Striatal Fos Expression Research Articles

Impacts of maternal separation stress on ethanol-related responses, anxiety- and depressive-like behaviors in adolescent mice

The present work evaluated the consequences of chronic maternal separation (MS), an animal model of early-life stress, on ethanol intake and striatal Fos expression induced by ethanol consumption. Furthermore, we analyzed MS impacts on anxiety- and depressive-like behaviors and on locomotor and plasma corticosterone responses to intraperitoneal treatment with ethanol in adolescent mice. For that, male and female C57BL/6J mice were exposed or not to MS stress, for 3 h per day, from postnatal day (PND) 1 to 14, and submitted to behavioral tests from PND 28. In Experiment 1, MS and control groups of mice were submitted to an involuntary ethanol intake protocol, and striatal Fos expression following ethanol exposure was analyzed. In Experiment 2, mice behavior was assessed in elevated plus-maze, sucrose splash, saccharin preference, and open field tests. Locomotor and plasma corticosterone responses induced by a systemic dose of ethanol (1.75 g/kg) were also evaluated. Our results demonstrated that MS increased ethanol intake only in an acute manner and did not impact ethanol-induced Fos expression in the dorsal striatum and nucleus accumbens (NAc) core and shell subregions. MS did not change the parameters analyzed during elevated plus-maze, sucrose splash, preference for saccharin, and open field tests. MS did not affect locomotor activity following ethanol injection nor plasma corticosterone response to the drug. Thus, our data showed that MS transiently increased ethanol intake. However, early-life stress did not impact Fos, locomotor, or plasma corticosterone responses to the drug. In addition, MS did not affect anxiety- and depressive-like behaviors in adolescent mice.

Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin

Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3–1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3–1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1–3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.

Abnormal involuntary movement (AIM) expression following D2 dopamine agonist challenge is determined by the nature of prior dopamine receptor stimulation (priming) in 6-hydroxydopamine lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions show sensitization (priming) of rotational behavior upon repeated treatment with dopamine agonists. To relate these observations to dyskinesias exhibited by Parkinson's Disease patients, we assessed abnormal involuntary movements (AIMs) in 6-OHDA rats, which were primed with three injections of either the following: water, D1/D2 agonist apomorphine (Apo) (0.5mg/kg), D1 agonist SKF38393 (SKF) (10mg/kg) or D2 agonist quinpirole (Quin) (1 or 2.5mg/kg). The rats were challenged one week later with Quin (0.25mg/kg). Axial, limb, orolingual, locomotor, and grooming AIMs were scored (0–4) every 5min. Priming with water did not produce AIMs. Priming with Quin (1mg/kg) produced axial and locomotor AIMs, while priming with Apo, SKF or Quin (2.5mg/kg) produced axial, locomotor, limb, and grooming AIMs. The disparity in AIM profiles between Quin (1mg/kg) and (2.5mg/kg) was not the result of D1 receptor stimulation since there was little striatal Fos expression following the third priming injection with Quin (1 or 2.5mg/kg) compared to following SKF, which led to robust striatal Fos expression. Challenge with Quin (0.25mg/kg) essentially reproduced the categories of AIMs exhibited during priming, with no AIMs in water-primed 6-OHDA rats, mild, non-significant, axial and locomotor AIMs in Quin (1 and 2.5mg/kg)-primed 6-OHDA rats, and axial, limb, locomotor, and grooming AIMs in Apo- and SKF-primed 6-OHDA rats. These data suggest that the types of AIMs expressed following challenge with Quin depend on the dopamine receptor subtype and dose of dopamine agonist used during priming.

Mutation of MeCP2 alters transcriptional regulation of select immediate-early genes

Loss-of-function mutations in the methyl-DNA binding protein MeCP2 are associated with neurological dysfunction and impaired neural plasticity. However, the transcriptional changes that underlie these deficits remain poorly understood. Here, we show that mice bearing a C-terminal truncating mutation in Mecp2 (Mecp2308) are hypersensitive to the locomotor stimulating effects of cocaine. Furthermore, these mice have gene-specific alterations in striatal immediate-early gene (IEG) induction following cocaine administration. MeCP2 mutant mice show normal levels of baseline and cocaine-induced striatal Fos expression compared with their wild-type littermates. However, the mutant mice have enhanced cocaine-induced transcription of Junb and Arc. At the chromatin level, we find increased histone H3 acetylation at gene promoters in the Mecp2 mutant mice compared with their wild-type littermates, whereas two sites of repressive histone methylation are unchanged. Interestingly, we find that MeCP2 mutant mice show increased steady-state association of elongation-competent RNA Polymerase II (RNAP II) with the Junb and Arc promoters, whereas levels of RNAP II association at the Fos promoter are unchanged. These data reveal a gene-specific effect of MeCP2 on the recruitment of RNAP II to gene promoters that may modulate the inducibility of IEGs. In addition, our findings raise the possibility that aberrant regulation of IEGs including Junb and Arc may contribute to altered cocaine-induced neuronal and behavioral plasticity in Mecp2 mutant mice.

Atypical antipsychotic properties of blonanserin, a novel dopamine D 2 and 5-HT 2A antagonist

Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D 2 and 5-HT 2A receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3–10 mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3–3 mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1–3 mg/kg, s.c.) with haloperidol (0.5 mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin.

D1 priming enhances both D1- and D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization upon repeated treatment with dopamine agonists, a phenomenon called ‘priming’. We examined the effectiveness of priming with D1 or D2 agonists on rotational behavior and striatal Fos expression following challenge with D1 or D2 agonists. Twenty-one days post-lesion, rats received three priming injections, spaced 3–6 days apart, with water, D1 agonist SKF38393 (10 mg/kg) or D2 agonist quinpirole (1 mg/kg). One week later, 6-OHDA rats were challenged with water, SKF38393 (1 or 10 mg/kg) or quinpirole (0.25 mg/kg). 6-OHDA rats challenged with SKF38393 (1 mg/kg) showed no contralateral rotational behavior, but robust striatal Fos expression in D1-primed animals. Challenge with SKF38393 (10 mg/kg) led to pronounced contralateral rotational behavior and striatal Fos expression in all priming groups — with the largest behavioral response in D1- and D2-primed rats. Quinpirole challenge (0.25 mg/kg) led to robust contralateral rotational behavior and striatal Fos expression in D1-primed animals, but only mild rotational behavior and baseline levels of striatal Fos expression in D2-primed animals. These data suggest that D1- or D2-priming enhances rotational behavior following challenge with D1 or D2 agonist, but only D1-priming enhances D1- and D2-mediated striatal Fos expression in 6-OHDA rats.

Effects of Tandospirone, a 5-HT1A Agonistic Anxiolytic Agent, on Haloperidol-Induced Catalepsy and Forebrain Fos Expression in Mice

We studied the effects of tandospirone, a 5-HT1A agonistic anxiolytic agent, on haloperidol-induced catalepsy and forebrain Fos expression in mice. Haloperidol (0.5 mg/kg, i.p.) markedly increased the catalepsy time and enhanced Fos expression in the shell (AcS) and core (AcC) regions of the nucleus accumbens, the dorsolateral striatum (dlST), and the lateral septal nucleus (LSN). Tandospirone (0.1 – 1 mg/kg, s.c.) significantly alleviated haloperidol-induced catalepsy in a dose-dependent manner, which was antagonized by WAY-100135 (a selective 5-HT1A antagonist). The anticataleptic dose of tandospirone (1 mg/kg, s.c.) significantly reduced haloperidol-induced Fos expression in the dlST. This inhibition by tandospirone was regionally specific, and it failed to affect haloperidol-induced Fos expression either in the AcS, AcC, or LSN. In addition, the reversal of haloperidol-induced striatal Fos expression by tandospirone was antagonized by WAY-100135. These results support the notion that stimulation of 5-HT1A receptors region-specifically counteracts the D2-blocking actions of haloperidol in the striatum, which may account for the ameliorative effects of 5-HT1A agonists on antipsychotic-associated extrapyramidal disorders.

The effects of apomorphine and d-amphetamine on striatal c-Fos expression in Sprague–Dawley and Long Evans rats and their F1 progeny

We previously reported that Sprague–Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to disruption of prepulse inhibition (PPI) of the startle reflex by the dopamine agonists, apomorphine (APO) and d-amphetamine (AMPH). This susceptibility is inherited through F1 (SD × LE) and N2 backcross (F1 × SD) generations via an orderly pattern (SD > N2 > F1 > LE). Here we examined systemic APO (0.5 mg/kg) and AMPH (4.5 mg/kg) modulation of neural activity in four regions of the striatum suspected to be involved in the dopaminergic regulation of PPI – dorsolateral (dlCPu) and medial (mCPu) caudate/putamen and core (NACc) and medial shell (NACms) regions of nucleus accumbens – under conditions that mimicked those used to assess PPI. Immunohistochemical quantification of c-Fos protein expression was used as the surrogate measure of neural activity in SD and LE rats and their F1 crosses. Vehicle-treatment showed significant regional differences in Fos expression, particularly between the dlCPu and the other three areas, but no strain-related differences were observed. Three of four brain areas examined (dlCPu, mCPu and NACc) exhibited drug-induced changes in Fos expression—APO decreased and AMPH increased Fos expression in each region. The aggregate effect across these three regions revealed Fos expression to be significantly greater in LE compared to SD rats for both drugs, with F1 rats intermediate. This pattern of inheritance (LE > F1 > SD) reveals an inverse relationship between striatal Fos expression and PPI sensitivity for these drugs; and a positive relationship with reported heritable differences in D2-linked G-protein binding in the CPu and NACc, and with locomotor activation/suppression by AMPH and APO.

Amphetamine-elicited striatal Fos expression is attenuated in neurotensin null mutant mice

Neurotensin (NT) has been suggested to interact with dopamine systems in different forebrain sites to exert both antipsychotic- and psychostimulant-like effects. We previously found that genetic or pharmacological manipulations that disrupt endogenous NT signaling attenuate antipsychotic drug-induced Fos expression in the dorsolateral and central striatum but not other striatal regions. To assess the role of NT in psychostimulant responses, we examined the ability of d-amphetamine (AMP) to induce Fos in wild-type and NT null mutant mice. AMP-elicited Fos expression was significantly attenuated in the medial striatum of NT null mutant mice, but was unaffected in other striatal territories. Similar results were obtained in rats and mice pretreated with the high affinity neurotensin receptor (NTR1) antagonist SR 48692. The effect of the NTR1 antagonist was particularly apparent in the striatal patch (striosome) compartment, as defined by μ-opioid receptor immunoreactivity. These data suggest that NT is required for the full activation by AMP of medial striatal neurons.

The selective m1 muscarinic antagonist MT-7 blocks pilocarpine-induced striatal Fos expression

Systemic administration of the nonselective muscarinic agonist pilocarpine induces pronounced striatal Fos expression. Intrastriatal injections of the mamba snake toxin MT-7, a highly selective and irreversible m1 muscarinic antagonist, drastically attenuated this response when given 2, but not 8, days before pilocarpine. In contrast, MT-7 did not alter the response to amphetamine (5 mg/kg). These results suggest that pilocarpine induces Fos expression in the striatum as a result of stimulating m1 muscarinic receptors located within this structure and demonstrate the utility of the MT-7 for in vivo studies of cholinergic function.

The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats

The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a necessary requirement for the induction of striatal Fos expression in intact animals and suggest that alternative signal transduction pathways may play a role in dopamine agonist induced Fos expression, especially in dopamine-depleted subjects.

Muscarinic receptor blockade attenuates reserpine-mediated Fos induction in the rat striatopallidal pathway

Acute administration of the dopamine-depleting agent reserpine (10 mg/kg) induces Fos expression in striatopallidal neurons of intact rats—an effect that is blocked by pretreatment with the D2 agonist quinpirole (0.5 mg/kg). Systemic administration of the muscarinic antagonist scopolamine (50 mg/kg) partially attenuates reserpine-mediated striatal Fos expression. These data suggest that muscarinic receptors, either within the striatum or in extrastriatal sites, regulate D2 receptor-mediated Fos expression in rat striatopallidal neurons.

Contrasting loxapine to its isomer isoloxapine—the critical role of in vivo D 2 blockade in determining atypicality

Background Loxapine is a typical antipsychotic while isoloxapine, its 8Cl-isomer, shows atypicality in some animal models. The basis for this difference is not well understood. The purpose of this study was to systematically compare the two drugs in in vitro and in vivo animal models, and to understand mechanisms underlying their differential typical/atypical profiles. Methods The in vitro and in vivo receptor profiles as well as the action of loxapine and isoloxapine on rat conditioned avoidance response (CAR), catalepsy (CAT), striatal FOS expression and prolactin levels were determined. To understand loxapine's typical profile, we added MDL100,907, to provide loxapine + MDL the same in vivo 5-HT 2 / D 2 ratio as isoloxapine, while holding its D 2 component constant. Results Isoloxapine behaved as an “atypical” antipsychotic demonstrating CAR inhibition, low CAT, no significant prolactin elevation, and minimal FOS expression in the dorsolateral striatum. Loxapine behaved like a typical antipsychotic, showing unexpectedly high in vivo D 2 occupancy. Addition of MDL100,907, which resulted in a very high 5-HT 2 / D 2 in vivo ratio, did not alter loxapine + MDL's typical profile. Conclusions Loxapine's behaviour as a typical antipsychotic is most likely due to its disproportionately high D 2 occupancy. Appropriate action at D 2 receptors in vivo, rather than the high 5-HT 2 / D 2 ratio, seems to be critical in determining why isoloxapine behaves like an atypical antipsychotic.

Role of NMDA and AMPA glutamate receptors in the induction and the expression of dopamine-mediated sensitization in 6-hydroxydopamine-lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization following repeated treatment with dopamine agonists, a phenomenon called "priming." Priming has two distinct phases: induction and expression. Priming induction using three injections with D1/D2 agonist apomorphine (0.5 mg/kg) or D1 agonist SKF38393 (10 mg/kg) allows priming expression, robust contralateral rotational behavior and striatal Fos expression, following a challenge with the D2 agonist quinpirole (0.25 mg/kg). We examined the roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors on dopamine agonist priming. Administration of the NMDA antagonist (+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) (0.5 mg/kg) blocked apomorphine-priming of quinpirole-mediated responses, while MK801 dose-dependently attenuated SKF38393-priming of quinpirole-mediated striatal Fos expression and had no effect on SKF38393-priming of quinpirole-mediated rotational behavior. In contrast, administration of the AMPA antagonist 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo[f]quinoxaline (NBQX) (5 or 10 mg/kg) potentiated apomorphine- and SKF38393-priming of quinpirole-mediated striatal Fos expression, but had no effect on their priming of quinpirole-mediated rotational behavior. In SKF38393-primed 6-OHDA rats, administration of MK801 (0.5 mg/kg) blocked the expression of quinpirole-mediated responses, while administration of NBQX (10 mg/kg) or the noncompetitive AMPA antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine dihydrochloride (GYKI52466) (5 or 15 mg/kg) had no effect. These results suggest that NMDA and AMPA glutamate receptors have differing roles in dopamine agonist priming-with NMDA receptors required for D1/D2 priming induction and D2-mediated priming expression, and AMPA receptors inhibiting priming induction of D2-mediated immediate early gene expression in the striatum, but not affecting priming induction of D2-mediated rotational behavior or the expression of D2-mediated responses.

Interaction between the noradrenergic and serotonergic systems in locomotor hyperactivity and striatal expression of Fos induced by amphetamine in rats.

It is classically considered that Amphetamine acts by increasing extracellular dopamine levels. However, some data suggest a relevant role of other neurochemical systems. The striatum is of particular interest to the study of this question. We have investigated the involvement of the noradrenergic and serotonergic systems and their possible interaction in the striatal responses to Amphetamine using a double behavioral and immunohistochemical approach (i.e., changes in locomotor activity and striatal expression of Fos). In normal rats, Amphetamine induced locomotor hyperactivity and striatal expression of Fos. Pretreatment with the alpha1-adrenergic-receptor antagonist Prazosin or lesion of the serotonergic system significantly reduced the locomotor hyperactivity and striatal Fos expression induced by Amphetamine. Administration of Prazosin to rats with serotonergic denervation did not produce any further reduction in the Amphetamine-induced locomotor hyperactivity or striatal Fos expression compared with that observed in rats with serotonergic denervation only. Amphetamine did not induce a detectable increase in Fos expression in dopamine-denervated striata, and elicited intense rotation towards the dopamine-denervated side. This suggests that striatal dopamine release is essential in the Amphetamine-induced effects on striatal neurons. However, the noradrenergic system plays an important role, and the serotonergic system is necessary for mediating the effects of the Amphetamine-induced noradrenergic stimulation. Concurrent stimulation of dopaminergic and serotonergic receptors appears necessary to regulate Amphetamine-induced responses in the striatal neurons.

The neurotensin antagonist SR 48692 attenuates haloperidol-induced striatal Fos expression in the rat

Neurotensin interacts with central dopamine systems and has been suggested to exert antipsychotic drug-like actions. Antipsychotic drugs such as haloperidol induce striatal immediate-early gene expression. In order to study neurotensin's role in antipsychotic drug actions, rats were pretreated with the neurotensin antagonist SR 48692 and then injected with haloperidol. SR 48692 dose-dependently decreased haloperidol-elicited immediate-early gene expression in the dorsolateral and central striatum but not other striatal areas. SR 48692 reduced Fos expression in the striatal patch (striosome) and matrix compartments, with a significantly greater effect in the patch. These data suggest that neurotensin may play a role in the actions of haloperidol. In view of proposed functional roles of the striatal patch and matrix, we suggest that neurotensin may be important in the therapeutic rather than side effects of antipsychotic drugs.

NMDA glutamate receptor stimulation is required for the expression of D2 dopamine mediated responses in apomorphine primed 6-hydroxydopamine lesioned rats

Three priming injections with the D1/D2 dopamine agonist apomorphine permits a challenge with the D2 agonist quinpirole to elicit robust contralateral rotation and ipsilateral striatal Fos expression in 6-hydroxydopamine lesioned rats. Pretreatment with NMDA glutamate antagonists MK-801 or CPP dose-dependently attenuates these quinpirole-mediated responses. These findings suggest that concomitant NMDA receptor stimulation is required for the expression of D2-mediated responses in apomorphine primed dopamine-depleted rats.

Comparative effects of scopolamine and quinpirole on the striatal fos expression induced by stimulation of D 1 dopamine receptors in the rat

Treatment of intact rats with the full D 1 dopamine agonist A-77636 induced Fos-like immunoreactivity in the medial and, to a lesser extent, the lateral portions of the striatum. Pretreatment with the muscarinic antagonist scopolamine hydrobromide (1.5–6 mg/kg) potentiated the response to A-77636 and eliminated the mediolateral staining gradient seen after A-77636 alone. Similar effects were not produced by scopolamine methylbromide, which fails to cross the blood–brain barrier, demonstrating that the actions of scopolamine were centrally mediated. The effects of scopolamine were further compared to those of the D 2-like dopamine agonist quinpirole using a factorial design in which subjects were pretreated with either scopolamine, quinpirole, or a combination of the two drugs before receiving A-77636. Pretreatment with either scopolamine or quinpirole increased staining in the lateral striatum, but the combination of the two drugs was no more effective than was quinpirole alone. Pretreatment with quinpirole, but not scopolamine, resulted in a markedly ‘patchy’ pattern of staining and actually suppressed staining in the region between patches in the medial striatum. These findings demonstrate that there are both differences and similarities between the effects of scopolamine and quinpirole on D 1 agonist-induced Fos expression and suggest that although inhibition of cholinergic neurons may be one of the mechanisms through which the effects of quinpirole are produced, other factors must also contribute.

Effects of repeated methyl levodopa administration on apomorphine sensitivity of rotational behavior and striatal Fos expression of rats with unilateral 6-OHDA lesions.

This study was designed to elucidate the mechanism to develop levodopa-induced dyskinesia in patients with Parkinson's disease. For this purpose, we administered methyl levodopa repeatedly to a rat model of Parkinson's disease with unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine pathway. After a washout period, we measured apomorphine sensitivity of contralateral rotation and made parallel determination of Fos expression in the caudate-putamen and globus pallidus of the same animal. Once daily, i.p. injection of methyl levodopa plus benserazide for 10 days increased the number of rotations over time. A challenge dose of apomorphine showed enhanced rotational response in rats pretreated with methyl levodopa. Repeated administration of methyl levodopa resulted in diminished apomorphine sensitivity of Fos expression in the dopamine depleted caudate-putamen and in enhanced sensitivity in the globus pallidus of the same side. Present results may add evidence to the idea that repeated administration of levodopa develops dopaminergic sensitization mediated by augmented activation of pallidal neurons involved in D2-responsive pallidal output pathway.

A comparison of the patterns of striatal Fos-like immunoreactivity induced by various dopamine agonists in rats

In contrast to the highly patchy patterns of Fos-like immunoreactivity seen in the rostral striatum after administration of a number of dopamine agonists, the monoamine uptake blocker cocaine has been reported to produce a relatively homogenous pattern of gene expression. In the current study we extended these observations by using a quantitative technique to demonstrate that while amphetamine and apomorphine produce patchy striatal Fos expression, the selective dopamine uptake inhibitors amfonelic acid, nomifensine and GBR-12909 all, like cocaine, produce near random patterns of gene expression. These findings suggest that the production of relatively ‘non-patchy’ patterns of immediate early gene expression may be a general property of dopamine transport inhibitors unrelated to any unique pharmacological properties of cocaine.