Role of striatal acetylcholine on dopamine D1 receptor agonist-induced turning behavior in 6-hydroxydopamine lesioned rats: a microdialysis-behavioral study

The effects of MK-801, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, of quinpirole, a dopamine (DA) D₂ receptor agonist, and of SCH 58261, an A_2A adenosine antagonist, were studied on acetylcholine (ACh) release in the striatum of 6-hydroxydopamine (60HDA) lesioned rats and on turning behavior induced by the administration of the DA D₁ agonist CY 208-243. Administration of CY 208-243 to 60HDA lesioned rats induced turning behavior and dose-dependently stimulated ACh release. At the dose of 50 μg/kg, MK-801 failed to affect basal ACh, while at 100 μg/kg MK-801 reduced it; however, MK-801 (50 and 100 μg/kg) potentiated the turning behavior elicited by CY 208-243, but failed to affect the CY 208-243-induced increase of striatal ACh release. The administration of quinpirole induced low-intensity turning behavior and decreased basal ACh release; on the other hand, quinpirole potentiated the turning behavior induced by CY 208-243, but failed to affect the CY 208-243-elicited increase of ACh release. Finally, intravenous administration of SCH 58261 stimulated basal ACh release but not turning behavior, SCH 58261, however, potentiated turning behavior induced by CY 208-243, while failing to affect the D₁-elicited increase of ACh release. These results indicate that potentiation of D₁-dependent turning behavior by MK-801, quinpirole and SCH 58261 is not mediated by a reduced ability of D₁-agonists to stimulate ACh release from the denervated striatum.     

Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: Electrophysiological and behavioral studies

Many effects resulting from D₂ dopamine (DA) receptor stimulation are manifest only when D₁ DA receptors are stimulated by endogenous DA. When D₁ receptor stimulation is enhanced by administration of selective D₁ receptor agonists, the functional effects of selective D₂ agonists are markedly increased. These qualitative and quantitative forms of D₁/D₂ DA receptor synergism are abolished by chronic DA depletion when both D₁ and D₂ DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D₁ and D₂ renaptnr supersensitivity, induced by repeated administration of selective D₁ or D₂ receptor antagonists, on the synergistic relationships between D₁ and D₂ receptors. Daily administration of the selective D₂ antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D₂ agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D₁ agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D₂ receptors from the necessity of D₁ receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (sterotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D₁ receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D₁ receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390-pretreated rats. When such Dl-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D₁-sensitized rats are due to a heterologous sensitization of D₂ receptors rather than to enhanced enabling resulting from supersensitive D₁ receptors. It is suggested that supersensitivity of either D₁ or D₂ receptors can lead to an uncoupling of normal qualitative and quantitative D₁/D₂ synergisms and that the heterologous regulation of D₂ receptor sensitivity by D₁ receptors may be related to uncoupling of functional D₁/D₂ synergisms.     

A within-subjects microdialysis/behavioural study of the role of striatal acetylcholine in D1-dependent turning.

In rats lesioned with 6-hydroxydopamine (6-OHDA) the effect of the noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, MK-801, the dopamine (DA) D2 receptor agonist quinpirole and the A2A adenosine antagonist SCH 58261 was studied on acetylcholine (ACh) release in the lesioned striatum and contralateral turning behaviour stimulated by the administration of the DA D1 receptor agonist CY 208-243. Administration of CY 208-243 (75, 100 and 200 microg/kg) to 6-OHDA-lesioned rats dose-dependently stimulated ACh release and induced contralateral turning. MK-801 (50 and 100 microg/kg) reduced basal ACh release (max 22%) and did not elicit any turning. MK-801 (50 and 100 microg/kg) potentiated the contralateral turning, but failed to modify the stimulation of ACh release elicited by 100 and 200 microg/kg of CY 208-243. MK-801 (100 microg/kg) prevented the increase in striatal ACh release evoked by the lower dose of CY 208-243 (75 microg/kg) but contralateral turning was not observed. The D2 receptor agonist quinpirole (30 and 60 microg/kg) elicited low-intensity contralateral turning and decreased basal ACh release. Quinpirole potentiated the D1-mediated contralateral turning behaviour elicited by CY 208-243 (100 microg/kg), but failed to affect the increase in ACh release elicited by the D1 agonist. The adenosine A2A receptor antagonist SCH 58261 (1 microg/kg i.v.) failed per se to elicit contralateral turning behaviour. SCH 58261 potentiated the contraversive turning induced by CY 208-243 but failed to affect the increase of ACh release. The results of the present study indicate that blockade of NMDA receptors by MK-801. stimulation of DA D2 receptors by quinpirole and blockade of adenosine A2A receptors by SCH 58261 potentiate the D1-mediated contralateral turning behaviour in DA denervated rats without affecting the action of the D1 agonist on ACh release. These observations do not support the hypothesis that the potentiation of D1-dependent contralateral turning by MK-801, quinpirole or SCH 58261 is mediated by changes in D1-stimulated release of ACh in the striatum.     

Regulation of Dopamine D1 and D2 Receptors on Striatal Acetylcholine Release in Rats

The effects of dopamine (DA) D₁ and D₂ receptors on striatal acetylcholine (ACh) releases were investigated by in vivo microdialysis. All drugs were applied via dialysis membrane directly to the striatum. The levels of ACh release were increased by 10⁻⁴ M SKF38393, a D₁ receptor agonist. Although 10⁻⁴ M SCH23390, a D₁ receptor antagonist, exhibited an increase in the levels of ACh release, the agonist (10⁻⁴ M) induced-increase in the levels of ACh release was suppressed by coperfusion of the antagonist (10⁻⁴ M). In contrast, the levels of ACh release were decreased by the D₂ receptor agonist, N-434, in a dose-dependent manner (10⁻⁵ M to 10⁻⁷ M) and increased by the D₂ receptor antagonist, sulpiride, in a dose-dependent manner (10⁻⁵ M to 10⁻⁷ M). The agonist (10⁻⁵ M) induced-decrease in the levels of ACh release was suppressed by coperfusion of the antagonist (10⁻⁶ M). Coperfusion of D₁ (10⁻⁴ M) and D₂ (10⁻⁵ M) agonists blocked both effects of respective drug alone. In order to clarify the effect of endogenous DA, two drugs with different mechanisms for enhancing DA concentration in the synaptic cleft, the DA release-inducer methamphetamine, and the DA uptake inhibitor nomifensine were perfused separately. Both (10⁻⁴ M to 10⁻⁶ M) produced a dose- and a time-dependent decrease in the levels of ACh release. Significant higher levels of ACh release were observed in the striatum of the 6-hydroxydopamine (8

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)-treated rats with significant depletion of striatal DA content. These results suggest that in striatal DA-ACh interaction ACh release, as cholinergic interneuron's activity, is tonically inhibited via the D₂ receptor, mainly by dopaminergic input, and the D₁ receptor probably modifies the effect of the D₂ receptor indirectly.     

5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices

The role of 5-hydroxytryptamine (5-HT) receptor subtypes in acetylcholine (ACh) release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D₁ receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the K⁺-evoked [³H]ACh release while SCH 23390, a dopamine D₁ receptor antagonist, had no effect. [³H]ACh release was decreased by the dopamine D₂ receptor agonist LY 171555 (quinpirole) and slightly potentiated by the dopamine D₂ receptor antagonist haloperidol. The selective neurokinin NK₁ receptor agonist [Sar⁹, met(O₂)¹¹]SP also potentiated K⁺-evoked release of [³H]ACh. GR 82334, a NK₁ receptor antagonist, blocked not only the effect of [Sar⁹, met(O₂)¹¹]SP but also the release of ACh induced by the D₁ receptor agonist SKF 38393. Among the 5-HT agents studied, only the 5-HT_2A receptor antagonists ketanserin and ritanserin were able to reduce the ACh release induced by dopamine D₁ receptor stimulation. Mesulergine, a more selective 5-HT_2C antagonist, showed an intrinsic releasing effect but did not affect K⁺-evoked ACh release induced by SKF 38393. Methysergide and methiothepin, mixed 5-HT_1/2 antagonists, as well as ondansetron, a 5-HT₃ receptor antagonist, showed an intrinsic effect on ACh release, their effects being additive to that of SKF 38393. 5-HT₂ receptor agonists were ineffective. However, the 5-HT₂ agonist DOI was able to prevent the antagonism by ketanserin of the increased [³H]ACh efflux elicited by SKF 38393, suggesting a permissive role of 5-HT_2A receptors. None of the above indicated 5-HT agents was able to reduce the ACh release induced by the selective NK₁ agonist. The results suggest that 5-HT₂ receptors, probably of the 5-HT_2A subtype, modulate the release of ACh observed in slices from the rat striatum after stimulation of dopamine D₁ receptors. It seems that this serotonergic control is exerted on the interposed collaterals of substance P-containing neurons which promote ACh efflux through activation of NK₁ receptors located on cholinergic interneurons.     

Selective unilateral inactivation of striatal D1 and D2 dopamine receptor subtypes by EEDQ: turning behavior elicited by D2 dopamine receptor agonists

The unilateral intrastriatal injection of the irreversible dopamine (DA) receptor blockerN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a marked decrease in the density of D₁ (-48%) and D₂ (-51%) DA receptors available for binding to [³H]SCH 23390 and [³H]raclopride, respectively. A challenge dose of the D₂ agonist LY 171555 (1 mg/kg, i.p., 24 h after EEDQ) causes intensive ipsiversive circling behavior, whereas the selective D₁ agonist SKF 38393 (20 mg/kg, i.p., 24 h after EEDQ) is unable to induce rotations. The density of D₁ and D₂ DA receptors returns to basal levels by 7 days after the intrastriatal infusion of EEDQ. This biochemical recovery is associated with a progressive decrease in the number of rotations elicited by a challenge dose of LY 171555, suggesting the EEDQ does not cause any relevant neuronal damage. A selective inactivation of striatal D₁ or D₂ DA receptors can be obtained by injecting EEDQ 30 min after the administration of the D₂ antagonist raclopride (20 mg/kg, i.p.) or of the D₁ antagonist SCH 23390 (2 mg/kg, s.c.), respectively. The intensity of the circling behavior induced by LY 171555 24 h after EEDQ in animals with a selective inactivation of D₂ DA receptors is similar to that found in rats in which both D₁ and D₂ DA receptors have been inactivated. In contrast, LY 171555 does not cause rotations when the density of D₁ DA receptors is selectively decreased by EEDQ in rats pretreated with raclopride. These results indicate that the imbalance in striatal D₂ receptors, but not in D₁ receptors, is a critical factor for the expression of the motor effects elicited by LY 171555 in EEDQ-treated rats.     

Adenosine A2a receptor antagonists attenuate striatal adaptations following dopamine depletion

The motor symptoms of Parkinson's disease (PD) are widely thought to arise from an imbalance in the activity of the two major striatal efferent pathways following the loss of dopamine (DA) signaling. In striatopallidal, indirect pathway spiny projection neurons (iSPNs), intrinsic excitability rises following the loss of inhibitory D2 receptor signaling. Because these receptors are normally counterbalanced by adenosine A2a adenosine receptors, antagonists of these receptors are being examined as an adjunct to conventional pharmacological therapies. However, little is known about the effects of sustained A2a receptor antagonism on striatal adaptations in PD models. To address this issue, the A2a receptor antagonist SCH58261 was systemically administered to DA-depleted mice. After 5 days of treatment, the effects of SCH58261 on iSPNs were examined in brain slices using electrophysiological and optical approaches. SCH58261 treatment did not prevent spine loss in iSPNs following depletion, but did significantly attenuate alterations in synaptic currents, spine morphology and dendritic excitability. In part, these effects were attributable to the ability of SCH58261 to blunt the effects of DA depletion on cholinergic interneurons, another striatal cell type that co-expresses A2a and D₂ receptors. Collectively, these results suggest that A2a receptor antagonism improves striatal function in PD models by attenuating iSPN adaptations to DA depletion.     

A critical role for D1 receptors in the 5-HT1A-mediated facilitation of in vivo acetylcholine release in rat frontal cortex

Subcutaneous administration of 8-OH-DPAT dose-dependently increased acetylcholine (ACh) output in frontal cortex of awake rats. The maximal effect of 8-OH-DPAT (0.5 mg/kg, s.c.) was prevented by the 5-HT_1A antagonist WAY 100635 (1 mg/kg, s.c.) and by the D₁ antagonists SCH 23390 or SCH 39166 (both 0.3 mg/kg, s.c.) but not seven days after chemical lesion of the raphe serotoninergic neurons. It is postulated that the 8-OH-DPAT activation of postsynaptic 5-HT_1A receptors enhances the release of dopamine which, by acting at D₁ receptors, stimulates the release of ACh in the frontal cortex.     

Modulation of acetylcholine release by D1, D2 dopamine receptors in rat striatum under freely moving conditions

Using in vivo brain dialysis under freely moving conditions, we have studied the effects of dopamine (DA) agonists and antagonists on acetylcholine (ACh) and DA release in rat striatum. The striatal infusion of the D1 DA receptor specific agonist, SKF38393, increased striatal ACh release in a dose-dependent manner (10(-6) to 10(-4) M), and 3 x 10(-5) M SKF38393 elicited a 60% augmentation in the level of ACh release. The level of ACh was increased with perfusion of 10(-4) M SCH23390, a D1 specific antagonist, but decreased with 10(-3) M SCH23390. The D2 specific agonist, LY171555, and the antagonist, sulpiride, slightly altered the level of ACh in the striatum. On the other hand the level of DA dramatically increased in a dose-dependent manner with SKF38393 or SCH23390 and decreased with LY171555. LY171555 inhibited the effect of 10(-4) M SKF38393 on ACh release, and enhanced the effect of SKF38393 on DA release. These results suggest that the D1 DA receptor mainly mediates ACh release and the D2 DA receptor modifies the effects of the D1 receptor.     

Ontogenetic quinpirole treatments fail to prime for D<Subscript>2</Subscript> agonist-enhancement of locomotor activity in 6-hydroxydopamine-lesioned rats

Repeated treatments with a dopamine (DA) D₂ receptor agonist result in the induction of DA D₂ receptor supersensitivity, as evidenced by enhanced behavioral responses to subsequent D₂ agonist treatments—a phenomenon known aspriming of receptors. Priming of D₂ receptors has been well-studied in otherwise intact (non-lesioned) rats. In contrast to D₂ priming, repeated treatments with a DA D₁ agonist are unable to prime D₁ receptors unless nigrostriatal DA fibers are largely destroyed in early postnatal ontogeny. In order to determine if D₂ receptors could be primed in rats in which nigrostriatal DA fibers were largely destroyed in early postnatal ontogeny, rats were (a) lesioned at 3 days after birth with 6-hydroxydopamine (67 μg in each lateral ventricle; desipramine, 20 mg/kg IP, 1 h; 6-OHDA), (b) treated daily for the first 28 days after birth with the D₂ agonist quinpirole HCl (3.0 mg/kg IP), and (c) observed in adulthood for both quinpirole-induced and SKF 38393- (D₁ agonist-) induced locomotor activity and stereotyped activities. In 6-OHDA-lesioned rats in which endogenous striatal DA was reduced by 99%, quinpirole did not produce enhanced locomotor or stereotyped activities. However, SKF 38393 produced increased locomotor and stereotyped activities even after the first dose of SKF 38393. These findings demonstrate that D₂ receptors are not primed by ontogenetic quinpirole treatments of neonatally 6-OHDA-lesioned rats, although D₂ agonist treatments do at least partially prime D₁ receptors in 6-OHDA-lesioned rats.     

Repeated quinpirole treatment: Locomotor activity,dopamine synthesis,and effects of selective dopamine antagonists

Repeated treatment with the non-selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D₂-type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D₂-type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty-four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4-dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD-1015, was enhanced in the striatum, but not nucleus accumbensolfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D₁ antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) × two (vehicle or SCH 23390) design. Quinpirolealone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390-alone and quinpirole-SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect. In Experiment 3, rats were treated for 10 days with vehicle, 3.0 mg/kg quinpirole or the D₂ antagonist eticlopride (1.0 mg/kg) in a two (vehicle or quinpirole) × two (vehicle or eticlopride) design. As in the first two experiments, repeated quinpirolealone treatment resulted in a reduction of the locomotor suppressant effects of the drug; however, locomotor activity in this group was enhanced compared to vehicle controls on day 10. Eticlopridealone and eticlopride-quinpirole treated rats had suppressed locomotor activity across the 10 days. DOPA accumulation was enhanced by both repeated quinpirole and repeated eticlopride treatment in the striatum and NAOT. DOPA accumulation in eticlopride-quinpirole treated rats was not different from vehicle control levels in the NAOT, while no significant difference was obtained between the eticlopridealone and eticlopride-quinpirole groups in the striatum. The locomotor activity data suggest that repeated quinpirole treatment results in tolerance to the locomotor suppressant effect of the drug. Evidence for sensitization was obtained in two out of three of the experiments. These results suggest that enhanced dopamine synthesis after repeated non-selective dopamine agonist treatment is modulated by D₂-type dopamine receptors. © 1995 Wiley-Liss, Inc.     

Tyrosine hydroxylase, aromatic -amino acid decarboxylase and dopamine metabolism after chronic treatment with dopaminergic drugs

Mice were treated with dopamine (DA) receptor agonist and antagonist drugs: Agonists: (±)-SKF 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) [DA D₁-like]; bromocriptine, [DA D₂ selective]; quinpirole, [DA D₂/D₃ preferring]; (±)-7-hydroxy-dipropylamino-tetralin (7-OH-DPAT), [DA D₃/D₂ preferring], Antagonists: R(+)-SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), [DA D₁-like]; and haloperidol, [DA D₂-like]. All drugs were administered intraperitoneally, two injections daily 8 h apart for 30 days. Aromatic -amino acid decarboxylase (AAAD) and tyrosine hydroxylase (TH) activity, protein and mRNA, as well as DA metabolism were followed with time thereafter in the nigrostriatal neurons. We observed that chronic administration of D₁-like agonists had no effect on TH or AAAD activity, while D₂-like agonists decreased AAAD, but not TH activity. Additionally, chronic blockade of DA D₂-like receptors resulted in prolonged induction of TH and AAAD, while chronic blockade of DA D₁-like receptors induced changes of AAAD only. Compared to TH the induction of AAAD was longer lasting. DA metabolism was altered by chronic administration of drugs acting on DA D₂-like, but not DA D₁-like receptors, and in general the patterns of change did not follow those for TH or AAAD. When studied 48 h after the last dose of the chronic haloperidol schedule TH displayed tolerance to acute drug challenge. At the same time interval, there was tolerance to the enhancing effects of haloperidol and SCH 23390 on DA metabolism. The induction of AAAD by haloperidol or SCH 23990 did not appear to develop tolerance after chronic administration. These observations complement existing knowledge, and provide novel information about AAAD that may have practical importance for Parkinson's patients on -DOPA therapy.     

Altered dopaminergic function in the prefrontal cortex, nucleus accumbens and caudate-putamen of an animal model of attention-deficit hyperactivity disorder — the spontaneously hypertensive rat

The spontaneously hypertensive rat (SHR) has been proposed as an animal model for Attention-Deficit Hyperactivity Disorder (ADHD). The behavioural problems of ADHD have been suggested to be secondary to altered reinforcement mechanisms resulting from dysfunction of the mesolimbic and mesocortical dopaminergic systems. The present study therefore investigated whether there are regional differences in dopamine (DA) and acetylcholine (ACh) release and DA D₂-receptor function in SHR compared to their normotensive Wistar-Kyoto (WKY) controls. The DA D₂-receptor agonist, quinpirole, caused significantly greater inhibition of DA release from caudate-putamen but not from nucleus accumbens or prefrontal cortex slices of SHR relative to WKY. DA D₂-receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in DA release from nucleus accumbens slices of SHR compared to WKY suggesting increased efficacy of DA autoreceptors at low endogenous agonist concentrations in the nucleus accumbens of SHR. The electrically-stimulated release of DA was significantly lower in caudate-putamen and prefrontal cortex slices of SHR than in slices of WKY. This could be attributed to increased autoreceptor-mediated inhibition of DA release in caudate-putamen slices but not in the prefrontal cortex. No difference was observed between SHR and WKY with respect to DA D₂-receptor-mediated inhibition of ACh release from caudate-putamen or nucleus accumbens slices, suggesting that postsynaptic DA D₂-receptor function is not altered in SHR relative to WKY.     

Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats

Acetylcholine (ACh) systems have been widely shown to be important for memory. In particular, ACh hippocampal neurons are critical for memory formation, though ACh innervation of other areas such as the nucleus accumbens may also be important. There has also been increasing interest in ACh and dopaminergic (DA) interactions with regard to short-term spatial memory. In a series of studies, we have found that ACh and DA agonists and antagonists given systemically interact to influence memory. The critical neural loci of these interactions are not currently known. In the present study, we used local infusion techniques to examine the role of ACh and DA transmitter systems in the nucleus accumbens and the ventral hippocampus on radial-arm maze (RAM) working memory performance. Into the nucleus accumbens of rats, we infused the nicotinic ACh agonist nicotine, the nicotinic ACh antagonist mecamylamine, the DA agonist apomorphine, or the DA antagonist haloperidol. Into the ventral hippocampus, we infused nicotine, mecamylamine, the muscarinic ACh agonist pilocarpine, or the muscarinic ACh antagonist, scopolamine. The nicotinic ACh and DA interaction was tested by a hippocampal infusion of mecamylamine alone or together with the DA D₂ agonist quinpirole given via subcutaneous injection. The results confirmed that both nicotinic and muscarinic ACh receptors in the ventral hippocampus play a significant role in spatial working memory. Blockade of either nicotinic or muscarinic ACh receptors caused significant impairments in RAM choice accuracy. However, infusion of either nicotinic or muscarinic agonists failed to improve choice accuracy. The interaction of DA D₂ systems is different with hippocampal nicotinic blockade than with general nicotinic blockade. Systemic administration of quinpirole potentiated the amnestic effect of mecamylamine infused into the ventral hippocampus, whereas it was previously found to reverse the amnestic effect of systemically administered mecamylamine. In contrast to the significant effects of mecamylamine in the hippocampus, no effects were found after infusion into the nucleus accumbens. Nicotine also was not found to have a significant effect on memory after intra-accumbens infusion. Neither the DA agonist apomorphine nor the DA antagonist haloperidol had a significant effect on memory after infusion into the nucleus accumbens. This study provides support for the involvement of nicotinic and muscarinic receptors in the ventral hippocampus in memory function. Ventral hippocampal nicotinic systems have significant interactions with D₂ systems, but these differ from their systemic interactions. In contrast, nicotinic ACh and DA systems in the nucleus accumbens were not found in the current study to be important for working memory performance in the RAM.     

GABAB modulation of dopamine release in the nucleus accumbens core

Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ‐Aminobutyric acid type B (GABA_B) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABA_B receptors, can decrease drug‐seeking behaviours. However, the mechanism by which GABA_B receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast‐scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration‐dependently decreased single pulse‐evoked DA release. This effect was blocked by the GABA_B antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D₂ receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D₂ receptors. Baclofen‐mediated suppression of DA release persisted after a locomotor‐sensitizing cocaine treatment, indicating that GABA_B receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen‐mediated suppression of terminal DA release is due to GABA_B activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment.     

Dopamine displays an identical apparent affinity towards functional dopamine D1 and D2 receptors in rat striatal slices: Possible implications for the regulatory role of D2 receptors

In this study we examined the selectivity of dopamine (DA) for rat striatal DA D₁ and D₂ receptors. In a Krebs-HEPES buffer, the K_i values of DA for D₁ binding sites (labelled with [³H]SCH23390) and D₂ binding sites (labelled with [³H]spiroperidol) in striatal membranes amounted to about 30 and.0.3 μM, respectively. However, the EC50s of DA (3 μM) and the DA releasing drug amphetamine (1 μM) were identical considering D₁ receptor-stimulated and D₂ receptor-inhibited adenylate cyclase activity in superfused striatal slices. Moreover, these EC₅₀ values were also obtained studying DA- and amphetamine-induced D₂ receptor activation, resulting in inhibition of the electrically evoked release of [¹⁴C]acetylcholine from the slices. Therefore, with regard to the apparent affinity of exogenous and endogenous DA for D₁ and D₂ receptors in rat striatal slices, the ligand-receptor binding data appeared to be misleading. Thus, our data show that in rat striatal slices DA has an identical apparent affinity towards functional D₁ and D₂ receptors, which is particularly intriguing in view of the very high receptor selectivity of synthetic D₁ and D₂ receptor agonists for these functional receptors in superfused brain slices as predicted on the basis of binding assays. This may have important implications for our understanding of central DA neurotransmission. For instance, since the inhibitory effect of opioid and muscarinic receptor activation on adenylate cyclase activity has been shown to be inversely related to the degree of DA D₂ receptor activation, the degree of activation of D₁ and D₂ receptors by released DA is suggested to act as a functional gate allowing distinct neurotransmitters to play a role in striatal neurotransmission. © 1994 Wiley-Liss, Inc.     

Effects of repeated and acute aripiprazole or haloperidol treatment on dopamine synthesis in the dorsal striatum of young rats: comparison to adult rats

The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol alters dopamine (DA) synthesis characteristics in the dorsal striatum of young rats. To this end, rats received a daily pretreatment regimen of aripiprazole or haloperidol on postnatal days (PD) 10–20 and were tested 24 or 72 h later after an acute injection of vehicle, aripiprazole, haloperidol, or quinpirole (a D2 agonist). For comparison purposes, adult rats were pretreated with an 11-day regimen of saline or haloperidol on PD 70–80 and DA synthesis was measured after acute drug treatment on PD 83. Dorsal striatal DA synthesis was determined by measuring l-dihydroxyphenylalanine accumulation after NSD-1015 treatment. In a separate experiment, the ability of repeated drug treatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats 72 h after drug discontinuation. The major findings of this study were that: (a) acute treatment with haloperidol and aripiprazole increased DA synthesis while quinpirole reduced it; (b) pretreatment with haloperidol and aripiprazole blunted the synthesis-modulating effects of acutely administered dopaminergic drugs; and (c) DA synthesis of young and adult rats was affected in a qualitatively similar manner by DA agonist, antagonist, and partial agonist drugs. In conclusion, results from the present study suggest that synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by the end of the preweanling period and DA synthesis declines to near basal levels during the course of repeated aripiprazole treatment.     

SCH 23390-induced behavioral supersensitivity is not related to striatal c-fos levels

Stereotyped behavior and striatal c-fos levels induced by chronic treatment with the D₁ dopamine antagonist SCH 23390 have been investigated in rats which received subsequent subacute dopamine agonist treatment. SCH 23390 treatment (0.5 mg/kg/day) for 21 days increased both apomorphine-induced orofacial stereotypies and striatal c-fos levels. Treatment with the D₁ dopamine agonist SKF 38393 (10 mg/kg/day) and the combination of SKF 38393 with the D₂ dopamine agonist quinpirole (1 mg/kg/day), for 5 consecutive days, attenuated apomorphine-induced stereotypies without changing c-fos levels in rats previously treated with SCH 23390. These findings suggest that SCH 23390-induced behavioral supersensitivity and the increased striatal c-fos levels are concomitant but unrelated phenomena.     

Regulation of NMDA-stimulated [C]GABA and [H]acetylcholine release by striatal glutamate and dopamine receptors

Striatal function is heavily influenced by glutamatergic and dopaminergic afferent input. To ultimately better understand how the N-methyl- -aspartate (NMDA) antagonist, phencyclidine (PCP), alters striatal function, we sought to determine how NMDA receptor function is influenced by activation of other glutamatergic receptors and by dopaminergic receptors. To this end, we used NMDA-stimulated efflux of [¹⁴C]GABA and [³H]acetylcholine (ACh) from striatal slices to assess the influence of these receptors on NMDA function. NMDA-stimulated [¹⁴C]GABA release was more sensitive to NMDA and glycine antagonists than was [³H]ACh release, suggesting that different NMDA receptors regulate the release of these neurotransmitters. Furthermore, NMDA-stimulated [³H]ACh release was inhibited by a D₂ receptor mechanism whereas NMDA-stimulated [¹⁴C]GABA release was enhanced by D₁ receptor activation. NMDA and (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) interact additively to evoke [³H]ACh release, and synergistically to evoke [¹⁴C]GABA release. An additive effect of NMDA and kainate (KA) was found on [¹⁴C]GABA release, but NMDA and KA acted in a less than additive manner in evoking [³H]ACh release. KA-stimulated [³H]ACh release was largely blocked by NMDA antagonists, suggesting mediation through activation of NMDA receptors, probably secondary to KA-induced glutamate release. A selective group II metabotropic receptor agonist inhibited NMDA-stimulated [¹⁴C]GABA and [³H]ACh release. On the other hand, NMDA-stimulated [¹⁴C]GABA release was potentiated by activation of group I metabotropic receptors. Thus, in addition to the differential modulation by D₁- and D₂-like receptors, the release of striatal neurotransmitters by NMDA receptor activation depends on the extent to which the other glutamate receptors, both ionotropic and metabotropic, are activated.     

Lack of autoreceptor-mediated inhibitory control of dopamine release in striatal synaptosomes of D2 receptor-deficient mice

Mouse purified striatal synaptosomes were used to study the release of newly synthesised [³H]-dopamine ([³H]-DA) or of previously taken up [³H]-DA. Quinpirole (QP, 10 μM), a D2/D3 dopaminergic agonist, was found to reduce the release of newly synthesised [³H]-DA with a larger amplitude when 4-aminopyridine (100 μM) instead than veratridine (1 μM) or potassium (25 mM) was used to evoke DA release. Among the different D2/D3 dopaminergic agonists tested R(−)-propylnorapomorphine (NPA) and quinpirole were the most potent. These compounds reduced, in a concentration-dependent manner, the 4-aminopyridine-evoked release of [³H]-DA previously taken up by synaptosomes (50% maximal inhibition). In contrast, the D3 agonist PD-128,907 had little effect even when used at 100 nM. The QP (100 nM)-induced response was completely antagonised by sulpiride (1 μM). Strikingly, the NPA (100 nM) and PD-128,907 (100 nM)-evoked responses were completely suppressed in D2 receptor-deficient mice. This data strongly suggest that only D2 but not D3 receptors are involved in the autoreceptor-mediated inhibition of the evoked release of [³H]-DA. Interestingly, while amphetamine-induced release of [³H]-DA was not modified, a slight reduction of [³H]-DA efflux induced by the dopamine (DA) uptake inhibitor cocaine was observed in D2 receptor-deficient mice.