Role of AMPA and NMDA receptors in the nucleus accumbens shell in turning behaviour of rats: interaction with dopamine receptors

The role of AMPA and NMDA receptors in the shell of the nucleus accumbens in turning behaviour of rats was investigated. Unilateral injection of the AMPA receptor agonist, AMPA (0.25, 0.4, 0.5 and 1 microg), into the shell of the nucleus accumbens dose-dependently produced contraversive pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping, while injection of AMPA (0.5 microg) into the core produced only a marginal effect. This shell-specific AMPA effect was dose-dependently inhibited by the AMPA receptor antagonist, NBQX (1 and 10 ng), which alone did not produce turning behaviour. The AMPA-induced pivoting was also dose-dependently inhibited by the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.5 microg). Neither MK-801 (0.1, 0.5 and 5 microg) nor the NMDA receptor agonist, NMDA (0.5 and 1 microg), injected unilaterally into the shell, produced turning behaviour. Unilateral injection of a mixture of dopamine D(1) (SKF 38393, 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the shell has been found to elicit contraversive pivoting. The dopamine D(1)/D(2) receptor antagonist, cis-(Z)-flupentixol (1 and 10 microg), injected into the shell, in doses known to block dopamine D(1)/D(2) receptor-mediated pivoting, also significantly inhibited AMPA (0.5 microg)-induced pivoting. Moreover, both NBQX (1 and 10 ng) and MK-801 (0.1 and 0.5 microg), injected into the shell, significantly inhibited dopamine D(1)/D(2) receptor-mediated pivoting. It is therefore concluded that unilateral stimulation of AMPA receptors in the shell of the nucleus accumbens can elicit contraversive pivoting, and that both AMPA and dopamine D(1)/D(2) receptors play a critical role in shell-specific pivoting in contrast to NMDA receptors that at best play only a modulatory role.     

Role of orexin receptors in the nucleus accumbens in dopamine-dependent turning behaviour of rats

The role of orexin receptors in the nucleus accumbens shell in rat turning behaviour of rats was studied. Unilateral injection of neither the orexin 1 and 2 receptor agonist orexin A (2 microg) nor the orexin 1 receptor antagonist SB 334867 (20 ng) into the nucleus accumbens shell elicited turning behaviour. Unilateral injection of a mixture of dopamine D(1) (SKF 38393) and D2 (quinpirole) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting. Orexin A (1 and 2 microg) dose-dependently potentiated the contraversive pivoting induced by a mixture of SKF 38393 (1 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell whereas SB 334867 (10 and 20 ng) did not significantly affect the pivoting. The potentiating effect of orexin A (2 microg) on the dopaminergic pivoting was not significantly inhibited by SB 334867 (10 and 20 ng) injected into the nucleus accumbens shell. The contraversive pivoting induced by a mixture of SKF 38393 (1 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell was also potentiated by the orexin 2 receptor agonist orexin B (0.5, 1 and 2 microg), which alone did not elicit turning behaviour. These results suggest that orexin 2 receptors in the nucleus accumbens shell play a modulatory role in rat turning behaviour.     

Acetylcholine receptor effects on accumbal shell dopamine-mediated turning behaviour in rats

The nature of acetylcholine receptor effects on dopaminergic functions within the nucleus accumbens shell was studied in rats, using turning behaviour as read-out parameter. Unilateral injections of the acetylcholine receptor agonist, carbachol (1.0-5.0 microg), into the nucleus accumbens shell dose-dependently elicited contraversive circling. Unilateral injections of the combination of a fixed dose of the dopamine D(2) receptor agonist, quinpirole (10.0 microg), with increasing doses of the dopamine D(1) receptor agonist, SKF 38393 (1.0-5.0 microg), into the nucleus accumbens shell dose-dependently elicited contraversive pivoting. The same held for the combination of a fixed dose of SKF 38393 (5.0 microg) with increasing doses of quinpirole (5.0 and 10.0 microg), which was injected into the nucleus accumbens shell. The nicotinic acetylcholine receptor antagonist, mecamylamine (5.0 and 10.0 microg), injected into the nucleus accumbens shell, which alone did not elicit any turning behaviour, significantly suppressed both the contraversive circling induced by carbachol (5.0 microg) and the contraversive pivoting induced by the mixture of SKF 38393 (5.0 microg) and quinpirole (10.0 microg). The muscarinic acetylcholine receptor antagonist, methylscopolamine (1.0 and 2.5 microg), injected into the nucleus accumbens shell, which alone did not elicit any turning behaviour, significantly suppressed the contraversive circling induced by carbachol (5.0 microg), whereas it significantly increased the contraversive pivoting induced by both the mixture of SKF 38393 (1.0 microg) and quinpirole (10.0 microg) and the mixture of SKF 38393 (5.0 microg) and quinpirole (5.0 microg). Neither SKF 38393 (5.0 microg) nor quinpirole (10.0 microg) injected into the nucleus accumbens shell affected the contraversive circling induced by carbachol (5.0 microg). Carbachol (1.0 microg) injected into the nucleus accumbens shell caused a slight initial potentiation followed by an inhibition of the contraversive pivoting induced by the mixture of SKF 38393 (5.0 microg) and quinpirole (10.0 microg). These results confirm that stimulation of both nicotinic and muscarinic acetylcholine receptors in the nucleus accumbens shell is required for the accumbens-dependent, acetylcholine-mediated circling. The study provides the original evidence that stimulation of nicotinic acetylcholine receptors in the nucleus accumbens shell is required for the accumbens-dependent, dopamine-mediated pivoting. Finally, the present study shows that muscarinic acetylcholine receptors in the nucleus accumbens shell play an inhibitory role in the production of the accumbens-dependent, dopamine-mediated pivoting.     

Adrenergic receptors in the nucleus accumbens shell differentially modulate dopamine and acetylcholine receptor-mediated turning behaviour

The role of alpha- and beta-adrenoceptors in the nucleus accumbens shell in turning behaviour of rats was investigated. Unilateral injections of the alpha-adrenoceptor agonist (phenylephrine; 10 microg) and antagonist (phentolamine; 10 microg) as well as the beta-adrenoceptor agonist (isoprenaline; 1 microg) and antagonist (propranolol; 5 microg) into the nucleus accumbens shell did not produce turning behaviour more than that of control vehicle injection. Unilateral injection of a mixture of dopamine D(1) ((+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol, SKF 38393; 5 microg) and D(2) (quinpirole; 10 microg) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting. Such pivoting was dose-dependently inhibited by phenylephrine (5, 10 microg), injected into the nucleus accumbens shell, and the inhibitory effect of phenylephrine (10 microg) was antagonised by phentolamine (10 microg) that per se had no effect on this pivoting. Isoprenaline (0.5, 1 microg) dose-dependently increased the contraversive pivoting induced by the mixture of SKF 38393 (1 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell. The effect of isoprenaline (1 microg) was antagonised by propranolol (5 microg) that per se had no effect on this pivoting. It is concluded that stimulation of accumbal alpha-adrenoceptors inhibits the dopamine-dependent pivoting in contrast to stimulation of accumbal beta-adrenoceptors that facilitates this dopamine-dependent pivoting. Unilateral injection of the acetylcholine receptor agonist carbachol (5 microg) into the nucleus accumbens shell has been found to elicit contraversive circling. Such circling was significantly reduced by accumbal administration of either phenylephrine (10, 20 microg) or phentolamine (5, 10 microg) in a dose-independent manner; moreover, both drugs potentiated, but did not counteract, each other's effects. Carbachol-induced circling was also reduced by propranolol (2.5, 5 microg), but again in an aspecific manner. It is concluded that alpha- and beta-adrenergic agents have an effect on accumbal acetylcholine receptor-mediated circling through a non-adrenergic mechanism. The impact of the present study for putative new treatments of various neuropsychiatric and neurological disorders is discussed.     

GABAA and GABAB receptors in the nucleus accumbens shell differentially modulate dopamine and acetylcholine receptor-mediated turning behaviour

The ability of GABA_A and GABA_B receptors in the shell of the nucleus accumbens to modulate distinct types of turning behaviour was investigated in freely moving rats, using the unilateral injection technique. The GABA_A receptor agonist muscimol and the GABA_A receptor antagonist bicuculline did not produce turning behaviour; the same holds for the GABA_B agonist baclofen and the GABA_B antagonist 2-hydroxysaclofen. A mixture of the dopamine D₁ receptor agonist SKF 38393 and the dopamine D_2/3 receptor agonist quinpirole has been found to elicit contraversive pivoting, when injected into the shell. This pivoting was dose-dependently inhibited by muscimol, and the inhibitory effect of muscimol was antagonised by bicuculline. Pivoting was also dose-dependently inhibited by baclofen; however, 2-hydroxysaclofen did not antagonise the inhibitory effect. The acetylcholine receptor agonist carbachol has been found to elicit contraversive circling, when injected into the shell. This carbachol-induced circling was inhibited by baclofen, and 2-hydroxysaclofen antagonised the inhibitory effect. Carbachol-induced circling was also partially inhibited by muscimol; however, the inhibitory effect of muscimol was not antagonised by bicuculline. It is concluded that mesolimbic GABA_A receptors exert an inhibitory control on dopamine-dependent pivoting that can be elicited from the shell of the nucleus accumbens, and that GABA_B receptors exert an inhibitory control on acetylcholine-dependent circling that can be elicited from the shell of the nucleus accumbens. This data extends the earlier reported findings that the neurochemical substrate in the shell of the nucleus accumbens that mediates dopamine-dependent pivoting is fundamentally different from the shell substrate that mediates acetylcholine-dependent circling.     

Deltorphin II enhances extracellular levels of dopamine in the nucleus accumbens via opioid receptor-independent mechanisms

The effects of the delta2-opioid receptor agonist, deltorphin II, on extracellular levels of dopamine in the rat nucleus accumbens were investigated in awake animals by in vivo brain microdialysis. In agreement with previous studies, perfusion of deltorphin II (50.0 nmol) into the nucleus accumbens significantly increased the extracellular amount of accumbal dopamine. The effect of deltorphin II (50.0 nmol) was not altered by the selective delta2-opioid receptor antagonist, naltriben (1.5 nmol), which alone did not significantly affect the basal levels of dopamine. Selective antagonists of neither the mu-opioid receptors, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (0.15 nmol), nor the delta1-opioid receptors, (E)-7-benzylidenenaltrexone tartrate (0.15 nmol), failed to significantly alter the effects of deltorphin II. The nonselective opioid receptor antagonist, naloxone (0.75 and 1.5 nmol), which alone did not significantly affect the basal levels of dopamine, also failed to affect the effects of deltorphin II. Moreover, under the condition that the sodium channel blocker, tetrodotoxin (0.1 nmol), was perfused continuously into the nucleus accumbens, the deltorphin II-induced increase in extracellular levels of dopamine was reduced by 72%. These results suggest that deltorphin II enhances extracellular dopamine in the nucleus accumbens via opioid receptor-independent, tetrodotoxin-sensitive mechanisms.     

Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens

The mu- and delta-opioid receptors located at the terminal level in nucleus accumbens are involved in the opiate modulation of dopamine release in this brain area. However, recent studies suggest that the effects of opioid drugs on the core subregion of nucleus accumbens may completely differ from those observed in the shell. We used in vivo microdialysis to simultaneously apply selective mu- and delta-opioid receptor agonists and to measure extracellular levels of dopamine in three subregions of the accumbens, namely shell, core, and the transition zone between them. The regional analysis of these subregions of the accumbens demonstrated that basal levels of dopamine and its metabolites were higher in the core, and decreased from this subregion to the shell. Retrodialysis application to the core of both the selective mu-receptor agonist ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) (1 micromol/L)) and of the selective delta-opioid receptor agonist ([D-Pen(2), D-Pen(5)]-enkephalin (DPDPE) (50 nmol/L)) increased the dialysate levels of dopamine. However, the application of these drugs to the shell significantly reduced the dopamine levels in this subregion. Local application of the same doses of these drugs in the transition zone between the shell and the core did not significantly affect the dopamine levels in dialysates. These results suggest that the opioid circuits modulating dopaminergic activity in the shell could differ from those in the core of the nucleus accumbens.     

The role of delta-opioid receptor subtypes in neuropathic pain

A large body of evidence suggests an important role of delta-opioid receptor agonists in antinociception at the level of the spinal cord. Our study was undertaken to analyse the spinal antinociceptive and antiallodynic effects of delta(1)- and delta(2)-opioid receptor agonists and antagonist after their acute and chronic intrathecal administration in a neuropathic pain model in the rat. In rats with a crushed sciatic nerve, the delta(1)-opioid receptor agonist [D-Pen(2), D-Pen(5)]enkephalin (DPDPE, 5-25 microg i.t.) and the delta(2)-opioid receptor agonist deltorphin II (1.5-25 microg i.t.) dose dependently antagonized the cold-water allodynia which developed after sciatic nerve injury. These effects of DPDPE were antagonized by 7-benzylidenenaltrexon (BNTX, 1 microg i.t.) while the effects of deltorphin II were antagonized by 5'naltrindole izotiocyanate (5'NTII, 25 microg i.t.). Both agonists had a dose-dependent, statistically significant effect on the tail-flick latency in two tests, with focused light and cold water. Chronic administration of DPDPE (25 microg i.t.) and deltorphin II (15 microg i.t.) resulted in significant prolongation of the reaction time determined on days 2, 4 and 6 post-injury. In conclusion, our results show an antiallodynic and antinociceptive action of DPDPE and deltorphin II at the spinal cord level, which suggests that both delta-opioid receptor subtypes play a similar role in neuropathic pain. This indicates that not only delta(1)- but also delta(2)-opioid receptor agonists can be regarded as potential drugs for the therapy of neuropathic pain.     

Behavioural and neurochemical effects of cholinergic and dopaminergic agonists administered into the accumbal core and shell in rats.

The first goal of this study was to investigate whether turning behaviour elicited by unilateral injections of the cholinergic agonist carbachol into the shell of the nucleus accumbens differs from that elicited by similar injections into the core of this nucleus, and to compare the behavioural effects with the known effects of such injections of the mixture of the dopamine D1 and D2 receptor agonists SKF 38393 (5 microg) and quinpirole (10 microg). The second goal was to investigate whether these injections of carbachol produce neurochemical alterations in the ventrolateral striatum that differ from similar injections of the mixture of the dopamine D1 and D2 receptor agonists into these brain regions. Injections of carbachol into the shell produced predominantly (a) contralateral circling marked by normal stepping and running in wide circles during the initial 50 min and (b) postural asymmetry during the following 75 min; similar injections into the core produced (a) contralateral pivoting, namely pathological head-to-tail turning marked by abnormal hindlimb stepping during the initial 50 min and (b) postural asymmetry during the next 75 min. The postural asymmetry seen after the carbachol injections was closely associated with the drug-induced increase in the dopamine release measured by microdialysis in the ipsilateral striatum. Injections of the mixture of dopamine agonists into the shell, but not core, also produced pivoting. These shell injections increased the dopamine release in the ipsilateral striatum, and decreased it in the contralateral striatum. The relative increase in the ipsilateral striatum was closely associated with the drug-induced pivoting. The data show that stimulation of cholinergic and dopaminergic receptors in the shell and core elicit effects that vary according to the subregion of the nucleus accumbens. It is concluded that the accumbens-specific, cholinergic effects are mediated via substrates that differ from those involved in the shell-specific, dopaminergic effects.     

Differential inhibition by dopamine D-1 and D-2 antagonists of circling behaviour induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions

The selective dopamine (DA) D-1 antagonist SCH 23390 antagonized the contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 in rats lesioned unilaterally with 6-hydroxy-DA but had a 600 times weaker effect against the preferential DA D-2 agonist pergolide. The D-2 antagonists clebopride and spiroperidol had the reverse selectivity. The mixed D-1/D-2 antagonists cis(Z)-flupentixol and cis(Z)-clopenthixol blocked the circling induced by either agonist. It is concluded that circling behaviour is mediated by closely related but independent DA D-1 and D-2 receptor sites.     

Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: Involvement of central oxytocin

The effect of a pro-erectile dose of apomorphine, a mixed dopamine receptor agonist, and of PD-168077 (N-[4-(2-cyanophenyl)piperazin-1-ylmethyl]-3-methylbenzamide maleate), a selective dopamine D4 receptor agonist, injected into the paraventricular nucleus of the hypothalamus on the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate from the nucleus accumbens was studied in male rats. As expected, apomorphine (0.1microg) and PD-168077 (0.1microg) induced penile erection episodes, which occurred concomitantly to an increase in extra-cellular dopamine and DOPAC concentration in the dialysate from the shell of the nucleus accumbens, as measured by intracerebral microdialysis. When induced by apomorphine, these effects were reduced by 80% by raclopride, a selective D2/D3 receptor antagonist (1microg) and only by 40-45% by L-745,870 (1microg), a selective dopamine D4 receptor antagonist. When induced by PD-168077, these effects were reduced by more than 80% by L-745,870 (1microg), but only by 35-40% by raclopride. Irrespective of the dopamine agonist used to induce penile erection, the pro-erectile effect and the concomitant increase in dopamine and DOPAC concentration in the nucleus accumbens dialysate were almost completely abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin(1microg), a potent oxytocin receptor antagonist, given into the lateral ventricles. The present results suggest that stimulation of dopamine receptors (mainly of the D2 to D4 subtype) in the paraventricular nucleus induces the release of oxytocin in brain areas that influence the activity of mesolimbic dopaminergic neurons mediating the appetitive and reinforcing effects of sexual activity. This provides evidence for a role of oxytocin in neural circuits that integrate the activity of neural pathways controlling the consummatory aspects of sexual behaviour (e.g., penile erection) with those controlling sexual motivation and sexual arousal.     

A vehicle injection into the right core of the nucleus accumbens both reverses the region-specificity and alters the type of contralateral turning elicited by unilateral stimulation of dopamine D2/D3 and D1 receptors in the left core of the nucleus accumbens

The goal of the present study was to analyse to what extent variables such as (1) injected volume, (2) nature of the solvent of drugs (saline versus distilled water) and (3) placement of an additional cannula to inject the solvent of the drugs at the opposite side of the brain, influenced the behavioural effects of the combined administration of the dopamine D(1) receptor agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine-7,8-diol (SKF 38393, 5.0 microg) and the dopamine D(2)/D(3) receptor agonist quinpirole (10.0 microg) into the shell or core of the nucleus accumbens of freely moving rats. First, we found that increasing the injected volume from 0.2 microl to 0.5 microl significantly increased the amount of contralateral turning after injection of the drugs into the shell and, especially, the core of rats equipped with one cannula. More importantly, the type of turning behaviour changed: instead of a predominance of pivoting, both pivoting and circling appeared. Second, replacing the solvent saline by distilled water resulted in a minor, but significant, decrease of the amount of contralateral turning elicited from either the shell or the core of the nucleus accumbens of rats equipped with one cannula. The type of turning was not changed by this new solvent. Third, and most importantly, this study showed that the vehicle injection into the right core exerted a potentiating effect on the number of contralateral rotations elicited by injections of SKF 38393+quinpirole into the left core, whereas such a vehicle injection into the right shell did not affect the number of contralateral rotations elicited by injections of SKF 38393+quinpirole into the left shell. The type of turning in these rats was not changed when compared to rats equipped with one cannula. It is hypothesized that the fluid injected into the core, directly or indirectly, enhanced the dopaminergic asymmetry between the left and the right brain, implying that this manipulation anyhow reduced the dopaminergic activity in the region under discussion. In conclusion, subtle changes in the methodology used to study both the behaviour-specificity and the region-specificity of drug injections into the brain significantly directs the outcome of such studies.     

Dopamine depletion augments endogenous opioid-induced locomotion in the nucleus accumbens using bothμ1 andδ opioid receptors

The aim of this study is to analyze further the opioid receptor subtypes involved in the augmentation of behavioral activity after dopamine depletion in the nucleus accumbens of rats. Initially, the opioid receptors involved in the augmentation of locomotion produced by endogenous opioids were evaluated by microinjection of kelatorphan, an inhibitor of proteolytic enzymes that inactivates enkephalin, with or without specific antagonists forμ ₁ orδ-opioid receptors, naloxonazine or naltrindole, respectively. Kelatorphan produced a dose-dependent increase in horizontal photocell counts and vertical movements. At all doses examined the behavioral response was augmented in rats sustaining accumbal dopamine lesions. The augmentation in dopamine-depleted rats was partially blocked by naloxonazine or naltrindole. Since the motor stimulant response to intra-accumbens microinjection of theδ-opioid agonist, [d-penicillamine^2,5]-enkephalin, was not augmented in a previous study, we tested the behavioral response to a new endogenousδ-opioid agonist, [d-Ala²] deltorphin I. The locomotor response to deltorphin was slightly augmented in dopamine-depleted rats. These data suggest that the augmentation in the motor response elicited by endogenous opioids after dopamine lesions in the nucleus accumbens involves bothμ ₁ andδ-opioid receptors.     

Autoregulation of dopamine synthesis in subregions of the rat nucleus accumbens

The discovery of a core-shell dichotomy within the nucleus accumbens has opened new lines of investigation into the neuronal basis of psychiatric disorders and drug dependence. In the present study, the autoregulation of dopamine synthesis in subdivisions of the rat nucleus accumbens was examined. We measured the accumulation of L-3,4-dihydroxyphenylalanine (DOPA) after the inhibition of aromatic L-amino acid decarboxylase with 3-hydroxylbenzylhydrazine (NSD-1015, 100 mg kg(-1)) as an in vivo index of dopamine synthesis. The effect of the dopamine D(1)/D(2) receptor agonist apomorphine (0, 20, 100, 500 microgram kg(-1)) and the dopamine D(2)/D(3) receptor agonist quinpirole (0, 20, 100, 500 microgram kg(-1)) on dopamine synthesis was determined in the dorsolateral core, ventromedial shell, and rostral pole of the nucleus accumbens. DOPA accumulation was also measured in the frontal cortex, olfactory tubercle, and caudate nucleus of the same rats for comparative purposes. The results show that the three sectors of the nucleus accumbens had similar basal levels of DOPA. Both apomorphine and quinpirole produced a decrease in the dopamine synthesis rate in all brain regions examined. In general, the dopamine D(2)/D(3) receptor agonist quinpirole produced a significantly greater decrease in DOPA accumulation than the dopamine D(1)/D(2) receptor agonist apomorphine. Within the nucleus accumbens, we found no core-shell differences in the agonist-induced suppression of dopamine synthesis, but the rostral pole was less sensitive to the highest dose of both dopamine agonists. These results suggest that differences in dopamine function between the core and shell might not involve region-specific differences in the receptor-mediated autoregulation of dopamine neurotransmission. Moreover, the blunted effect of dopamine agonists in the rostral pole illustrates that this region of the accumbens is functionally distinct, possibly due to a lower dopamine receptor reserve when compared to the core and shell.     

Gradient of dopamine responsiveness to dopamine receptor agonists in subregions of the rat nucleus accumbens

The present study sought to investigate the possibility that the degree of selectivity of dopamine D3/D2 receptor agonists such as quinelorane, 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), quinpirole and apomorphine on dopamine D3 over D2 receptor subtypes can be assessed by measuring dopamine transmission in the shell vs. core compartments of the nucleus accumbens by using microdialysis in freely moving rats. Significant reductions in dialysate dopamine levels compared to vehicle-treated animals were observed in the shell of the nucleus accumbens with 3, 10 and 30 microg/kg quinelorane, 100 microg/kg 7-OH DPAT, 25 and 100 microg/kg quinpirole, and 100 microg/kg apomorphine. In the core subregion, significant reductions in dopamine were seen at 10 and 30 microg/kg quinelorane, 25 and 100 microg/kg 7-OH-DPAT, 100 microg/kg quinpirole and 100 microg/kg apomorphine. However, a significant shell/core dichotomy could only be observed in response to the lowest dose of quinelorane (3 microg/kg) with the shell being hyper-responsive compared with the core. The present findings suggest that quinelorane is one of the most selective dopamine D3 receptor agonists based on its ability to target the shell subregion of the nucleus accumbens.     

Dopamine D2 receptors and ingestive behavior: brainstem mediates inhibition of intraoral intake and accumbens mediates aversive taste behavior in male rats

RATIONALE: One of the factors that terminate the ingestion of an intraorally infused solution of sucrose may be an increase in the perceived aversiveness of its taste. OBJECTIVES: We tested the hypothesis that dopamine D(2), as opposed to D(1), receptors in the brainstem or nucleus accumbens inhibit intraoral intake by enhancing the aversiveness of the taste of the infused solution. METHODS: Male rats were infused intraorally with a 2 M sucrose solution (1 ml/min) and intake and the display of gapes and chin rubs, i.e. taste-related aversive behavior, was measured. Gapes and chin rubs were also measured in rats during and 40 s after brief intraoral infusion (1 ml/min during 20 s) of a 0.3 mM solution of quinine HCl. The full D(1) receptor agonist dihydrexidine (0.1-3.0 mg/kg) and antagonist SCH-23390 (0.03-0.1 mg/kg), the D(2) receptor agonist quinpirole (0.3 mg/kg) and antagonist raclopride (1.7 mg/kg) were injected IP. Quinpirole (14-55 microg) and raclopride (5 microg) were also infused into the fourth brain ventricle. In addition, quinpirole (2 or 10 microg) was infused into the shell region of the nucleus accumbens. RESULTS: IP dihydrexidine and quinpirole inhibited the intraoral intake of sucrose and pretreatment with raclopride, but (in the case of dihydrexidine) not SCH-23390, attenuated this effect. Injection of quinpirole into the fourth ventricle produced raclopride-reversible inhibition of intraoral intake but did not stimulate the display of gapes and chin rubs. Infusion of quinpirole into the shell region of the nucleus accumbens had the opposite effects. The intake of sucrose was suppressed by the addition of quinine HCl but this suppression was unaffected by dopamine agonist or antagonist treatment. CONCLUSIONS: It is suggested that brainstem dopamine D(2) receptors mediate suppression of consummatory ingestive behavior and that D(2) receptors in the shell region of the nucleus accumbens mediate the display of gapes and chin rubs, but that neither of these D(2) receptor populations mediate the hedonic evaluation of taste.     

Role of GABA(A) receptors in the retrorubral field and ventral pallidum in rat jaw movements elicited by dopaminergic stimulation of the nucleus accumbens shell

The role of gamma-aminobutyric acid (GABA)(A) receptors in the retrorubral field in the production of rat repetitive jaw movements was examined, as this nucleus receives a GABAergic, inhibitory input from the nucleus accumbens and is connected with the parvicellular reticular formation, a region that is directly connected with the orofacial motor nuclei. The GABA(A) receptor antagonist bicuculline (150 ng/0.2 microl per side) significantly produced repetitive jaw movements when injected bilaterally into the retrorubral field, but not the ventral pallidum. The effects of bicuculline were GABA(A) receptor specific, because the effects were abolished by muscimol, a GABA(A) receptor agonist, given into the same site. The bicuculline-induced jaw movements differed qualitatively from those elicited by injection of a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), agonist at dopamine D1 and D2 receptors respectively, into the nucleus accumbens shell. Nevertheless, bilateral injections of muscimol (10 ng, 25 ng and 50 ng/0.2 microl per side) into the retrorubral field significantly inhibited jaw movements evoked by the dopamine D1/D2 receptor stimulation in the nucleus accumbens shell. Bilateral injections of bicuculline (50 ng and 150 ng/0.2 microl per side) also reduced the dopamine D1/D2 receptor-mediated jaw movements. Essentially similar effects were obtained when muscimol and bicuculline were given into the ventral pallidum, a region that is also known to receive GABAergic inhibitory inputs from the nucleus accumbens. In conclusion, GABA(A) receptor blockade in the retrorubral field elicits characteristic repetitive jaw movements, and the GABA(A) receptors in that region as well as in the ventral pallidum modulate the accumbens-specific, dopamine D1/D2 receptor-mediated jaw movements.     

Dopamine D3 receptor modulation of dopamine efflux in the rat nucleus accumbens

The effect of antipsychotics on electrically evoked dopamine efflux in the rat nucleus accumbens core and shell was investigated, using in vitro fast cyclic voltammetry. In the nucleus accumbens core, the dopamine D2/D3 receptor agonist, (+/-)7-OH-DPAT ((+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene), inhibited dopamine efflux with a pEC50 of 8.1. Clozapine, haloperidol, sulpiride and the selective dopamine D3 receptor antagonist, SB-277011-A, had no effect on dopamine efflux per se but all attenuated the (+/-)7-OH-DPAT-induced-inhibition of dopamine efflux, with pA2 values of 6.6, 7.9, 7.0 and 7.6, respectively. In the nucleus accumbens shell, (+/-)7-OH-DPAT inhibited dopamine efflux with a pEC50 of 8.3. Clozapine and SB-277011-A had no effect on dopamine efflux. In contrast, haloperidol and sulpiride significantly increased dopamine efflux through a D2 receptor-mediated mechanism. Clozapine, haloperidol, sulpiride and SB-277011-A attenuated the (+/-)7-OH-DPAT-induced inhibition with pA2 values of 7.3, 8.6, 7.6 and 8.2, respectively. These data demonstrate that dopamine efflux is modulated by both dopamine D2 and D3 receptors in the rat nucleus accumbens.     

Contralateral turning elicited by unilateral stimulation of dopamine D2 and D1 receptors in the nucleus accumbens of rats is due to stimulation of these receptors in the shell,but not the core,of this nucleus

The goal of this study was to determine whether dopamine D₂ and/or D₁ receptors in the shell and the core of the nucleus accumbens of rats have a differential role in turning behaviour. Unilateral injection of a mixture of the dopamine D₂ receptor agonist quinpirole (10 µg) and the dopamine D₁ receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7, 8-diol (SKF 38393, 5 µg) into the shell of the nucleus accumbens produced contralateral turning, when doses which per se were ineffective were injected. This effect was far greater than that found after similar injections into the core of the nucleus accumbens. The effect elicited from the shell was significantly attenuated by prior administration of either the dopamine D₂ receptor antagonistl-sulpiride (25 ng/0.5 µl) or the dopamine D₁ receptor antagonist (8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol (SCH 23390, 0.5 µg/0.5 µl) into the same region. These data together with the fact thatl-sulpiride is known to be a valid tool to differentiate the involvement of distinct regions within the shell underlie the conclusion that dopamine D₂ and D₁ receptors in the shell, but not the core, of the nucleus accumbens play a critical role in the contralateral turning induced by unilateral injection of dopamine receptor agonists into this nucleus. The results are discussed in view of the known output pathways of the shell.     

Dopamine-opioid interactions in the rat striatum: a modulatory role for dopamine D1 receptors in delta opioid receptor-mediated signal transduction

Dopaminergic and opioidergic systems interact in the striatum to modulate locomotor and motivated behaviors. The present study investigated the molecular interactions of these two systems by determining the role of dopamine D1 and D2 receptors in the modulation of opioid receptor-mediated signal transduction. Male Fischer rats were injected daily for 10 days with either saline, the D1 receptor agonist SKF 82958, the D2 receptor agonist quinpirole, or both SKF 82958 and quinpirole. Administration of SKF 82958 alone or together with quinpirole attenuated the ability of the delta receptor agonist D-Pen2,D-Pen5-enkephalin (DPDPE) to inhibit adenylyl cyclase activity in the caudate putamen and nucleus accumbens. Quinpirole administration alone had no effect. The efficacy and potency of the mu opioid receptor agonist D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin (DAMGO) to inhibit adenylyl cyclase activity was unaltered following administration of either dopamine receptor agonist. Administration of SKF 82958 had no affect on delta receptor binding, forskolin-stimulated adenylyl cyclase activity, or G protein/adenylyl cyclase coupling. However, the ability of DPDPE to stimulate binding of [35S]GTPgammaS to inhibitory G proteins was attenuated in animals that received SKF 82958. These results suggest that repeated activation of D1 receptors attenuates the functional coupling of delta opioid receptors with adenylyl cyclase due to decreased coupling between delta receptors and G proteins.