Methylphenidate affects striatal dopamine differently in an animal model for attention-deficit/hyperactivity disorder—the spontaneously hypertensive rat

The spontaneously hypertensive rat (SHR) is used as a model for attention-deficit/hyperactivity disorder (ADHD) because it has behavioural characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to those of ADHD. ADHD children have been shown to have reduced striatal activation in certain tasks. SHR have reduced striatal dopamine release in response to electrical stimulation. The present study set out to investigate possible long-term effects of methylphenidate treatment on dopaminergic function in striatal slices of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. Methylphenidate treatment (3 mg/kg daily for 14 days) did not normalize the decreased electrically-stimulated release of [³H]dopamine from SHR caudate-putamen slices nor did it affect postsynaptic D₂ receptor function. However, the second electrical stimulus caused a relatively greater release of [³H]dopamine from caudate-putamen slices of methylphenidate-treated SHR than from vehicle-treated SHR, suggesting that presynaptic mechanisms controlling dopamine release had been altered. Interestingly, [³H]dopamine release from WKY caudate-putamen slices in response to D₂ autoreceptor blockade by the antagonist, sulpiride, was selectively increased by methylphenidate treatment. This effect was not seen in SHR possibly because D₂ autoreceptor function had already been up-regulated. The results show that methylphenidate is unable to enhance D₂ autoreceptor function in SHR.     

Increased noradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder--the spontaneously hypertensive rat

Spontaneously hypertensive rats (SHR) are used as a model for attention-deficit/hyperactivity disorder (ADHD) since SHR are hyperactive and they show defective sustained attention in behavioral tasks. Using an in vitro superfusion technique we showed that norepinephrine (NE) release from prefrontal cortex slices of SHR was not different from that of their Wistar-Kyoto (WKY) control rats when stimulated either electrically or by exposure to buffer containing 25 mM K(+). The monoamine vesicle transporter is, therefore, unlikely to be responsible for the deficiency in DA observed in SHR, since, in contrast to DA, vesicle stores of NE do not appear to be depleted in SHR. In addition, alpha(2)-adrenoceptor mediated inhibition of NE release was reduced in SHR, suggesting that autoreceptor function was deficient in prefrontal cortex of SHR. So, while DA neurotransmission appears to be down-regulated in SHR, the NE system appears to be under less inhibitory control than in WKY suggesting hypodopaminergic and hypernoradrenergic activity in prefrontal cortex of SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between NE and DA systems in the prefrontal cortex, with inhibitory DA activity being decreased and NE activity increased relative to controls.     

Jaw muscle activity, the nucleus accumbens and dopaminergic agonists: A new approach

A method was developed to analyze electromyographic (EMG) signals in terms of power, viz., a measure for overall muscle activity, and number of seconds marked by distinct frequency ranges. With the help of this method, the effects of intraaccumbens administration of distilled water, the D1 receptor agonist SK&F 38393 (SKF; 5 micrograms), the D2 receptor agonist LY 171555 (LY; 10 micrograms), and their combination upon the EMG signals of the masseter and the digastric muscle were analysed in freely moving rats. Only the combined treatment affected the power: The noted increase was limited to the digastric muscle. The time/frequency analysis was limited to frequency ranges 3-4 Hz (class A), 4-5 and 5-6 Hz (class B), and 6-7, 7-8, ..., 12-13, and 13-14 Hz (class C). Apart from a small effect of SKF alone and of SKF in combination with LY on class B of the masseter muscle, neither SKF nor LY affected class A or B. SKF and LY increased and decreased, respectively, class C in both muscles. The data suggest that SKF and LY elicited both opposite and synergistic effects. The method is a new tool to analyze EMG signals in freely moving rats.     

Modifications of head turning and circling movement following sulpiride microinjections into nucleus accumbens in the rat

The aim of this study was to determine whether a relationship exists between nucleus accumbens D₂ receptors, circling behavior, and its first stage, the head turning. Rats were unilaterally lesioned in the substantia nigra with 6-hydroxydopamine and afterward treated with d-amphetamine IP Following bilateral intraaccumbens microinjections (1, 5, 10 μg/0.5 μl) of sulpiride, a D₂ receptor antagonist. Computer-assisted video analysis allowed the study of some parameters (number of turns, type of turn, head turning duration, degree and speed) characterizing rotatory activity. Sulpiride microinfusion resulted in a dose-dependent decrease of the number of turns and head rotation speed and in a dose-dependent increase of head-turning duration. Two turn types were observed in relation to the animal's position: a large head-to-tail position with a short-diameter turn type following sulpiride microinjection, and a close head-to-tail position in relation to a wide diameter turn type in the control condition (saline). The results show a relationship between head turning parameters, circling behavior, and D₂ receptors in nucleus accumbens, which may be also involved in the regulation of some mechanisms related to sensory-motor integration in the rat.     

Extracellular dopamine in the rat ventral tegmental area and nucleus accumbens following ventral tegmental infusion of cocaine

Rats were implanted with dual dialysis probes, one in the ventral tegmental area, and another one ipsilateral in the nucleus accumbens. Infusion of cocaine (10, 100, 1000 mM) into the ventral tegmental area gradually increased extracellular dopamine to 164, 329 and 991% of baseline in the ventral tegmental area, but reduced dopamine to 76, 47 and 38% of baseline in the nucleus acumbens. These results are consistent with cocaine-induced feedback regulation of dopamine cell activity involving somatodendritec impulse-regulating dopamine D₂ autoreceptors.     

D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment

The antipsychotic effects of neuroleptic drugs are believed to be achieved by chronic blockade of dopaminergic transmission in the limbic system. Nevertheless, the effects of chronic (3-12 months) haloperidol administration on the dopaminergic transmission in the nucleus accumbens of rodents remains poorly understood. Studies of spontaneous locomotor activity (SLA), a behavioral measure related to limbic dopamine transmission, and of dopamine D2 receptor density in the nucleus accumbens after chronic oral haloperidol treatment have yielded conflicting results. We evaluated these indices after 8 months of parenteral administration of haloperidol decanoate. We report here that, after 8 months of parenteral treatment, SLA stays significantly decreased and D2 receptors in the nucleus accumbens exhibit the same up-regulation as in the striatum (about 50%). These results fail to support the notion of a different pattern of D2 receptor adaptation to neuroleptic treatment between the nucleus accumbens and the striatum. In contrast, dopamine D1 receptors were found to be unaffected in the nucleus accumbens but decreased in the striatum by 22% after 8 months of treatment. This observation could be relevant to the pathogenesis of tardive dyskinesia.     

Dopamine receptors mediate drug-induced but not Pavlovian conditioned contralateral rotation in the unilateral 6-OHDA animal model

Following Pavlovian conditioning treatment sessions with apomorphine, animals receiving the paired treatment showed substantial contralateral rotation when placed without drug into the test environment previously paired to the apomorphine (0.5 mg/kg) injection while animals in the unpaired control treatment showed only ipsilateral rotation. Subsequent tests with the D1 antagonist (SCH 23390), or the D2 antagonist (haloperidol) partially suppressed and the combined D1-D2 antagonists completely suppressed the apomorphine-induced response of contralateral rotation. The identical contralateral rotation response occurring as a Pavlovian conditioned response in the paired apomorphine treatment group was not attenuated by dopamine receptor blockade. In both paired and unpaired groups, the spontaneous ipsilateral rotation response was completely blocked. Thus, non-dopaminergic mechanisms mediate conditioned rotation whereas the drug-induced as well as the spontaneous rotation responses require stimulation of striatal dopamine receptors.     

Rostral-caudal differences in effects of nucleus accumbens amphetamine on VTA ICSS

That dopamine (DA) plays a role in reward-related learning is well documented but the mechanisms through which it acts are not well understood. The present set of experiments investigated the role of DA receptor subtypes within DA-innervated forebrain regions in brain stimulation reward (BSR). Thirty-two rats were implanted with electrodes in the ventral tegmental area (VTA) and cannulae aimed at the caudal nucleus accumbens (NAcc), the caudate-putamen (CP) or cortex. Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding (thresholds). After BSR thresholds stabilized rats received treatments with DA agonists and their effects on thresholds were analyzed. Systemic treatments consisted of injections of (+)-amphetamine (1.0 mg/kg, i.p., 10 min before testing), the D₂ agonist quinpirole (1.0 mg/kg, i.p., 10 min before testing), the novel D₁ agonist A-77636 (3.0 mg/kg, s.c., 90 min before testing) or their vehicle (distilled H₂O). Central treatments consisted of microinjections of quinpirole (0.3 – 10.0 μg/0.5 μl) directly into the caudal NAcc, CP or cortex or A-77636 (30 μg/0.5 μl) into the caudal NAcc or CP. Results showed that all three agonists, when injected systemically, significantly reduced the threshold frequency required for VTA BSR, indicating a potentiative effect on reward. Central injections of quinpirole in the caudal NAcc, CP or cortex produced significant increases in BSR thresholds indicative of reduced rewarding efficacy of stimulation. Central injections of A-77636 into the caudal NAcc, but not the CP, were associated with a reduction in VTA BSR thresholds, suggesting an increase in reward. These results suggest that stimulation of D₁ or D₂ receptors enhances the rewarding effect of brain stimulation. In the case of the systemic quinpirole enhancement of reward, the present results suggest that this may not occur in the caudal NAcc, CP or cortex. Finally, the present results suggest that D₁ receptor stimulation in the caudal NAcc can facilitate reward-related learning.     

Stimulation of D2-receptors in rat nucleus accumbens slices inhibits dopamine and acetylcholine release but not cyclic AMP formation

We compared some functional responses of D1- and D2-receptor stimulation in tissue slices of rat neostriatum with those in slices of the nucleus accumbens. In both brain regions D2-receptor stimulation inhibited the electrically evoked release of radiolabeled dopamine and acetylcholine. In both brain regions D1-receptor stimulation and forskolin increased the cyclic AMP formation. Only in the neostriatum, stimulation of D2-receptors inhibited the formation of cyclic AMP, brought about by forskolin or by D1-receptor stimulation. It is concluded from these experiments that, although functional responses of D2-receptor stimulation can be demonstrated in the nucleus accumbens, D2-receptors in this brain region are apparently uncoupled to adenylate cyclase.     

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. I. 6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from rats which had received unilateral 6-hydroxydopamine (6-OHDA) injections destroying ascending nigrostriatal neurones. The binding of both ligands to striatal sections was first shown to be saturable, reversible and of high affinity and specificity [( 3H]SCH 23390: Bmax 2.16 pmol/mg protein, Kd 1.4 nM; [3H]sulpiride; Bmax 0.67 pmol/mg protein, Kd 10.7 nM). After unilateral stereotaxic 6-OHDA injections, rats rotated contralaterally when challenged with apomorphine (0.5 mg/kg), or specific D1 or D2 agonists, SKF 38393 (1.0-5.0 mg/kg) and LY 171555 (0.05-0.5 mg/kg), respectively. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A loss of approximately 90-95% of uptake sites was reproducibly accompanied by an enhanced density of binding ipsilaterally for the D2 ligand, [3H]sulpiride, in all areas of the striatum, but most markedly in the lateral areas. An increase in the D2 binding site density was also seen in the ipsilateral nucleus accumbens and the olfactory tubercle. In contrast, in the same animals, the striatal D1 receptors were far less affected by dopaminergic denervation, with no consistent changes seen in the binding of [3H]SCH 23390. These results suggest that dopamine D2 receptors are more susceptible than D1 receptors to changes after dopaminergic denervation, which is expressed as an increase in the density of binding sites revealed here with [3H]sulpiride.     

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.     

Behavioral sensitization following a single apomorphine pretreatment — selective effects on the dopamine release process

Once daily subchronic pretreatments with the dopamine (DA) agonist apomorphine (APO) increase striatal DA synthesis and metabolism. Such changes imply that adaptation to APO do not dissipate completely with in 24 h. In the present report we evaluated the effects of a single APO treatment 24 h prior to euthanasia on behavior and on striatal DA synthesis, metabolism, release and receptor binding. The single APO pretreatment reduced DA release from striatal synaptosomes. In contrast, striatal DA synthesis, metabolism, and the high-affinity binding of DA to the D₂ receptor were unaltered 24 h after agonist pretreatment. At this time the stereotypic response to a subsequent APO challenge was enhanced. This adaptive pattern is different from that observed 60 min following an acute APO pretreatment, when high-affinity D₂ binding is reduced. The pattern 24 h following a single APO pretreatment is also different from that observed following subchronic agonist dosing, when stereotypic behavior is enhanced, while basal DA synthesis and metabolism are increased.     

Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD)

A good model of a disorder is one that: (a) mimics, although in a simpler form than the full-blown clinical case, the fundamentals of the behavioral characteristics, in this case of people with Attention-Deficit/Hyperactivity Disorder (AD/HD;face validity); (b) conforms with a theoretical rationale for the disorder (construct validity); and (c) is able to predict aspects of behavior, genetics and neurobiology previously uncharted in the clinics (predictive validity). This article discusses the Spontaneously Hypertensive Rat (SHR) and some other putative animal models of AD/HD. It is argued that although other strains and species may be hyperactive and/or show attention deficits following genetic, environmental or pharmacological interventions, the SHR is presently the only strain shown to have the major behavioral symptoms of AD/HD. This does not mean that investigating other models cannot give valuable information.     

Influences of neuronal uptake and D2 autoreceptors on regulation of extracellular dopamine in the core, shell and rostral pole of the rat nucleus accumbens

Fast cyclic voltammetry in rat brain slices containing the nucleus accumbens, was used to examine the regulation of the extracellular concentration of electrically stimulated dopamine overflow in the core, shell and rostral pole. One μM (−)-sulpiride, significantly increased dopamine overflow in all 3 regions but only when the duration of stimulation was greater than 500 ms. One μM cocaine, significantly potentiated dopamine overflow in all 3 regions following all patterns of stimulation. In the presence of 1 μM cocaine, superfusion with 1 μM (−)-sulpiride did not result in a further increase in dopamine overflow at any frequency of stimulation in the rostral pole, but significant increases in dopamine overflow were observed after stimulation with 20 pulses at 10 or 20 Hz in the core or shell; the degree of potentiation was greater in the shell than core. Quinpirole inhibited single pulse stimulated dopamine overflow in a concentration dependent manner (maximum inhibition (100%) in all regions) but was significantly less potent in the rostral pole than in the core or shell. Increasing the number of pulses to 2 or 4 pulses at 50 Hz resulted in a shift of the quinpirole dose-response curve to the right in all regions and in the rostral pole, a significant reduction in the maximum inhibition of dopamine overflow to both stimulation parameters. In the shell a significant reduction in maximum inhibition was only seen with 4 pulses at 50 Hz stimulation, whereas in the core there was no change in the maximum inhibitory effect of quinpirole. Neuronal uptake and D₂ autoreceptor activity contribute to regulation of the extracellular concentration of dopamine in core, shell and rostral pole. The relative importance of either uptake or autoreceptor control is region and stimulus dependent.     

DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein, is present in corticothalamic neurons of the rat cingulate cortex

DARPP-32 immunocytochemistry and retrograde axonal labeling were combined to determine whether DARPP-32-containing neurons of the rat anterior cingulate cortex project to thalamus. Following injections of fluorescent latex microspheres into the mediodorsal thalamic nuclei, a large proportion of the DARPP-32 immunostained neurons in layer VI were also retrogradely labeled. In area 24a, these neurons were mostly found in layer VIb, whereas in area 24b, they were visible throughout layer VI. The presence of DARPP-32 in certain corticothalamic neurons suggests that these cells may be modulated by dopamine, which increases DARPP-32 phosphorylation, and possibly by glutamate, which antagonizes DARPP-32 phosphorylation via the N-methyl-D-aspartate (NMDA) receptor.     

Dopaminergic regulation of serotonin release in the substantia nigra of the freely moving rat using microdialysis

The functional regulation by dopamine (DA) receptors of serotonin (5-HT) release from the rat substantia nigra (SN) was investigated using in vivo microdialysis. A D₁- and D₂-receptor-mediated inhibition of nigral 5-HT release was demonstrated in this study. Continuous administration of the D₁-receptor agonist CY 208243 (10 μM) through the probe did not alter extracellular DA nor 5-HT from the SN, whereas intranigral administration of the D₁-receptor antagonist SCH-23390 HCl (10 μM) significantly increased both DA (to 214%) and 5-HT release (to 168%) from the SN. Co-perfusion of the D₁-receptor agonist and antagonist did not change nigral DA nor 5-HT release compared to perfusion of the antagonist alone. The continuous intranigral perfusion of the D₂-receptor agonist, (−)-quinpirole HCl (1 μM) significantly decreased both DA and 5-HT release to 71% and 78%, respectively. These decreases were abolished when the D₂-receptor antagonist S(−)-sulpiride (10 μM) and the D₂-receptor agonist (−)-quinpirole HCl (1 μM) were co-perfused. In contrast, the intranigral perfusion of the DA precursor, -DOPA (5 μM; 1 h), significantly increased nigral and striatal 5-HT release to 202% and 155%, respectively. This enhanced nigral 5-HT release might not be receptor-mediated. The results of the present study suggest a D₁ and D₂ regulation of nigral 5-HT release, either directly mediated by DA receptors on nigral 5-HT terminals or indirectly by nigral GABA, Glu or Asp. Alternatively, the observed DA–5HT-interaction in the SN might not reflect a local interaction but might involve an interaction at the level of the serotonin cell body region, the dorsal raphe nuclei (DRN).     

Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is known to be associated with altered medial prefrontal activation in response to threatening stimuli and with behavioural deficits in prefrontal functions such as working memory and attention. Given the importance of these areas and processes for decision-making, this functional magnetic resonance imaging study investigated whether decision-making is altered in patients with PTSD. In particular, the neural response to gain and loss feedback was evaluated in a decision-making task in which subjects could maximise their number of points total by learning a particular response pattern. Behaviourally, controls learned the correct response pattern faster than patients. Functionally, patients and controls differed in their neural response to gains, but not in their response to losses. During the processing of gains in the late phase of learning, PTSD patients as compared to controls showed lower activation in the nucleus accumbens and the mesial PFC, critical structures in the reward pathway. This reduced activation was not due to different rates of learning, since it was similarly present in patients with unimpaired learning performance. These findings suggest that positive outcome information lost its salience for patients with PTSD. This may reflect decreasing motivation as the task progressed.     

Analysis of dopamine receptor antagonism upon feeding elicited by mu and delta opioid agonists in the shell region of the nucleus accumbens

The nucleus accumbens (NAcc) has been implicated as an important reward site for the mediation of unconditioned reinforcers such as food. Although both mu-selective and delta-selective opioid agonists in the NAcc induce spontaneous and palatable feeding, these effects are mediated by multiple opioid receptor subtypes within the nucleus. A role for dopaminergic mediation of feeding in the NAcc is based upon selective antagonist-induced suppression of feeding induced by systemic amphetamine. The present study investigated whether feeding elicited by infusion of either mu ([D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin) or delta(2) ([D-Ala(2), Glu(4)]-deltorphin) opioid receptor subtype agonists in the shell region of the NAcc would be modified by intra-accumbens pretreatment with equimolar (12-100 nmol) doses of either D(1)-selective (SCH23390) or D(2)-selective (raclopride) antagonists. Both opioid agonists displayed comparable magnitudes and durations of feeding responses in the NAcc. SCH23390 significantly and dose-dependently reduced mu agonist-induced feeding in the NAcc with significant reductions noted following the two higher, but not two lower doses. In contrast, raclopride pretreatment produced inconsistent effects upon mu agonist-induced feeding with limited actions across doses and test times. Further, neither SCH23390 nor raclopride pretreatment in the NAcc affected feeding elicited by the delta(2) opioid agonist. These data indicate that the role of dopamine receptors in mediating opioid-induced feeding within the shell region of the NAcc is both dependent upon the dopamine receptor subtype that was blocked (D(1) vs. D(2)) as well as the opioid receptor subtype which was being stimulated mu vs. delta(2)).     

D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists,but not by sibutramine hydrochloride,antidepressants or treatments which enhance central dopaminergic function

Summary [³H]SCH 23390 is a selective high affinity ligand for D₁ receptors in vitro. Using this ligand persistent blockade of D₁ receptors by SCH 23390 and cis-flupenthixol was shown to significantly increase the number of D₁ receptor binding sites in rat striatum. In contrast, repeated administration of the D₂-selective antagonist, clebopride, resulted in a small, but significant, reduction in number. No differences in binding affinity were observed and a single dose of these compounds was without effect. The D₂-selective antagonist, haloperidol, the non-selective D₁/D₂ receptor antagonist, chlorpromazine, the dopamine reuptake inhibitors, bupropion, GBR 12909 and nomifensine, and the dopamine releasing agent, d-amphetamine, had no effect on D₁ receptors. The antidepressant treatments, desipramine, zimeldine, amitriptyline, tranylcypromine, mianserin and ECS and the monoamine reuptake inhibitor, sibutramine, similarly did not alter striatal D₁ sites. Thus, of the treatments investigated only chronic receptor blockade by high affinity antagonists altered D₁ receptor binding in rat striatum.     

R(+)-8-OH-DPAT, a selective 5-HT1A receptor agonist, attenuated amphetamine-induced dopamine synthesis in rat striatum, but not nucleus accumbens or medial prefrontal cortex

R(+)-8-OH-DPAT (0.05, but not 0.025, 0.1, 1 mg/kg), a 5-HT_1A receptor agonist, decreased l-3,4-dihydroxyphenylalanine (DOPA) accumulation in rat striatum following NSD-1015, an l-aromatic amino acid decarboxylase inhibitor. Amphetamine (1 mg/kg) increased striatal DOPA accumulation, an effect attenuated by R(+)-8-OH-DPAT (0.05 mg/kg). However, both amphetamine (1 mg/kg) and R(+)-8-OH-DPAT (0.05 mg/kg) decreased cortical DOPA accumulation; there were no additional decreases from their combination. Neither amphetamine (1 mg/kg), R(+)-8-OH-DPAT (0.05 mg/kg), or the combination, significantly affected DOPA accumulation in the nucleus accumbens. The significance of and possible mechanisms for these findings are discussed.