Interaction between dopamine D1 and D2 receptors in modulation of the immune response

The interaction between dopamine D₁ and D₂ receptors plays a role in immunomodulation. The results of thus interaction depends on the degree of receptor activation with selective agonists in different doses. Combined treatment with agonists of D₁ and D₂ receptors in high doses had a synergistic effect in the mechanisms of immunomodulation. Receptor agonists in low doses suppressed the immune response. Our results suggest that weak activation of one of these receptors is accompanied by inactivation of the other receptor type. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 141, No. 5, pp. 488–490, May, 2006     

Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system

The anatomical distributions and affinity states of dopamine D₁ and D₂ receptors were compared in the rat central nervous system using quantitative autoradiography. [³H]SCH23390 and [³H]spiperone (in the presence of 100 nM mianserin) were used to label the D₁, and D₂ receptors, respectively. The densities of D₁ and D₂ receptors displayed a positive correlation among 21 brain regions (Pearson correlation coefficient, r = 0.80, P < 0.001).

The affinity states for the D₁ and D₂ receptors were found to be quite different from each other, and different from the results obtained by others using homogenate preparations. Both the D₁ and D₂ receptors were best modeled using a two-state model. In the absence of exogenous guanine nucleotides and using the nonselective agonist dopamine as the competitor, the D₁ receptor was primarily in a low affinity agonist state (R_H = 21 ± 6%), whereas the D₂ receptor was primarily in the high affinity agonist state (R_H = 77 ± 3%). In the presence of 10 μM guanylyl-imidodiphosphate orguanosine-5'-O-(2-thiophosphate) both the D₁ and the D₂ receptor were completely in a low affinity agonist state (R_L = 100%). These affinity states were found both in the nucleus accumbens and olfactory tubercle using dopamine as the competitor and in the striatum using selective D₁ or D₂ agonists as competitors.

Receptor occupancy of the D₂ receptor with either an agonist or antagonist did not alter the affinity states of the D₁ receptor, and conversely, receptor occupancy of the D₁ receptor did not alter the affinity states of the D₂ receptor.

The correlation between densities of D₁ and D₂ receptors provides an anatomical framework for evaluating behavioral and electrophysiological evidence of an interaction between the two dopamine receptor subtypes. This interaction does not appear to be due to a sharing or coupling of G-proteins in such a way that binding to one dopamine receptor subtype alters the affinity state of the other receptor subtype. The differences between dopamine receptor distributions described by labeled agonists and antagonists may be due in part to differences in their affinity states. The low proportion of high affinity state D₁ receptors may explain some of the difficulties in assigning specific behavioral roles to the D₁ receptor.     

Repeated stimulation of D1 dopamine receptors causes time-dependent alterations in the sensitivity of both D1 and D2 dopamine receptors within the rat striatum.

Recent evidence suggests that repeated stimulation of D1 dopamine receptors within the rat striatum leads to an enhancement of both D1 and D2 dopamine receptor-mediated responses. The present study used both behavioral observations and extracellular single unit recording techniques to investigate this phenomenon following repeated administration of selective D1 dopamine receptor agonists. Groups of rats received twice daily administration of either saline or the partial D1 dopamine receptor agonist SKF 38393 (8 mg/kg, s.c.) for three weeks. Rats were tolerant to the ability of SKF 38393 to enhance grooming behavior when tested immediately following the last of the 42 treatment injections. However, the ability of this last SKF 38393 injection to potentiate oral stereotyped behavior following administration of the D2 DA agonist quinpirole was still evident. Following a one-day withdrawal, grooming responses to SKF 38393 had returned to normal. At this time, administration of quinpirole, without concomitant SKF 38393, failed to significantly promote oral stereotypies, as is typical of normal rats. Following a one-week withdrawal period, SKF 38393-induced grooming behavior was significantly enhanced and quinpirole, administered without SKF 38393, produced pronounced oral stereotyped behavior in 10 of 12 rats tested. Following a one-month withdrawal, these sensitized responses were no longer evident. Single-cell recordings from rat lateral striatal neurons revealed similar time-dependent alterations in the effects of iontophoretically administered SKF 38393 and quinpirole. Current-response curves revealed that, without a withdrawal period, striatal neurons were subsensitive to the inhibitory effects of SKF 38393 but not quinpirole. The decreased inhibitory responses of striatal neurons to SKF 38393 returned to normal levels after a one-day withdrawal. Following a one-week withdrawal, the effects of both agonists were significantly greater than that in saline-treated controls. Normosensitivity was evident following a one-month withdrawal. Repeated administration of the full D1 DA agonist SKF 81297 (0.5 mg/kg, s.c., twice daily) also resulted in sensitized responses of striatal neurons following a one-week withdrawal, demonstrating that the sensitization to SKF 38393 was not due to its partial agonist character. The present findings provide both behavioral and electrophysiological evidence that repeated stimulation of D1 dopamine receptors results in a brief subsensitivity, followed by transient sensitization of the D1 receptors. The enhanced effects of D2 dopamine agonists might be due to an enhanced synergism (enabling) produced by endogenous dopamine stimulating supersensitive D1 receptors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Autoradiographic localization of D1 and D2 dopamine receptors in the human brain

The distribution of dopamine D1 and D2 receptors in several human brain regions was investigated using autoradiography with the radioligands [3H]SCH 23390 and [3H]spiroperidol. The highest densities of both dopamine receptor types are seen in the nucleus caudatus, putamen and nucleus accumbens. Whereas the density of the D2 receptors is similar in the two segments of the globus pallidus, the pars medialis of the globus pallidus contains a three-fold higher concentration of D1 receptors than the pars lateralis. D1 and D2 receptors are present in the amygdala and substantia nigra. Both receptor types are absent in the cerebellum. The thalamus contains low densities of D1 receptors but no D2 receptors. Only D2 receptors are seen in the anterior lobe of the pituitary gland. The whole cerebral cortex is rich in D1 receptors, while D2 receptors, in low concentrations, are confined to the entorhinal area and cingulate cortex.     

Role of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2A receptor signaling in the neostriatum

Adenosine is known to modulate the function of neostriatal neurons. Adenosine acting on A(2A) receptors increases the phosphorylation of dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) at Thr34 (the cAMP-dependent protein kinase [PKA] site) in striatopallidal neurons, and opposes dopamine D2 receptor signaling. In contrast, the role of adenosine A(1) receptors in the regulation of dopamine/DARPP-32 signaling is not clearly understood. Here, we investigated the effect of adenosine A(1) receptors on D(1), D(2) and A(2A) receptor signaling using mouse neostriatal slices. An A(1) receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (100 nM), caused a transient increase, followed by a transient decrease, in DARPP-32 Thr34 phosphorylation. Our data support the following model for the actions of the A(1) receptor agonist. The A(1) receptor-induced early increase in Thr34 phosphorylation was mediated by presynaptic inhibition of dopamine release, and the subsequent removal of tonic inhibition by D(2) receptors of A(2A) receptor/G(olf)/cAMP/PKA signaling. The A(1) receptor-induced late decrease in Thr34 phosphorylation was mediated by a postsynaptic G(i) mechanism, resulting in inhibition of D(1) and A(2A) receptor-coupled G(olf)/cAMP/PKA signaling in direct and indirect pathway neurons, respectively. In conclusion, A(1) receptors play a major modulatory role in dopamine and adenosine receptor signaling.     

Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum

Compelling evidence indicates that the long (D2L) and the short (D2S) isoform of dopamine (DA) D2 receptors serve distinct physiological functions in vivo. To address the involvement of these isoforms in the control of synaptic transmission in the striatum, we measured the sensitivity to D2 receptor stimulation of glutamate- and GABA-mediated currents recorded from striatal neurons of three mutant mice, in which the expression of D2L and D2S receptors was either ablated or variably altered. Our data indicate that both isoforms participate in the presynaptic inhibition of GABA transmission in the striatum, while the D2-receptor-dependent modulation of glutamate release preferentially involves the D2S receptor. Accordingly, the inhibitory effects of the DA D2 receptor agonist quinpirole (10 microM) on GABA(A)-mediated spontaneous inhibitory postsynaptic currents (IPSCs)correlate with the total number of D2 receptor sites in the striatum, irrespective of the specific receptor isoform expressed. In contrast, glutamate-mediated spontaneous excitatory postsynaptic currents (EPSCs) were significantly inhibited by quinpirole only when the total number of D2 receptor sites, normally composed by both D2L and D2S receptors in a ratio favoring the D2L isoform, was modified to express only the D2S isoform at higher than normal levels. Understanding the physiological roles of DA D2 receptors in the striatum is essential for the treatment of several neuropsychiatric conditions, such as Parkinson's disease, Tourette's syndrome, schizophrenia, and drug addiction.     

Hyperthermic and lethal effects of methamphetamine: roles of dopamine D1 and D2 receptors

Both human and animal studies suggest that hyperthermia contributes to the lethal effects of methamphetamine. To elucidate the roles of dopamine D1 and D2 receptors in methamphetamine-induced hyperthermia and lethal effects, we used D1 knockout (D1KO) mice, D2 knockout (D2KO) mice, and wild-type littermates. After the administration (i.p.) of a single dose of 30 mg/kg methamphetamine, no hyperthermic effect on body temperature was observed in D2KO mice, though there was a slight elevation in D1KO mice and a marked elevation in wild-type mice. Approximately 27% of the wild-type mice died after the administration, compared to only 7% of D1KO mice and 4% of D2KO mice. In conclusion, both D1 and D2 receptors play roles in the lethal toxic effects of methamphetamine, and mainly the D2 receptor is involved in the elevation of body temperature.     

The roles of accumbal dopamine D1 and D2 receptors in maternal memory in rats

Female rats show enhanced maternal responsiveness toward their young if they have had maternal experiences before. This kind of maternal experience-based memory is critically dependent on the mesolimbic dopamine (DA) system, especially the nucleus accumbens (NA) shell. However, the relative contributions of the two main DA receptor systems (D1 and D2) within the shell have not been delineated. This study investigates the roles of dopamine D1 and D2 receptors in maternal memory by infusing a selective D1 antagonist, SCH-23390; a selective D2 antagonist, sulpiride; or a combination D-1/D-2 antagonist, cis-Z-flupenthixol, into the NA shell of postpartum female rats. Sulpiride-infused rats showed a significantly longer latency to exhibit full maternal behavior following a 10-day pup isolation period in comparison to the controls that received a vehicle. Cis-Z-flupenthixol disrupted maternal memory to a greater extent, as rats receiving this showed the longest latencies to express maternal behavior. SCH-23390 infusions had only marginal effects. These findings suggest that both the D1 and the D2 receptor subtypes play a role in the consolidation of maternal memory and they might do so by mediating the motivational salience of pup stimulation.     

Control of the subthalamic innervation of substantia nigra pars reticulata by D1 and D2 dopamine receptors

The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed.     

Adaptive changes in the expression of central opioid receptors in mice lacking the dopamine D2 receptor gene

On the basis of numerous studies that have described interactions between the dopaminergic and opioidergic systems, we have investigated whether genetic deletion of dopamine D2 receptors (D2R) might influence the expression of central opioid receptors. The levels of mu, delta, kappa and nociceptin opioid peptide receptors were determined in the brains and spinal cords of D2R knockout mice using quantitative autoradiography. The significant changes in opioid receptor binding found in the brains of heterozygous and homozygous mice were mainly restricted to the basal ganglia. In homozygous mice, a down-regulation of mu and delta receptors was observed in the striatal and pallidal areas. This alteration may be an adaptive response to the increase in enkephalin levels previously described in the striatum of these mutant mice. On the contrary, an up-regulation of kappa receptors was found in the striatal and nigral regions and might be related to a change in dynorphin levels. Significant increases in nociceptin receptor binding were also observed in homozygous mice in brain areas involved in motor behavior. At the spinal level, only kappa and nociceptin receptor binding showed significant overall differences between genotypes. The functional consequences of these adaptive changes are discussed in relation to the findings of behavioral and neurochemical studies reported to date in D2R knockout mice.     

Stimulation of D1 dopamine receptors reveals direct effects of the preferential dopamine autoreceptor agonist B-HT 920 on postsynaptic dopamine receptors

Possible postsynaptic effects of the preferential dopamine autoreceptor agonist B-HT 920 were studied by means of the mouse motor activity. In reserpine-treated mice, B-HT 920 did not cause any motor activity by itself but it markedly potentiated the slight stimulating effect of the D1 dopamine agonist SKF 38 393. The effect was blocked by either the D2-receptor antagonist sulpiride or the D1-receptor antagonist SCH 23 390, indicating that motor activity is dependent on simultaneous activation of both dopamine receptor types. The hyperactivity produced by 0.1 mg kg-1 B-HT 920 in combination with SKF 38 393 in reserpine-treated mice was at least as great as that following a maximal dose of apomorphine, indicating that B-HT 920 is a full agonist at postsynaptic D2 receptors. The effect of 0.1 mg kg-1 B-HT 920 peaked earlier than those of 1 mg kg-1 and particularly, 10 mg kg-1 suggesting additional effects of the later two doses. B-HT 920 stimulates dopamine autoreceptors almost maximally following 0.1 or 1 mg kg-1 but only the latter dose (with or without SKF 38 393) caused hyperactivity of mice not treated with reserpine. This finding indicates that the postsynaptic D2 receptors are less sensitive to B-HT 920 than the D2 dopamine autoreceptors.     

Ultrastructural analysis of prefrontal cortical inputs to the rat amygdala: spatial relationships to presumed dopamine axons and D1 and D2 receptors

Projections from the prefrontal cortex (PFC) to the amygdala (AMG) regulate affective behaviors in a manner that is modulated by dopamine (DA). Although PFC and DA inputs overlap within the basolateral nucleus (BLA) and intercalated cell masses (ICMs), the spatial relationship between these afferents has not been investigated, nor is it known how DA D1 (D1R) and D2 (D2R) receptors are localized in relationship to PFC terminals. We therefore combined tract-tracing from the rat PFC to the AMG with immunocytochemical labeling of tyrosine hydroxylase (TH) to identify presumed DA axons or D1R and D2R. In both the ICMs and BLA, PFC terminals formed asymmetric synapses onto spines that typically did not receive secondary synaptic inputs. TH-immunoreactive (-ir) fibers in the adjacent neuropil typically contacted different structures. Although PFC and TH-ir axons were sometimes apposed to the same dendrites or to each other, PFC terminals only rarely synapsed onto dendrites that also received synapses from TH-ir axons. D1R-ir spines and dendrites were observed commonly within the ICMs but less frequently within the BLA, and PFC axons in the ICMs occasionally synapsed onto D1R-ir spines. Within both regions, D2R-ir spines, dendrites, and axons were observed. PFC terminals occasionally contained presynaptic labeling for D2R but were not observed to synapse onto D2R-ir targets. The infrequent observation of synaptic convergence between PFC and presumed DA terminals within the AMG suggests that DA modulates PFC inputs primarily via extrasynaptic mechanisms, a conclusion supported by the localization of D2R within and D1R postsynaptic to PFC terminals.     

D1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons.

The expression of Fos, the product of the proto-oncogene c-fos, is thought to be a marker of neuronal activity. D1, but not D2, dopamine receptor agonists have previously been shown to increase Fos immunoreactivity in striatonigral neurons ipsilateral to a 6-hydroxydopamine lesion of the nigrostriatal pathway. In the present study, it was demonstrated that the D1 receptor agonist SKF 38393 rarely increased Fos in striatopallidal neurons of the 6-hydroxydopamine denervated striatum. Conversely, in the intact striatum, the D2 receptor antagonist haloperidol enhanced Fos expression predominantly in striatopallidal neurons labelled retrogradely from the globus pallidus or with an oligonucleotide probe complementary to mRNA encoding enkephalin. These results are consistent with studies suggesting that D1 receptors are located predominantly on striatonigral neurons and that D2 receptors reside principally on enkephalin-containing striatopallidal neurons. They also provide a neuroanatomical basis for neurochemical and neurophysiological observations indicating that dopamine facilitates the activity of striatonigral neurons but inhibits striatopallidal neurons. In another experiment the selective D2 receptor agonist quinpirole was found to increase Fos immunoreactivity in the globus pallidus ipsilateral to a 6-hydroxydopamine lesion. It is proposed that this may have been due to a D2 receptor-mediated inhibition of enkephalin and GABA release from striatopallidal terminals that in turn disinhibited the pallidal neurons. In a final series of experiments, brain microdialysis was used to determine the location of dopamine receptors regulating striatal Fos expression. Local application of the selective D1 receptor agonist CY 208-243 in the 6-hydroxydopamine-denervated striatum, or of haloperidol in the intact striatum via the dialysis probe increased Fos immunoreactivity in the immediate vicinity of the probe. Hence, the inductive effects of these systematically administered compounds on Fos expression in the striatum are mediated at least partly by local dopamine receptors in the striatum. Taken together, these results suggest that the differential regulation of striatonigral and striatopallidal activity by dopamine is mediated by the largely separate location of D1 and D2 receptors on these outputs.     

Coactivation of D1 and D2 dopamine receptors is required for long-term synaptic depression in the striatum.

Long-term changes of synaptic transmission following brief trains of high-frequency stimulation of excitatory pathways in the brain have attracted attention as a possible correlate of memory. In the cerebellum, concurrent activation of parallel fibers and climbing fibers leads to a long-term depression (LTD) of synaptic transmission, which may be the cellular substrate of motor learning in this structure. We report here for the first time that high-frequency stimulation of corticostriatal glutamatergic fibers in the striatum, another brain structure strongly involved in motor control, also induces LTD of synaptic transmission. Induction of striatal LTD is blocked either by SCH 23390, a D1 dopamine (DA) receptor antagonist or by L-sulpiride, a D2 DA receptor antagonist. The lesion of the nigrostriatal DAergic pathway abolishes LTD. After DA depletion, LTD can be restored by the application of exogenous DA. LTD can also be restored by coadministration of D1 and D2 DA receptor agonists, but not by the application of a single class of DA agonists alone. Our data show that coactivation of D1 and D2 DA receptors is required for LTD in the striatum. D1/D2 receptor cooperation in the induction of LTD may play a crucial role in the behavioural function of DA and in the therapeutic effects of DA agonists in Parkinson's disease.     

Behavioural role of dopamine D1 receptors in the reserpine-treated mouse

The effects of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) (D1 agonist) on the motor behaviour of mice rendered hypokinetic with reserpine, were studied in the absence and presence of additional treatment with N-n-propyl-N-phenylethyl-p(3-hydroxyphenyl)ethylamine hydrochloride (RU 24213), lisuride (D2 agonists) or apomorphine (mixed D1/D2 agonist). Three hours after reserpine (5 mg/kg) stimulating dopamine D2 receptors evoked slow, ponderous walking and head-down sniffing. SKF 38393 (1.5-15 mg/kg) had no direct effect of its own, but greatly amplified the D2 response, giving more fluent locomotion, rearing and grooming. The facilitatory action of SKF 38393 was inhibited by the D1 antagonist (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin l -7-ol (SCH 23390) (0.05 mg/kg), whereas D2-mediated responses were sensitive both to SCH 23390 and the D2 antagonist metoclopramide (0.5 mg/kg). Mice treated with reserpine for 24 h became more sensitive to the motor stimulant actions of all four agonists. SKF 38393 now promoted rapid locomotion, rearing and grooming directly. The effects of D2 stimulation were weak by comparison and often antagonistic (not synergistic) with those of the D1 agonist. Both sets of agonists were now attenuated only by their respective antagonists. Reserpine caused pronounced falls in the concentrations of dopamine, 5-hydroxytryptamine and noradrenaline in the striatum, olfactory tubercle and cerebral cortex, with correspondingly elevated metabolite levels. These results indicate that D1 and D2 agonists at doses that are relatively ineffective at stimulating behaviour when given in isolation 3 h after reserpine, interact when given together to partially restore locomotion, rearing and grooming. This interaction is not apparent 24 h post-reserpine, a time at which D1 and D2 agonists produce significant effects of their own.     

Evidence for the presence of D2 but not D1 dopamine receptors in rat hypothalamic perifornical area

Behavioural studies have shown that the perifornical hypothalamus (PFH) plays a fundamental role in mediating dopamine-induced anorexia. In the present report, we provide biochemical evidence for the occurrence of dopamine receptors in the PFH, but not in the paraventricular nucleus of the hypothalamus. Dopamine as well as bromocriptine, a D2 dopamine receptor agonist, strongly reduced the adenylate cyclase activity in the PFH. This inhibitory effect was reversed by haloperidol and by (-)-sulpiride, but not by (+)-sulpiride. On the contrary, the selective D1 dopamine agonist SKF 82526 was completely inactive in affecting adenylate cyclase activity. Our conclusion asserts the existence of dopamine D2 but not D1 receptors in the PFH, which therefore can be conceived as the only region in the brain where a single class of dopamine receptors is present.     

Distribution of D1 and D5 dopamine receptors in the primate and rat basolateral amygdala

Dopamine, acting at the D1 family receptors (D1R) is critical for the functioning of the amygdala, including fear conditioning and cue-induced reinstatement of drug self administration. However, little is known about the different contributions of the two D1R subtypes, D₁ and D₅. We identified D₁-immunoreactive patches in the primate that appear similar to the intercalated cell masses reported in the rodent; however, both receptors were present across the subdivisions of the primate amygdala including the basolateral amygdala (BLA). Using immunoelectron microscopy, we established that both receptors have widespread distributions in BLA. The D1R subtypes colocalize in dendritic spines and terminals, with D₁ predominant in spines and D₅ in terminals. Single-cell RT-PCR confirmed that individual BLA projection neurons express both D₁ and D₅ mRNA. The responses of primate BLA neurons to dopamine and D1R drugs were studied using in vitro slices. We found that responses were similar to those previously reported in rat BLA neurons and included a mixture of postsynaptic and presynaptic actions. We investigated the distribution of D1R in the rat BLA and found that there were similarities between the species, such as more prominent D₅ localization to presynaptic structures. The higher affinity of D₅ for dopamine suggests that presynaptic actions may predominate in the BLA at low levels of dopamine, while postsynaptic effects increase and dominate as dopaminergic drive increases. The results presented here suggest a complex action of dopamine on BLA circuitry that may evolve with different degrees of dopaminergic stimulation.     

Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 receptors.

Within the D2-class of dopamine receptors, the D2 and D3 subtypes share the highest degree of similarity in their primary structure. However, the extent to which these two receptor subtypes have similar or different functional properties is unclear. The present study used gene targeting to generate mice deficient for D2, D3, and D2/D3 receptors. A comparative analysis of D2 and D3 single mutants and D2/D3 double mutants revealed that D2/D3 double mutants develop motor phenotypes that, although qualitatively similar to those seen in D2 single mutants, are significantly more severe. Furthermore, increased levels of the dopamine metabolites dihydroxyphenyl acetic acid and homovanillic acid are found in the dorsal striatum of D2 single mutants. The levels of these metabolites, however, are significantly higher in mice lacking D2 and D3 receptors. In addition, results of immunoprecipitation experiments revealed that D2 single mutants express higher levels of D3 receptor proteins during later stages of their postnatal development. These results suggest that D3 receptors compensate for some of the lacking D2 receptor functions and that these functional properties of D3 receptors, detected in mice with a D2 mutant genetic background, remain masked when the abundant D2 receptor is expressed.     

The role of D1 and D2 dopamine receptors in oral stereotypy induced by dopaminergic stimulation of the ventrolateral striatum

Microinjection of amphetamine into the ventrolateral region of the striatum results in compulsive and intense oral stereotypies in the rat. Although these stereotyped behaviors are known to be a direct result of excessive stimulation of the striatal dopamine neurons, the relative roles of the D1 and D2 receptors in oral stereotypies are not clearly understood. It is reported here that microinjection of the selective D1 agonist, SKF 38393 (0, 0.3, 3.0, 30.0 micrograms in 0.5 microliters vehicle) into the ventrolateral striatum resulted in no observable changes in behavior during the 30-min test period. However, it was observed that intense self-biting emerged 3-4 h following injection. Examination of histology from these animals revealed extensive tissue damage and the delayed onset of biting was hypothesized to result from a neurotoxic effect of SKF 38393. Infusion of quinpirole (0, 0.3, 3.0, 30.0 micrograms in 0.5 microliter vehicle), a selective D2 agonist, resulted in a dose-dependent increase in orofacial behaviors such as licking, wood-chip eating, head-down sniffing and mouth movements. Intense oral stereotypies such as biting or gnawing were not observed following treatment with quinpirole. Infusion of the mixed agonist dopamine (0, 2.0, 10.0, 20.0 micrograms in 0.5 microliter vehicle) into the ventrolateral striatum was found to elicit intense oral stereotypy. This behavior consisted almost exclusively of self-biting similar to that observed following amphetamine microinjection into this region. Haloperidol, when given as either a systemic (0.2 mg/kg) or intra-ventrolateral striatum (2.5 micrograms/0.5 microliter) pretreatment, effectively blocked oral stereotypies induced by amphetamine microinjection into the ventrolateral striatum. Pretreatment with either the D1 antagonist SCH 23390 (0, 0.01, 0.1 mg/kg, i.p.) or the D2 antagonist raclopride (0, 0.05, 0.50, 1.0 mg/kg, i.p.) antagonized amphetamine-induced oral stereotypy in a dose-dependent manner. These findings demonstrate that within the striatal site specifically implicated in oral behavior, concurrent stimulation of both receptor subtypes is necessary for the expression of intense oral stereotypies.     

Excitatory and inhibitory action of dopamine on hippocampal neurons in vitro. Involvement of D2 and D1 receptors

The study examined the effects of dopaminergic agonists on the extracellularly recorded spontaneous activity of CA1 neurons in hippocampal slices of the rat. Dopamine evoked excitation or inhibition of the neuronal firing rate, the first reaction being more sensitive to the substance. Having used selective dopaminergic agonists (pergolide and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepines) and selective antagonists (haloperidol, spiperone, sulpiride and (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol), it was concluded that the excitation evoked by dopamine was due to activation of D2 dopamine receptors, while the inhibition was the result of D1 receptor activation. The effects of the dopamine agonists on the firing of CA1 neurons were long-lasting, which suggests a modulating role of dopamine in the hippocampus.