Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment

Chronic levodopa treatment for Parkinson's disease often results in the development of abnormal involuntary movement, known as L ‐dopa‐induced dyskinesia (LIDs). Studies suggest that LIDs may be associated with aberrant corticostriatal plasticity. Using in vivo extracellular recordings from identified Type I and Type II medium spiny striatal neurons, chronic L ‐dopa treatment was found to produce abnormal corticostriatal information processing. Specifically, after chronic L ‐dopa treatment in dopamine‐depleted rats, there was a transition from a cortically evoked long‐term depression (LTD) to a complementary but opposing form of plasticity, long‐term potentiation, in Type II “indirect” pathway neurons. In contrast, LTD could still be induced in Type I neurons. Interestingly, the one parameter that correlated best with dyskinesias was the inability to de‐depress established LTD in Type I medium spiny striatal neurons. Taken as a whole, we propose that the induction of LIDs is due, at least in part, to an aberrant induction of plasticity within the Type II indirect pathway neurons combined with an inability to de‐depress established plastic responses in Type I neurons. Such information is critical for understanding the cellular mechanisms underlying one of the major caveats to L ‐dopa therapy. © 2010 Movement Disorder Society     

Immunohistochemical localization of DARPP-32 in striatal projection neurons and striatal interneurons: implications for the localization of D1-like dopamine receptors on different types of striatal neurons

Immunohistochemical double-label techniques were used to study the localization of DARPP-32, a phosphoprotein that is enriched in neurons possessing members of the D₁ subfamily of dopamine receptors, in several different types of striatal neurons in the rat basal ganglia. The vast majority (94.1%) of striatonigral projection neurons (the vast majority of which contain substance P), identified by retrograde labeling with fluorogold, were observed to contain DARPP-32. Similarly, the vast majority of striatopallidal projection neurons (87.7%), identified by immunofluorescence labeling for enkephalin (ENK), were found to label for DARPP-32. In contrast, cholinergic and neuropeptide Y-containing striatal interneurons were never observed to contain DARPP-32. These results suggest that essentially all major types of striatal medium spiny projection neurons may possess members of the D₁ subfamily of dopamine receptors, but that striatal local circuit neurons do not possess members of the D₁ subfamily of receptors.     

D₁-NMDA receptor interactions in the rat nucleus accumbens change during adolescence

Many aspects of the dopamine (DA) system mature during adolescence. For example, the DA modulation of glutamate responses in the rat prefrontal cortex (PFC) acquires adult characteristics during late adolescence. In the striatum, D₁ receptors modulate NMDA responses, but whether this behaviorally important interaction matures during adolescence is not known. Here, we tested whether the D₁ agonist SKF38393 affects NMDA actions on nucleus accumbens medium spiny neuron (MSN) excitability in slices from juvenile and young adult rats. NMDA dose‐dependently increased excitability in both age groups, and the D₁ agonist produced a marginal increase of MSN excitability. In juvenile slices, the most common interaction was a downregulation of NMDA effects on excitability by the D₁ agonist, whereas in most adult MSN, the D₁ agonist increased NMDA effects on MSN excitability. These results suggest that D₁–NMDA receptor interactions in the nucleus accumbens change during adolescence, a change that may result in different processing of reward functions during this critical developmental stage. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Dopamine D2 receptor-mediated modulation of the GABAergic inhibition of substantia nigra pars reticulata neurons

Neurons of the substantia nigra pars reticulata can be readily and fully inhibited by endogenously released or iontophoretically applied GABA. We have previously shown that co-application of dopamine or the D₂-like agonist quinpirole causes a current-dependent attenuation of the inhibitory response of these neurons to GABA. To determine if the modulation of GABA responsiveness was mediated by activation of D₂ receptors, effects of iontophoretic quinpirole were examined after various treatments which block or inactivate D₂ receptors, or uncouple D₂ receptors from their G-proteins. Results showed that the GABA-attenuating effect of quinpirole could be attributed to stimulation of D₂ receptors, and not a non-specific effect of the drug, since (1) co-iontophoresis of the D₂ antagonist YM 09151-2 antagonized the GABA-modulatory effect of quinpirole, (2) prior intranigral injection of the receptor inactivatorN-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 50 nmol/0.5 ml one day before recording) prevented the response to quinpirole, and (3) prior intranigral injection of the G_i-G_o-protein inactivator pertussis toxin (1 mg/ml 0.9% NaCl 24 h before recording) completely abolished the ability of quinpirole to lessen the inhibitory response to GABA. The location of the involved D₂ receptors was examined using selective lesioning approaches. Kainic acid lesions of the striatonigral pathway did not prevent the ability of quinpirole to attenuate responses of pars reticulata neurons to GABA. Similarly, in previous studies [59], 6-hydroxydopamine lesions of the adjacent pars compacta dopamine neurons were found not to abolish the GABA-attenuating effect of dopamine. Thus, it appears that the receptors mediating the response are not localized to either striatonigral terminals nor to the adjacent dopamine neurons, leaving open the possibility that the response is mediated by D₂ receptors located on pars reticulata neurons. Collectively these results suggest that dendritically released dopamine may act via nigral D₂ receptors, perhaps located on pars reticulata neurons themselves, to regulate basal ganglia output from the substantia nigra.     

Corticostriatal synaptic plasticity alterations in the R6/1 transgenic mouse model of Huntington's disease

Huntington's disease (HD) is a genetic neurodegenerative condition characterized by abnormal dopamine (DA)–glutamate interactions, severe alterations in motor control, and reduced behavioral flexibility. Experimental models of disease show that during symptomatic phases, HD shares with other hyperkinetic disorders the loss of synaptic depotentiation in the striatal spiny projection neurons (SPNs). Here we test the hypothesis that corticostriatal long-term depression (LTD), a well-conserved synaptic scaling down response to environmental stimuli, is also altered in symptomatic male R6/1 mice, a HD model with gradual development of symptoms. In vitro patch-clamp and intracellular recordings of corticostriatal slices from R6/1 mice confirm that, similar to other models characterized by hyperkinesia and striatal DA D1 receptor pathway dysregulation, once long-term potentiation (LTP) is induced, synaptic depotentiation is lost. Our new observations show that activity-dependent LTD was abolished in SPNs of mutant mice. In an experimental condition in which N-methyl-d -aspartate (NMDA) receptors are normally not recruited, in vitro bath application of DA revealed an abnormal response of D1 receptors that caused a shift in synaptic plasticity direction resulting in an NMDA-dependent LTP. Our results demonstrate that corticostriatal LTD is lost in R6/1 mouse model and confirm the role of aberrant DA–glutamate interactions in the alterations of synaptic scaling down associated with HD symptoms.     

Localization of D1 dopamine receptors on live cultured striatal neurons by quantitative fluorescence microscopy

Single neurons in culture express a heterogeneity of neurotransmitter receptor subtypes. The study of the effects of neurotransmitters on neuronal function is complicated by this heterogeneity. It would therefore be useful to be able to identify live neurons that express the receptors of interest and then use these neurons for functional studies. We have used quantitative fluorescence microscopy to identify single live striatal neurons that express D₁ dopamine receptors. The binding of the fluorescent D₁ dopamine receptor antagonist bodipy-SCH 23390 was measured in 2–3-week-old primary striatal cultures derived from fetal rats (embryonic day 18). Binding of bodipy-SCH 23390 to live neurons was displaced by (+)-butaclamol, dopamine or SCH 23390, indicating that it specifically labelled D₁ dopamine receptors. However, the fraction of bodipy-SCH 23390 binding that was specific varied substantially among individual neurons indicating heterogeneity of D₁ dopamine receptor expression. Interestingly, bodipy-SCH 23390 also specifically labelled discrete spots of receptors on the neuronal processes. This technique should prove useful in the study of the effects of dopaminergic drugs on neuronal function in primary culture.     

Selective remodeling of glutamatergic transmission to striatal cholinergic interneurons after dopamine depletion

The widely held view that the pathophysiology of Parkinson's disease arises from an under‐activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre‐dependent channelrhodopsin‐2 (ChR2) the PfN of Vglut2‐Cre mice that were dopamine‐depleted with 6‐hydroxydopamine (6‐OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6‐OHDA‐treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6‐OHDA lesions failed to affect short‐term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA‐to‐AMPA ratios at PfN synapses—that were significantly larger than NMDA‐to‐AMPA ratios at cortical synapses—were reduced by 6‐OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D₅ dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short‐term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de‐potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.     

Dopamine and 7-OH-DPAT may act on D3 receptors to inhibit tuberoinfundibular dopaminergic neurons

Whether the tuberoinfundibular dopaminergic (TIDA) neurons resided in the dorsomedial arcuate nucleus (dmARN) can respond to dopamine and a dopamine D₃ receptor agonist, 7-hydroxydipropylaminotetralin (7-OH-DPAT), was the focus of this study. In studies using extracellular single-unit recording of dmARN neurons in brain slices obtained from ovariectomized rats, dopamine and 7-OH-DPAT inhibited 60.1% (n = 141) and 80.9% (n = 47) of recorded dmARN neurons, respectively. Other dopamine D₁ or D₂ receptor agonists were not as effective. Intracerebroventricular injection of 7-OH-DPAT (10⁻⁹ mol/3 μl) in ovariectomized, estrogen-primed rats significantly lowered the TIDA neuronal activity as determined by 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence. Co-administration of a putative D₃ receptor antagonist, U-99194A, could prevent the effect of 7-OH-DPAT. Unilateral microinjection of 7-OH-DPAT or dopamine itself (10⁻¹¹–10⁻⁹ mol/0.2 μl) into the right dmARN exhibited the same inhibitory effect on TIDA neurons. In all, dopamine may act on D₃ receptors to exhibit an inhibitory effect on its own release from the TIDA neurons.     

D2 Receptors Mediate Dopamine Suppression of irANF Release and Pro-ANF mRNA Expression of Rat Hypothalamic Neurons in Culture

Although N-terminal truncated forms of atrial natriuretic factor (ANF) are produced and released from rat hypothalamic neurons, the intrahypothalamic regulation of these processes remains unclear. Employing a well-characterized hypothalamic cell culture system, we report here that dopamine, mediating through D₂ receptors, inhibits the synthesis and release of ANF. In long-term cultures of hypothalamic neurons, daily treatment for 4 days with quinpirole, a D₂ agonist, significantly suppressed the basal irANF release in a time-related and a dose-dependent manner. The ED₅₀ and E_max of the drugs were 9.1 × 10^-8M and 10^-5M, respectively. This effect of quinpirole was mimicked by 10^-7M of dopamine, a physiological ligand for D₂ receptor. Furthermore, the suppressing effects of both quinpirole and dopamine were abolished by sulpiride, a D₂ antagonist. Whereas 10^-6M of forskolin treatment consistently enhanced the release of irANF through activating the adenylyl cyclase-cAMP system, this stimulatory effect was suppressed by quinpirole in a dose-related manner. In addition, the application of pertussis toxin, a bacterial toxin which inactivated G_i protein activity, reversed the suppressing effect of quinpirole or dopamine on irANF release. These immunoassay findings were accompanied by corresponding changes in the abundance of pro-ANF mRNA in the cultures as determined by colorimetric Northern blot analysis. By combining the techniques of in situ hybridization and immunocytochemistry, the mRNA of D₂ receptor was colocalized with irANF at a single cell level by double fluorescent staining. We thus conclude that the release and gene expression of ANF in rat hypothalamic neurons are directly suppressed by dopamine acting through its D₂ receptors on ANF neurons. This inhibitory effect is likely to be mediated, at least in part, through G_i protein-induced suppression of the adenylyl cyclase-cAMP system.     

Dopamine-mediated regulation of corticostriatal synaptic plasticity

The striatum represents the main input into the basal ganglia. Neurons projecting from the striatum receive a large convergence of afferents from all areas of the cortex and transmit neural information to the basal ganglia output structures. Corticostriatal transmission is essential in the regulation of voluntary movement, in addition to behavioural control, cognitive function and reward mechanisms. Long-term potentiation (LTP) and long-term depression (LTD), the two main forms of synaptic plasticity, are both represented at corticostriatal synapses and strongly depend on the activation of dopamine receptors. Here, we discuss possible feedforward and feedback mechanisms by which striatal interneurons, in association with striatal spiny neurons and endogenous dopamine, influence the formation and maintenance of both LTP and LTD. We also propose a model in which the spontaneous membrane oscillations of neurons projecting from the striatum (named 'up' and 'down' states), in addition to the pattern of release of endogenous dopamine, bias the synapse towards preferential induction of LTP or LTD. Finally, we discuss how endogenous dopamine crucially influences changes in synaptic plasticity induced by pathological stimuli, such as energy deprivation.     

Differences in excitatory transmission between thalamic and cortical afferents to single spiny efferent neurons of rat dorsal striatum

The striatum is crucially involved in motor and cognitive function, and receives significant glutamate input from the cortex and thalamus. The corticostriatal pathway arises from diverse regions of the cortex and is thought to provide information to the basal ganglia from which motor actions are selected and modified. The thalamostriatal pathway arises from specific thalamic nuclei and is involved in attention and possibly strategy switching. Despite these fundamental functional differences, direct comparisons of the properties of these pathways are lacking. N‐methyl‐d ‐aspartate (NMDA) receptors at synapses powerfully affect postsynaptic processing, and incorporation of different NR2 subunits into NMDA receptors has profound effects on the pharmacological and biophysical properties of the receptor. Utilization of different NMDA receptors at thalamostriatal and corticostriatal synapses could allow for afferent‐specific differences in information processing. We used a novel rat brain slice preparation preserving corticostriatal and thalamostriatal pathways to medium spiny neurons to examine the properties of NMDA receptor‐mediated excitatory postsynaptic currents (EPSCs) recorded using the whole‐cell, patch‐clamp technique. Within the same neuron, the NMDA/non‐NMDA ratio is greater for excitatory responses evoked from the thalamostriatal pathway than for those evoked from the corticostriatal pathway. In addition, reversal potentials and decay kinetics of the NMDA receptor‐mediated EPSCs suggest that the thalamostriatal synapse is more distant on the dendritic arbor. Finally, results obtained with antagonists specific for NR2B‐containing NMDA receptors imply that NMDA receptors at corticostriatal synapses contain more NR2B subunits. These synapse‐specific differences in NMDA receptor content and pharmacology provide potential differential sites of action for NMDA receptor subtype‐specific antagonists proposed for the treatment of Parkinson’s disease.     

Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum

We have previously found, in striatal membrane preparations from young (2 months old) rats, that stimulation of adenosine A₂ receptors (with the selective adenosine A₂ agonist CGS 21680) increases the dissociation constants of high- (K_h) and low-affinity (K_l) dopamine D₂ binding sites (labelled with the selective dopamine D₂ antagonist [³H]raclopride) without changing the proportion of high affinity binding sites (R_h). In the present study in striatal preparations from adult (6 months old) rats, it was found that in addition to the increase in both K_h and K_l values, stimulation of adenosine A₂ receptors is associated with an increase in R_h. These result suggest that, in the adult rat, adenosine A₂ stimulation may inhibit the behavioural effects induced by dopamine D₂ stimulation both by decreasing the affinity and the transduction of dopamine D₂ receptors. We have also studied the intramembrane A₂-D₂ receptor interaction in an experimental model of Parkinson's disease, namely in rats with a unilateral 6-OH-dopamine-induced lesion of the nigro-striatal dopamine pathway. It was found that a unilateral dopamine denervation is associated with a higher density of striatal dopamine D₂ receptors in the order of 20%, without any change in their affinity compared with the unlesioned neostriatum. Furthermore, the density (B_max values) of dopamine D₂ receptors in the contralateral neostriatum was significantly higher (about 20%) than in the striatum from native animals. This finding suggests that an unilateral dopamine denervation also induces compensatory long-lasting changes of dopamine D₂ receptors in the contralateral neostriatum. In addition to the hightened sensitivity to dopamine agonists, it is known that the dopamine denervated striatum is more sensitive to adenosine antagonists like methylxanthines. If the adenosine A₂-dopamine D₂ interaction is the main mechanism of action mediating the central effects of methylxanthines, the dopamine denervation might also potentiate this interaction, i.e., dopamine D₂ receptors could be not only more sensitive to dopamine but also to adenosine A₂ receptor activation. Our results support this hypothesis, since membrane preparations from the denervated neostriatum are more sensitive to the effect of CGS 21680 on dopamine D₂ receptors. Thus a low dose of CGS 21680 (3 nM), which is not effective in membrane preparations from the neostriatum of naive animals, is still effective in membranes from the denervated neostriatum. These results underline the potential antiparkinsonian activity of adenosine A₂ antagonists.     

Effect of aging on vulnerability of striatal D1 And D2 dopamine receptor-containing neurons to kainic acid

Kainic acid lesions elicit reductions in ligand binding to both D₁ and D₂ striata dopamine receptors in young and old rats. Relative reductions are greatest for both receptors in young animals than old. In addition, D₁ receptor binding is reduced more than D₂ at both ages. These findings support the idea that those dopamine receptor neurons lost during aging may reside in a kainic acid sensitive population.     

Dopamine signals and physiological origin of cognitive dysfunction in Parkinson's disease

The pathological hallmark of Parkinson's disease (PD) is the degeneration of midbrain dopamine neurons. Cognitive dysfunction is a feature of PD patients even at the early stages of the disease. Electrophysiological studies on dopamine neurons in awake animals provide contradictory accounts of the role of dopamine. These studies have established that dopamine neurons convey a unique signal associated with rewards rather than cognitive functions. Emphasizing their role in reward processing leads to difficulty in developing hypothesis as to how cognitive impairments in PD are associated with the degeneration of dopamine circuitry. A hint to resolve this contradiction came from recent electrophysiological studies reporting that dopamine neurons transmit more diverse signals than previously thought. These studies suggest that dopamine neurons are divided into at least two functional subgroups, one signaling “motivational value” and the other signaling “salience.” The former subgroup fits well with the conventional reward theory, whereas the latter subgroup has been shown to transmit signals related to salient but non‐rewarding experiences such as aversive stimulations and cognitively demanding situations. This article reviews recent advances in understanding the non‐reward functions of dopamine, and then discusses the possibility that cognitive dysfunction in PD is at least partially caused by the degeneration of the dopamine neuron subgroup signaling the salience of events in the environment. 2015 International Parkinson and Movement Disorder Society     

New rules governing synaptic plasticity in core nucleus accumbens medium spiny neurons

The nucleus accumbens is a forebrain region responsible for drug reward and goal‐directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic communication over long periods of time. To date, attempts at understanding the relationship between drugs of abuse and synaptic plasticity have relied on the high‐frequency long‐term potentiation model of T.V. Bliss & T. Lømo [(1973) Journal of Physiology, 232, 331–356]. We examined synaptic plasticity using spike‐timing‐dependent plasticity, a stimulation paradigm that reflects more closely the in vivo firing patterns of mouse core nucleus accumbens medium spiny neurons and their afferents. In contrast to other brain regions, the same stimulation paradigm evoked bidirectional long‐term plasticity. The magnitude of spike‐timing‐dependent long‐term potentiation (tLTP) changed with the delay between action potentials and excitatory post‐synaptic potentials, and frequency, whereas that of spike‐timing‐dependent long‐term depression (tLTD) remained unchanged. We showed that tLTP depended on N‐methyl‐d ‐aspartate receptors, whereas tLTD relied on action potentials. Importantly, the intracellular calcium signaling pathways mobilised during tLTP and tLTD were different. Thus, calcium‐induced calcium release underlies tLTD but not tLTP. Finally, we found that the firing pattern of a subset of medium spiny neurons was strongly inhibited by dopamine receptor agonists. Surprisingly, these neurons were exclusively associated with tLTP but not with tLTD. Taken together, these data point to the existence of two subgroups of medium spiny neurons with distinct properties, each displaying unique abilities to undergo synaptic plasticity.     

Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine

Dopamine D₃ receptors are structurally highly homologous to other D₂-like dopamine receptors, but differ from them pharmacologically. D₃ receptors are notably resistant to alkylation by 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which readily alkylates D₂ receptors. We compared EEDQ with N-(p-isothiocyanatophenethyl)spiperone (NIPS), a selective D₂-like receptor alkylating agent, for effects on D₃ and D₂ receptors in rat brain using autoradiographic analysis. Neither agent occluded D₃ receptors in vivo at doses that produced substantial blockade of D₂ receptors, even after catecholamine-depleting pretreatments. In vitro, however, D₃ receptors were readily alkylated by both NIPS (IC₅₀=40 nM) and EEDQ (IC₅₀=12 μM). These effects on D₃ sites were blocked by nM concentrations of dopamine, whereas μM concentrations were required to protect D₂ receptors from the alkylating agents. The findings are consistent with the view that alkylation of D₃ receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine.     

Intracellularly recorded response of rat striatal neurons in vitro to fenoldopam and SKF 38393 following lesions of midbrain dopamine cells

The effect of long-term (6–19 weeks) 6-hydroxydopamine-induced (6-OHDA) lesions of midbrain dopamine cells on dopamine D₁-like agonist-induced changes in the excitability of rat striatal neurons was investigated in vitro using tissue slices and intracellular recording techniques. Fenoldopam and (±)-SKF 38393 predominantly decreased excitability in control preparations including striatal neurons located contralateral to 6-OHDA injection sites and neurons obtained from rats receiving sham injections or no treatment. Fenoldopam also inhibited neurons ipsilateral to lesions of midbrain dopamine cells. (±)-SKF 33393, unlike fenoldopam, produced predominantly increases in the excitability of ipsilateral striatal neurons. Superfusion of the D₁ receptor antagonist, SCH 23390, blocked fenoldopam-induced decreases in excitability but not the (±)-SKF 38393-induced excitation of neurons ipsilateral to the lesion. Sequential application of fenoldopam and quinpirole, a D₂/D₃ receptor agonist, produced responses to both drugs in a majority of neurons. The results demonstrate that inhibitory responses to fenoldopam are mediated by D₁ receptors, while excitatory effects of (±)-SKF 38393 in the striatum ipsilateral to the lesion are apparently not dependent on D₁ receptor activation. These findings also suggest that dopamine D₁ and D2/D3 receptors are able to concurrently influence the excitability of striatal neurons in the dopamine deafferentated striatum. Similar regulation of striatal neurons in vivo may contribute to dopaminergic regulation of basal ganglia output and the ability of dopaminomimetic agents to ameliorate symptoms of dopaminergic deficiency in Parkinson's disease. © 1994 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus.

Glutamatergic neurons within the deep layers of the prefrontal cortex and dopaminergic neurons of the substantia nigra pars compacta preferentially terminate in patch-like regions within the caudate putamen nucleus (CPN). Activation of dopamine D2 receptors is known to potently modulate striatal glutamatergic transmission and may play a role in reward-based motor learning. To determine the cellular substrate for D2-mediated regulation of prefrontal corticostriatal transmission in striatal patches, we combined anterograde transport of biotinylated dextran amine (BDA) with immunogold-silver labeling of a D2 receptor antipeptide antiserum in rat brain. Injections centered in deep layers of the dorsal part of the anterior cingulate cortex, one of the prefrontal cortical regions, produced varicose axonal BDA labeling in a patch-like distribution in the dorsomedial CPN. Electron microscopy showed that in these patch compartments, BDA labeling was present exclusively in axons and terminals (total number = 581), 9% of which contained detectable D2-like immunoreactivity. Thirty percent of the BDA-labeled terminals formed asymmetric excitatory synapses with dendritic spine heads, and the remainder were without recognizable junctions. The recipient spines were unlabeled or contained immunogold-silver particles for D2 receptors. A few of the D2-labeled spines also received convergent, often nonsynaptic contact from D2-labeled terminals resembling dopaminergic afferents. In addition, the corticostriatal terminals often apposed spiny and nonspiny neuronal profiles that contained D2 labeling. These results suggest that dopamine D2 receptors are strategically positioned for presynaptic and postsynaptic modulation of prefrontal corticostriatal excitation of spiny neurons in striatal patches. The findings have direct implications for D2-mediated control of reward-related motor learning.     

The involvement of dopamine in nociception: the role of D1 and D2 receptors in the dorsolateral striatum

Determination of the neuroanatomical and neurochemical factors that contribute to nociception is an essential element in the study and treatment of pain. Several lines of evidence have implicated nuclei and neurotransmitters within the basal ganglia in nociception. For example, previous studies have shown that dopamine receptors in the striatum are involved in acute nociception, however, it remains to be determined if dopamine receptors in the dorsolateral striatum are involved in persistent nociception. The purpose of the present study was therefore to determine whether activation or antagonism of dopamine receptors in the dorsolateral striatum influences the nociceptive responses of rats in the formalin test, a model of persistent pain. It was found that micro-injection of the non-selective dopamine antagonist haloperidol into the dorsolateral striatum increases formalin-induced nociception whereas injection of the non-selective dopamine agonist apomorphine reduces formalin-induced nociception. Injection of the D₁ antagonist SCH23390 or the D₁ agonist SKF38393 does not affect formalin-induced nociception. In contrast, injection of the D₂ antagonist eticlopride enhances formalin-induced nociception, whereas injection of the D₂ agonist quinpirole reduces formalin-induced nociception. These results provide additional evidence that dopamine receptors in the striatum are involved in nociception. Furthermore, this study strongly suggests that D₂, but not D₁, dopamine receptors in the dorsolateral striatum are involved in modulation of persistent nociception.     

Dopaminergic Agonists Have Both Presynaptic and Postsynaptic Effects on the Guinea-pig's Medial Vestibular Nucleus Neurons

A number of studies have indicated a possible interaction between dopamine and the vestibular system. Using intracellular recordings in brainstem slices, we have tested the effects of dopamine and other dopaminergic compounds on guinea-pig medial vestibular nucleus (MVN) neurons. In normal medium, MVN neurons were depolarized by dopamine as well as by (-)quinpirole and piribedil, which are selective D₂ dopaminergic agonists. The dependence of this effect on the presence of D₂ receptors was confirmed by using (-)sulpiride, a D₂ antagonist which blocked the depolarizing effect of dopamine. Dopaminergic D₁ receptors were apparently not involved in this effect since a selective D₁ agonist, SKF-38393, had no effect on MVN neurons and the D₁ antagonist (+) SCH-23390 could not block the effect of dopamine. These depolarizing responses to dopamine must be due to a presynaptic action on terminals that normally release GABA spontaneously on MVN neurons, and tonically maintain them in a state of hyperpolarization. Indeed, such a spontaneous release was demonstrated to occur in the slice since application of bicuculline, a GABA_A antagonist, depolarized MVNneurons in normal saline, but not in a high Mg²⁺/low Ca²⁺ solution known to block synaptic transmission. When dopamine was applied in conditions in which no GABA_A-dependent transmission could occur (either in the presence of bicuculline or in a high Mg²⁺/low Ca²⁺ solution) only a hyperpolarizing, most probably postsynaptic, effect occurred. These results indicate that dopamine might exert in vivo a significant modulatory action on the vestibular system, either by a direct action on the vestibular neurons or by modulation of GABAergic transmission.