Striatopallidal Transmission Research Articles

Striatal μ-opioid receptor activation triggers direct-pathway GABAergic plasticity and induces negative affect.

Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which may drive relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain μ-opioid receptors (MORs). It remains unclear how chronic opioid exposure and withdrawal impact these MOR-expressing dMSNs and their outputs. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, withdrawal from repeated morphine or fentanyl administration potentiated this GABAergic transmission. Furthermore, intravenous fentanyl self-administration enhanced GABAergic striatonigral transmission and reduced midbrain dopaminergic activity. Fentanyl-activated striatal neurons mediated contextual memory retrieval required for conditioned place preference tests. Importantly, chemogenetic inhibition of striatal MOR+ neurons rescued fentanyl withdrawal-induced physical symptoms and anxiety-like behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, which may promote negative emotions and relapse.

Dysregulation of external globus pallidus-subthalamic nucleus network dynamics in parkinsonian mice during cortical slow-wave activity and activation.

Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Using cell class-specific optogenetic identification and inhibition during cortical slow-wave activity and activation, we report that, in dopamine-depleted mice, (1) D2 dopamine receptor expressing striatal projection neurons (D2-SPNs) discharge at higher rates, especially during cortical activation, (2) prototypic parvalbumin-expressing GPe neurons are excessively patterned by D2-SPNs even though their autonomous activity is upregulated, (3) despite being disinhibited, STN neurons are not hyperactive, and (4) STN activity opposes striatopallidal patterning. These data argue that in parkinsonian mice abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment. Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally positioned network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Following the loss of dopamine, the activities of GPe and STN neurons become more temporally offset and strongly correlated with cortical oscillations below 40Hz. Previous studies utilized cortical slow-wave activity and/or cortical activation (ACT) under anaesthesia to probe the mechanisms underlying the normal and pathological patterning of basal ganglia activity. Here, we combined this approach with in vivo optogenetic inhibition to identify and interrupt the activity of D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs), parvalbumin-expressing prototypic GPe (PV GPe) neurons, and STN neurons. We found that, in dopamine-depleted mice, (1) the firing rate of D2-SPNs was elevated, especially during cortical ACT, (2) abnormal phasic suppression of PV GPe neuron activity was ameliorated by optogenetic inhibition of coincident D2-SPN activity, (3) autonomous PV GPe neuron firing ex vivo was upregulated, presumably through homeostatic mechanisms, (4) STN neurons were not hyperactive, despite being disinhibited, (5) optogenetic inhibition of the STN exacerbated abnormal GPe activity, and (6) exaggerated beta band activity was not present in the cortex or GPe-STN network. Together with recent studies, these data suggest that in dopamine-depleted mice abnormally correlated and temporally offset PV GPe and STN neuron activity is generated in part by elevated striatopallidal transmission, while compensatory plasticity prevents STN hyperactivity and limits cortical entrainment.

Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%-75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction.

Impaired glutamate release in GPe astrocytes, disinhibits striatopallidal transmission in Parkinsonian mice.

Impaired glutamate release in GPe astrocytes, disinhibits striatopallidal transmission in Parkinsonian mice.

Blunted mGluR Activation Disinhibits Striatopallidal Transmission in Parkinsonian Mice

The prevailing circuit model predicts that hyperactivity of the striatopallidal pathway and subsequently increased inhibition of external globus pallidus (GPe) neurons lead to the hypokinetic symptoms of Parkinson's disease (PD). It is believed that hyperactivity ofthe striatopallidal pathway is due to inactivity of dopamine receptors on the somatodendritic membrane of striatopallidal neurons, but the exact cellular underpinnings remain unclear. In this study, we show that mouse GPe astrocytes critically control ambient glutamate level, which in turn gates striatopallidal transmission via the activation of presynaptic metabotropic glutamate receptors. This presynaptic inhibition of striatopallidal transmission is diminished after the chronic loss of dopamine. Elevation of intracellular glutamate content in astrocytes restores the proper regulation of the striatopallidal input in PD models. These findings argue that astrocytes are key regulators of the striatopallidal synapse. Targeting this cell class may serve as an alternative therapeutic strategy for PD.

Group III Metabotropic Glutamate Receptor-Mediated Modulation of the Striatopallidal Synapse

The globus pallidus (GP) is a key GABAergic nucleus in the basal ganglia (BG). The predominant input to the GP is an inhibitory striatal projection that forms the first synapse in the indirect pathway. The GP GABAergic neurons project to the subthalamic nucleus, providing an inhibitory control of these glutamatergic cells. Given its place within the BG circuit, it is not surprising that alterations in GP firing pattern are postulated to play a role in both normal and pathological motor behavior. Because the inhibitory striatal input to the GP may play an important role in shaping these firing patterns, we set out to determine the role that the group III metabotropic glutamate receptors (GluRs) play in modulating transmission at the striatopallidal synapse. In rat midbrain slices, electrical stimulation of the striatum evoked GABA(A)-mediated IPSCs recorded in all three types of GP neurons. The group III mGluR-selective agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) inhibited these IPSCs through a presynaptic mechanism of action. L-AP4 exhibited high potency and a pharmacological profile consistent with mediation by mGluR4. Furthermore, the effect of L-AP4 on striatopallidal transmission was absent in mGluR4 knock-out mice, providing convincing evidence that mGluR4 mediates this effect. The finding that mGluR4 may selectively modulate striatopallidal transmission raises the interesting possibility that activation of mGluR4 could decrease the excessive inhibition of the GP that has been postulated to occur in Parkinson's disease. Consistent with this, we find that intracerebroventricular injections of L-AP4 produce therapeutic benefit in both acute and chronic rodent models of Parkinson's disease.

Interactive role of adenosine and dopamine in the opiate withdrawal syndrome.

Adenosine reduces opioid withdrawal symptoms by activating A(1) adenosine receptors, probably by inhibiting excitatory amino acid release. Since blockade of A(2A) adenosine receptors seems to enhance dopaminergic striatopallidal transmission, we evaluated the role of the purinergic system in the opiate withdrawal syndrome by using two A(1) receptor agonists [ N(6)-cyclohexyladenosine, CHA and 2-chloro- N(6)-cyclopentyladenosine, CCPA], and two A(2A) receptor antagonists (SCH 58261 and 8-(3-chlorostyryl)caffeine, CSC). Male adult rats received increasing doses of morphine sulphate suspended in 5 ml/kg of a sustained release preparation (40-100 mg/kg s.c.) daily for 4 days and 20 h after the last administration, the withdrawal syndrome was evoked by naloxone (5 mg/kg i.p.). Animals were observed for 30 min for signs of opiate withdrawal. Other groups of rats were implanted with concentric probes for microdialysis and dopamine levels were measured in the nucleus accumbens. CHA and CCPA (0.05, 0.1 or 0.5 mg/kg i.p.) significantly reduced "wet-dog" shakes, diarrhoea, teeth chattering, jumping and writhing. SCH 58261 and CSC (0.1, 0.5 or 1 mg/kg i.p.), given 10 min before naloxone, also reduced signs of opiate withdrawal. CHA plus SCH 58261 and CCPA plus CSC greatly enhanced the reduction of withdrawal signs observed with CHA and CCPA or CSC and SCH 58261 alone. In vivo microdialysis showed that naloxone significantly decreased DA release; this effect was prevented by pretreatment with systemic SCH 58261 and CSC, but not with CHA and CCPA. Our results demonstrate that A(1) and A(2A) adenosine receptors mediate the effect induced by adenosine in opiate withdrawal syndrome and suggest that adenosine A(1) agonists and adenosine A(2A) antagonists may be beneficial in the treatment of this syndrome.

Relationships between the Prefrontal Cortex and the Basal Ganglia in the Rat: Physiology of the Cortico-Nigral Circuits

The prelimbic/medial orbital areas (PL/MO) of the rat prefrontal cortex are connected to substantia nigra pars reticulata (SNR) through three main circuits: a direct nucleus accumbens (NAcc)-SNR pathway, an indirect NAcc-SNR pathway involving the ventral pallidum (VP) and the subthalamic nucleus (STN), and a disynaptic cortico-STN-SNR pathway. The present study was undertaken to characterize the effect of PL/MO stimulation on SNR cells and to determine the contribution of these different pathways. The major pattern of responses observed in the SNR was an inhibition preceded by an early excitation and followed or not by a late excitation. The inhibition resulted from the activation of the direct NAcc-SNR pathway because it disappeared after acute blockade of the glutamatergic cortico-striatal transmission by CNQX application into the NAcc. The late excitation resulted from the activation of the indirect NAcc-VP-STN-SNR pathway via a disinhibition of the STN because it disappeared after either CNQX application into the NAcc or blockade of the GABAergic striato-pallidal transmission by bicuculline application into the VP. The early excitation, which was markedly decreased after blockade of the cortico-STN transmission by CNQX application into the STN, resulted from the activation of the disynaptic cortico-STN-SNR pathway. Finally, the blockade of the cortico-STN-VP circuit by CNQX application into STN or VP modified the influence of the trans-striatal circuits on SNR cells. This study suggests that, in the prefrontal cortex-basal ganglia circuits, the trans-subthalamic pathways, by their excitatory effects, participate in the shaping of the inhibitory influence of the direct striato-nigral pathway on SNR neurons.

Relationships between the Prefrontal Cortex and the Basal Ganglia in the Rat: Physiology of the Corticosubthalamic Circuits

The prelimbic-medial orbital areas (PL/MO) of the prefrontal cortex are connected to the medial part of the subthalamic nucleus (STN) through a direct projection and an indirect circuit that involves the core of the nucleus accumbens (NAcc) and the ventral pallidum (VP). In the present study, the influence of the PL/MO on the discharge of STN cells has been characterized. The major pattern of the responses observed after stimulation of PL/MO consisted of two excitatory peaks often separated by a brief inhibitory period. The early excitation was most likely to be caused by the activation of direct cortical inputs because its latency matches the conduction time of the prefrontal STN projections. The late excitation resulted from the activation of the indirect PL/MO-STN pathway that operates through a disinhibitory process. Indeed, the late excitation was no longer observed after acute blockade of the glutamatergic corticostriatal transmission by CNQX application into the NAcc. A similar effect was obtained after the blockade of the GABAergic striatopallidal transmission by bicuculline application into the VP. Finally, the brief inhibition that followed the early excitation was likely to result from the activation of a feedback inhibitory loop through VP because this inhibition was no longer observed after the blockade of STN inputs by CNQX application into the VP. This study further indicates the implication of STN in prefrontal basal ganglia circuits and underlines that in addition to a direct excitatory input, medial STN receives an indirect excitatory influence from PL/MO through an NAcc-VP-STN disinhibitory circuit.