory and inhibitory synaptic transmission. However, the neurophysiological effects of these opposing synaptic actions have not been investigated in vivo. To this purpose, single-unit extracellular recordings were performed in urethane anaesthetized rats in order to determine whether exogenously applied cannabinoids influenced the spontaneous or evoked electrical activity of neurons in the BLA. The effects of cannabinoids were found to be dependent on the characteristics of the neurons examined and on the properties of the agents used. We tested and compared two structurally different synthetic cannabinoid receptor agonists, the highly potent HU-210 (0.125-1.0 mg/kg, i.v.) and WIN55212-2 (WIN, 0.125-1.0 mg/kg, i.v.). With a CB1 cannabinoid receptor-dependent mechanism, HU-210 potently inhibited the firing rate of BLA interneurons whereas WIN modulated the discharge rate in a biphasic manner. By contrast, BLA projection neurons, antidromically identified from the shell of the nucleus accumbens, were significantly inhibited by WIN at all doses tested, while HU-210 administration led to less consistent effects, since only 1.0 mg/kg inhibited firing rate in the majority of recorded neurons. Additionally, WIN, but not HU-210, significantly attenuated short-latency spiking activity in BLA projection neurons evoked by electrical stimulation of the medial prefrontal cortex. In these neurons, WIN-induced effects were antagonised by the non-selective cannabinoid receptor antagonist SR141716A and by the vanilloid receptor antagonist capsazepine, but not by the selective CB1 antagonist AM-251. Taken together, our findings indicate that the overall excitability of efferent neurons in the BLA is strongly reduced by WIN in a non-CB1-dependent manner. In this effect, the contribution of a novel cannabinoid-vanilloid-sensitive putative non-CB1 receptors, the existence of which was postulated in recent reports, might play a role.
[show abstract][hide abstract] ABSTRACT: The nucleus accumbens (NAc) represents a critical site for the rewarding properties of diverse classes of drugs of abuse. Glutamatergic afferents to the NAc are involved in the actions of psychostimulants and opioids, while the potentiation of dopaminergic neurotransmission in the NAc is a common feature of abused drugs, including cannabinoids. Cannabinoid receptors (CB1) are densely expressed in regions that provide excitatory innervation to the NAc, such as the amygdala, the cortex and the hippocampus. Recent in vitro evidence suggests that indeed cannabinoids modulate glutamatergic synapses in the NAc. In this study we recorded extracellularly from neurons in the shell of the NAc which responded to the stimulation of the baso-lateral amygdala (BLA) or the medial prefrontal cortex (PFC) in urethane anaesthetized rats. BLA or PFC stimulation induced generation of action potentials in NAc neurons. This excitatory effect was strongly inhibited by the synthetic cannabinoid agonists WIN 55212,2 (0.062-0.25 mg/kg, i.v.) and HU-210 (0.125-0.25 mg/kg, i.v.) or the psychoactive principle of Cannabis delta(9)-tetrahydrocannabinol (1.0 mg/kg, i.v.). Neither the D1 or D2 dopamine receptor antagonists (SCH23390 0.5-1.0 mg/kg, sulpiride 5-10 mg/kg, i.v.) or the opioid antagonist naloxone (1.0 mg/kg, i.v.) were able to reverse the action of cannabinoids, while the selective CB1 receptor antagonist/reverse agonist SR141716A (0.5 mg/kg, i.v.) fully suppressed the action of cannabinoid agonists, whereas per se had no significant effect. These results provide evidence that cannabinoids, in common with other drugs of abuse, in vivo strongly inhibit the excitability of neurons in the shell of the NAc.
European Journal of Neuroscience 07/2002; 15(11):1795-802. · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cellular substrates of opiate withdrawal syndrome involve several brain areas, in particular the mesolimbic dopaminergic and noradrenergic systems, but the interactions between the two pathways remain unclear.
The aim of the present work was to investigate the effects of the alpha2-agonist clonidine on ventral tegmental area dopamine neurons during morphine withdrawal syndrome by recording their neuronal activity before and after the administration of low and relatively high doses of clonidine (from 5 to 100 microg/kg).
The spontaneous neuronal activity of meso-accumbens dopaminergic neurons, identified by antidromical stimulation from the nucleus accumbens, was recorded by use of in vivo extracellular single-unit recordings in control and morphine-withdrawn rats after chronic administration (15 days).
Control rats showed a mean spontaneous firing frequency of 2.47+/-0.48 Hz, percentage of burst firing of 22+/-12 and an increase in firing after the administration of cumulative doses of clonidine (5, 10, 20, 40, 100 microg/kg). Conversely, both spontaneous firing rate (1.55+/-0.25 Hz) and the percentage of burst firing (5+/-2) were found to be significantly reduced in rats abstinent for 24 h, and increasing doses of clonidine did not re-establish electrophysiological activity observed in the controls.
The results indicate that: 1) clonidine did not restore the decreased firing activity of DA neurons in morphine-withdrawn rats, and 2) high doses of clonidine increased firing in control rats but not in morphine-withdrawn rats.