Neurochemical correlates of behavioral sensitization following repeated apomorphine treatment: Assessment of the role of D1 dopamine receptor stimulation

Previous research has revealed a role of repeated D₁ dopamine receptor stimulation in the development of behavioral sensitization to the D₁/D₂ agonist apomorphine. The present experiments assessed the role of repeated D₁ receptor stimulation in neurochemical changes accompanying locomotor sensitization to apomorphine. To assess direct effects of D₁ stimulation on dopamine synthesis, rats were injected with the D₁ agonist SKF 38393 (8 mg/kg), followed by an injection with the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, NSD-1015. DOPA accumulation, assessed in striatal, nucleus accumbens-olfactory tubercle (NAOT), and ventral mesencephalon (VM) tissue samples, was not affected by acute SKF 38393. In the second experiment, rats were treated with 10 daily injections of vehicle, apomorphine (5 mg/kg) or the D₁ agonist SKF 38393 (8 or 16 mg/kg). Daily measures of locomotor activity demonstrated a progressive increase in the apomorphine-treated rats, but not the SKF 38393-treated rats, across the 10 days. On day 11, all rats were injected with NSD-1015 for measurement of DOPA accumulation. Dopamine synthesis was enhanced in the striatum after repeated apomorphine treatment. In contrast, repeated SKF 38393 treatment resulted in either a small decrease or no change in DOPA accumulation in the different brain regions (striatum, NAOT, VM). In the third experiment, tissue levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and [³H]SCH 23390 binding to D₁ receptors were measured in rats treated with 10 daily injections of vehicle, apomorphine (5 mg/kg), or SKF 38393 (16 mg/kg). In the striatum and NAOT, none of the repeated drug treatments had an effect on DOPAC or dopamine levels. In the VM, DOPAC levels were enhanced following repeated apomorphine, but not repeated SKF 38393, whereas dopamine levels were not affected by either drug treatment. D₁ binding was not altered by the repeated drug treatments. Since repeated D₁ stimulation by SKF 38393 did not produce the same alterations in dopamine synthesis and DOPAC levels as repeated apomorphine, the neurochemical effects accompanying locomotor sensitization to apomorphine probably are not mediated by D₁ receptors. © 1993 Wiley-Liss, Inc.     

Repeated intravenous cocaine administration: Locomotor activity and dopamine D2/D3 receptors

The dopamine D₃ receptor has been implicated as a possible mediator in the reinforcement or abuse of psychostimulants such as cocaine. The present studies examined the effects of repeated (14 day) intravenous cocaine administration (saline vehicle, 0.5, 1.0 and 3.0 mg/kg) on locomotor activity and dopamine D₂ and D₃ receptor density in the rat striatum and nucleus accumbens. Male Sprague-Dawley rats (n = 40) were implanted with an intravenous access port and allowed to recover for 2 days. An additional group of naive rats was included to control for surgical/injection stress (n = 10). Following 2 days of habituation trials, total, peripheral and central activity (photocell interruptions) data were collected during alternate daily 60-minute test sessions. Repeated cocaine treatment resulted in a significant dose-dependent increase in striatal D₃ receptors which was predicted by daily 60-minute central locomotor activity. Conversely, D₃ receptors in the nucleus accumbens exhibited a significant dose-dependent reduction which was predicted by the initial 5 minutes of central locomotor activity observed on peak sensitization days (days 6, 8 and 10). Sensitization to the locomotor stimulatory effects of cocaine was dose-dependent, with the time to peak sensitization day following the rank order of 0.5 > 1.0 > 3.0 mg/kg. The density of D₂ receptors in the striatum and nucleus accumbens was unchanged by cocaine administration. These data suggest striatal and nucleus accumbens D₃ receptor involvement in the expression of cocaine-induced behavioral sensitization. Thus, the D₃ receptors in the striatum and nucleus accumbens may be differentially involved in the locomotor stimulation (striatal D₃) and reinforcing aspects (nucleus accumbens D₃) of repeated cocaine administration. © 1996 Wiley-Liss, Inc.     

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

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

Quinpirole attenuates the striatal Fos expression induced by escape behavior

Several studies have shown that the D₂-like dopamine receptor agonist quinpirole is able to markedly potentiate the striatal Fos expression induced by D₁ agonists. The present study examined the effects of quinpirole on the striatal Fos-like immunoreactivity (FLI) induced by escape behavior. Male rats were pretreated with either saline or quinpirole (0.156, 0.625, 1.25 or 2.5 mg/kg) and 30 min later, placed in a shuttle box and required to crossover every 30 s in order to escape mild footshock. Animals were sacrificed 30 min following the completion of a 1-h block of escape trials and sections through the striatum were processed for FLI. Pretreatment with quinpirole produced a marked, dose-dependent, attenuation of escape-induced FLI in the striatum. These findings demonstrate that quinpirole affects the striatal Fos expression induced by shuttling in a very different fashion than it does that induced by D₁ agonists, and further support the view that dopaminergic mechanisms play an important role in behaviorally induced striatal Fos expression.     

Repeated administration of antidepressant drugs affects the levels of mRNA coding for D1 and D2 dopamine receptors in the rat brain

Summary The present study examined the effects of acute and repeated administration of three antidepressant drugs (imipramine, citalopram and (+)-oxaprotiline) on the levels of mRNA coding for dopamine D₁ and D₂ receptors in the rat brain. Quantitive in situ hybridization with³⁵S-labelled oligonucleotide probes has been utilised. The level of mRNA coding for dopamine D₁ receptor (D₁ mRNA) is decreased following repeated administration of imipramine, both in the nucleus accumbens and in the striatum. On the other hand, the repeated administration of citalopram, the selective inhibitor of serotonin reuptake, resulted in an increase in the level of D₁ mRNA in the striatum and in the core region of nucleus accumbens. A similar tendency, i.e.: an increase in the level of D₁ mRNA was observed after repeated administration of (+)-oxaprotiline, a selective inhibitor of noradrenaline reuptake. The level of mRNA coding for dopamine D₂ receptors (D₂ mRNA) was increased in all the brain regions studied, both after administration of imipramine and citalopram. (+)-Oxaprotiline did not produce any statistically significant changes in the level of D₂ mRNA.The results obtained in this study indicate that the levels of mRNA coding for dopamine D₁ and D₂ receptors are regulated by the antidepressant drugs. The changes concerning the dopamine D₂ receptors are more consistent and fit in with the previously described binding and behavioral effects and seem to be important for the mechanism of action of antidepressant drugs.     

Effects of intrastriatal infusion of D2 receptor antisense oligonucleotide on apomorphine-induced behaviors in the rat

An antisense oligonucleotide strategy was employed to specifically deplete postsynaptic striatal D₂ receptors in order to determine the possible role of presynaptic D₂ autoreceptors in mediating behavioral responses induced by low doses of apomorphine. A phosphorothioate-modified antisense oligonucleotide complementary to the first 19 bases of the coding region of D₂ receptor mRNA, a scrambled sequence comprising the same bases, or saline was infused bilaterally into the striatum of adult rats, twice daily for 2 days via indwelling cannulae. After an interval of 8–12 h, rats were habituated and challenged with high (300 μg/kg; subcutaneous) or low (50 μg/kg; s.c.) doses of apomorphine or its vehicle (0.1% ascorbic acid). Yawning, vacuous chewing mouth movements, hypoexploration, and penile grooming induced by low-dose apomorphine were unaffected by antisense infusion into the striatum, whereas stereotypic sniffing following high-dose apomorphine was markedly suppressed. Intrastriatal infusion of antisense resulted in significantly diminished [³H]-raclopride binding, while binding of [³H]-SCH 23390 (D₁ receptors) and [³H]-WIN 35428 (dopamine transporter) was unchanged. D₂ mRNA levels determined by quantitative in situ hybridization were normal in the striatum and the substantia nigra. Our results confirm that stereotypic sniffing is mediated via postsynaptic D₂ receptors in the striatum, and favor the notion that behavioral responses induced by low doses of apomorphine are mediated by presynaptic D₂ autoreceptors. Synapse 26:199–208, 1997. © 1997 Wiley-Liss Inc.     

Differential effect of MK 801 and scopolamine on c-fos expression induced by L-dopa in the striatum of 6-hydroxydopamine lesioned rats

In rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal pathway, striatal D_l-receptor-stimulated c-fos expression and turning behavior are positively modulated by D₂ receptor stimulation and by blockade of N-methyl-D-aspartate (NMDA) or muscarinic receptors. Combined D₁/D₂ receptor stimulation by L-dopa activates c-fos in a manner not additive with muscarinic receptor blockade by scopolamine. On the other hand, blockade of NMDA receptors by MK 801 reduced c-fos expression induced by L-dopa while, depending on the dose of L-dopa, differentially affecting contralateral turning behavior. The results are interpreted to suggest that D₂ receptor stimulation amplifies D₁-receptor-mediated c-fos expression by two mechanisms differentially related to muscarinic and NMDA receptors. ©1994 Wilev-Lisa. Inc.     

Quinolinic acid lesions of rat striatum abolish D1- and D2-dopamine receptor-mediated catalepsy

The selective D₁-dopamine receptor antagonist SCH23390 and the more D₂-selective antagonist haloperidol produced marked catalepsy in rats. The novel excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol and 225 nmol per side) abolished the cataleptic response to both SCH23390 and haloperidol. These data indicate that the D₁- and/or D₂-dopamine receptors which mediate the cateleptic response are restricted to QA-sensitive neurons in the rat striatum.     

Dopamine depletion induces neuron‐specific alterations of GABAergic transmission in the mouse striatum

Lack of dopamine (DA) in the striatum and the consequential dysregulation of thalamocortical circuits are major causes of motor impairments in Parkinson's disease. The striatum receives multiple cortical and subcortical afferents. Its role in movement control and motor skills learning is regulated by DA from the nigrostriatal pathway. In Parkinson's disease, DA loss affects striatal network activity and induces a functional imbalance of its output pathways, impairing thalamocortical function. Striatal projection neurons are GABAergic and form two functionally antagonistic pathways: the direct pathway, originating from DA receptor type 1‐expressing medium spiny neurons (D₁R‐MSN), and the indirect pathway, from D₂R‐MSN. Here, we investigated whether DA depletion in mouse striatum also affects GABAergic function. We recorded GABAergic miniature IPSCs (mIPSC) and tonic inhibition from D₁R‐ and D₂R‐MSN and used immunohistochemical labeling to study GABA_AR function and subcellular distribution in DA‐depleted and control mice. We observed slower decay kinetics and increased tonic inhibition in D₁R‐MSN, while D₂R‐MSN had increased mIPSC frequency after DA depletion. Perisomatic synapses containing the GABA_AR subunits α₁ or α₂ were not affected, but there was a strong decrease in non‐synaptic GABA_ARs containing these subunits, suggesting altered receptor trafficking. To broaden these findings, we also investigated GABA_ARs in GABAergic and cholinergic interneurons and found cell type‐specific alterations in receptor distribution, likely reflecting changes in connectivity. Our results reveal that chronic DA depletion alters striatal GABAergic transmission, thereby affecting cellular and circuit activity. These alterations either result from pathological changes or represent a compensatory mechanism to counteract imbalance of output pathways.     

Specificity of behavioral and neurochemical dysfunction in the chakragati mouse: a novel genetic model of a movement disorder

Thechakragati (ckr) mouse is a transgenic insertional mutant that displays lateralized circling behavior, locomotor hyperactivity, hyperexcitability as well as body weight deficits. The mutation is autosomal and recessive. We have previously found thatckr mice have bilateral asymmetric elevations in striatal dopamine (DA) D₂-like (D₂, D₃ and/or D₄), but not D₁-like (D₁ and/or D₅) receptors. Predictably, these mice increase turning in response to the D₂-like agonist quinpirole and spontaneously rotate contralateral to the striatal side with the higher D₂-lik3 receptors. The overall objective of the present study was to assess the neurochemical specificity of the mutation inckr mouse, particularly since motor behaviors can be elicited by a multitude of brain regions and neurotransmitter systems within the basal ganglia. Using quantitative receptor autoradiography, we examined the regional distribution of DA uptake sites and 5-HT_1A, 5-HT_1B/1D, GABA_A and μ opioid receptors. Also, we wanted to determine whether increased behavioral laterality as seen in rotation is evident with another test of laterality, such as lateral paw preference. Theckr mice showed greater paw preferences than normal mice; however, neither the degree nor direction of these preferences correlated with rotational behavior. Theckr mice showed moderate decreases in the density of DA uptakes sites in all subregions of the striatum, but not in the nucleus accumbens or olfactory tubercle. Interestingly, these decreases inckr mice were not accompanied by a reduction in striatal tissue DA content. 5-HT1 and μ opiate receptor populations were normal inckr mice. However, GABA_A sites in the mediodorsal thalamus and superior colliculus were bilaterally and asymmetrically elevated inckr mice. These data are consistent with the idea that the motor phenotypes of theckr mouse result from specific disturbances within nigro-striatal, striato-pallido-thalamic and striato-nigro-collicular circuitry. The implications of these and past findings are discussed in relation to current thinking about hyperkinetic motor syndromes in humans involving reduced basal ganglia outflow.     

Effects of intrastriatal cannabinoids on rotational behavior in rats: Interactions with the dopaminergic system

The effect of unilateral intrastriatal cannabinoid receptor stimulation on rotational behavior in rats was explored. The potent cannabinoid agonist CP 55,940 (5 μg/0.5 μl) induced contralateral turning when microinjected unilaterally into the striatum. The D₂dopamine agonist quinpirole reversed this contralateral rotation but failed to affect motor behavior on its own. Finally, the D₁dopamine agonist SKF 82958 inhibited movement when administered into the striatum and this inhibition was reversed by co-administration of the cannabinoid agonist. Surprisingly, microinjections of the cannabinoid agonist into the striatum induced movement through activation of the striatonigral pathway and/or inhibition of the striatopallidal pathway, while the D₁dopamine agonist produced the opposite effect. Synapse 30:221–226, 1998. © 1998 Wiley-Liss, Inc.     

Relationship between regional gray matter volumes and dopamine D2 receptor and transporter in living human brains

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D₂ receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D₂ receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [¹¹C]raclopride and [¹⁸F]FE‐PE2I, respectively, were acquired along with T1‐weighted magnetic resonance imaging data in our previous studies, and were re‐analyzed in this work. We quantified the binding potentials (BP _ND) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BP _ND and regional GM volume were then examined by voxel‐based morphometry. In line with the functional and anatomical connectivity, [¹¹C]raclopride BP _ND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BP _ND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BP _ND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [¹⁸F]FE‐PE2I BP _ND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D₂ receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.     

Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson's disease

Adenosine A_2A receptors are a new target for drug development in Parkinson’s disease. Some experimental and clinical data suggest that A_2A receptor antagonists can provide symptomatic improvement by potentiating the effects of -DOPA as well as a decrease in secondary effects such as -DOPA-induced dyskinesia. -DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of -DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A_2A receptor agonist CGS 21680 and the A_2A receptor antagonist MSX-3 on -DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. -DOPA-induced behavioral sensitization was determined as an increase in -DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyrosine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting -DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of -DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that -DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A_2A and D₂ receptor stimulation, since it was counteracted by MSX-3 and by the D₂ receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson’s disease.     

Substance P containing polymer implants protect against striatal excitotoxicity

The present study examined whether substance P (Sub P) could protect against quinolinic acid (QA)-induced lesions of the striatum, as measured by a loss of striatal D₁ dopamine receptors. Sub P was extruded into Evac polymer rods for slow release. One 4 mm rod segment was implanted unilaterally into the striatum of each rat. One week later, animals received a striatal injection of QA (50, 75 or 100 nmol/μl) medial to the implanted rod. Controls received QA alone. Three weeks later, there was a dose-dependent loss of D₁ receptors following QA. Sub P rods protected the striatum from QA-induced D₁ receptor loss at this time. These results support the neuroprotection of Sub P on excitotoxicity.     

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

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

Stereotypic Progressions in Psychotic Behavior

Dopamine receptor supersensitivity (DARSS) often is invoked as a mechanism possibly underlying disordered thought processes and agitation states in psychiatric disorders. This review is focused on identified means for producing DARSS and associating the role of other monoaminergic systems in modulating DARSS. Dopamine (DA) receptors, experimentally, are prone to become supersensitive and to thus elicit abnormal behaviors when coupled with DA or a receptor agonist. In intact (control) rats repeated DA D₁ agonist treatments fail to sensitize D₁ receptors, while repeated D₂ agonist treatments sensitize D₂ receptors. D₂ RSS is attenuated by a lesion with DSP-4 (N-(2-chlorethyl)-N-ethyl-2-bromobenzylamine) in early postnatal ontogeny, indicating that noradrenergic nerves have a permissive effect on D₂ DARSS. However, if DSP-4 is co-administered with 5,7-dihydroxytryptamine to destroy serotonin (5-HT) nerves, then D₂ RSS is restored. In rats treated early in postnatal ontogeny with the neurotoxin 6-hydroxydopamine to largely destroy DA innervation of striatum, both repeated D₁ and D₂ agonists sensitize D₁ receptors. 5-HT nerves appear to have a permissive effect on D₁ DARSS, as a 5-HT lesion reduces the otherwise enhanced effect of a D₁ agonist. The series of findings demonstrate that DARSS is able to be produced by repeated agonist treatments, albeit under different circumstances. The involvement of other neuronal phenotypes as modulators of DARSS provides the potential for targeting a variety of sites in the aim to prevent or attenuate DARSS. This therapeutic potential broadens the realm of approaches toward treating psychiatric disorders.     

Effects of a D1 antagonist and of sexual experience on copulation-induced Fos-like immunoreactivity in the medial preoptic nucleus

The medial preoptic nucleus (MPN) of the medial preoptic area (MPOA) and the medial amygdala are two brain regions in which male rat sexual behavior increased Fos-like immunoreactivity (Fos-Li). Dopamine is released in the MPOA during male rat sexual behavior and facilitates copulation. Psychostimulants, which increase dopamine levels, induce Fos-Li in the striatum through D₁ receptors. We examined whether copulation-induced Fos-Li in the MPN was also mediated through D₁ receptors. In Experiment 1, sexually inexperienced male rats that received the D₁ antagonist Schering 39166 prior to their first sexual experience had fewer Fos-Li cells in the MPN than did those that received vehicle. In Experiment 2, no significant effect of the D₁ antagonist was observed on copulation-induced Fos-Li in male rats that had received repeated sexual experiences prior to the drug test day. Sexual experience increases copulatory efficiency; the mechanisms by which this improvement occurs are unclear. In Experiment 3, copulation by highly experienced male rats led to greater Fos-Li in the MPN than did copulation by sexually naive males. Although there were no differences between groups in amygdala Fos-Li in these studies, in several groups Fos-Li in the medial amygdala was positively correlated with the post-ejaculatory interval. These experiments indicate that (1) stimulation of D₁ receptors may contribute to the transient copulation-induced increase in Fos-Li in the MPN, and (2) repeated sexual experiences enhanced copulation-induced Fos-Li in the MPN, which may represent a marker of altered responsiveness of neurons in the MPN to sexual or conditioned stimuli.     

The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression

The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D₂ receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D₁ and D₂ receptor agonists and antagonists, as well as the partial dopamine D₂ agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D₁ and D₂ compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D₂ receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D₂ receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-d-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.     

Synergistic interaction between an adenosine antagonist and a D1 dopamine agonist on rotational behavior and striatal c-Fos induction in 6-hydroxydopamine-lesioned rats

The interaction between adenosine and D₁ dopamine systems in regulating motor behavior and striatal c-Fos expression was examined in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. These results were compared to the synergistic interaction between D₁ and D₂ dopamine systems in 6-OHDA rats. Coadministration of the adenosine antagonist 3,7-dimethyl-1-propargylxanthine (DMPX: 10 mg/kg) and the D₁ dopamine agonist SKF38393 (0.5 mg/kg) to 6-OHDA-lesioned rats produced significant contralateral rotation and c-Fos expression in the ipsilateral striatum compared to 6-OHDA rats treated with either drug alone. However, the regional pattern of striatal c-Fos activation following treatment of 6-OHDA rats with SKF38393 and DMPX was different from the dorsolateral pattern of striatal c-Fos induction observed after coadministration of D₁ and D₂ dopamine agonists (SKF38393: 0.5 mg/kg+quinpirole: 0.05 mg/kg). These data are consistent with a functional interaction between D₁ dopamine and adenosine systems in the striatum, but suggest that activation of different subsets of striatal neurons underlie the behavioral synergy observed following combined adenosine antagonist-D₁ dopamine agonist and combined D₁ dopamine agonist–D₂ dopamine agonist treatment.     

Long-term Potentiation in the Striatum is Unmasked by Removing the Voltage-dependent Magnesium Block of NMDA Receptor Channels

We have studied the effects of tetanic stimulation of the corticostriatal pathway on the amplitude of striatal excitatory synaptic potentials. Recordings were obtained from a corticostriatal slice preparation by utilizing both extracellular and intracellular techniques. Under the control condition (1.2 mM external Mg2+), excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation were reversibly blocked by 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of dl-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) ionotropic glutamate receptors, while they were not affected by 30 - 50 microM 2-amino-5-phosphonovalerate (APV), an antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors. In the presence of 1.2 mM external Mg2+, tetanic activation of cortical inputs produced long-term depression (LTD) of both extracellularly and intracellularly recorded synaptic potentials. When Mg2+ was removed from the external medium, EPSP amplitude and duration increased. In Mg2+-free medium, cortically evoked EPSPs revealed an APV-sensitive component; in this condition tetanic stimulation produced long-term potentiation (LTP) of synaptic transmission. Incubation of the slices in 30 - 50 microM APV blocked striatal LTP, while it did not affect LTD. In Mg2+-free medium, incubation of the slices in 10 microM CNQX did not block the expression of striatal LTP. Intrinsic membrane properties (membrane potential, input resistance and firing pattern) of striatal neurons were altered neither by tetanic stimuli inducing LTD and LTP, nor by removal of Mg2+ from the external medium. These findings show that repetitive activation of cortical inputs can induce long-term changes of synaptic transmission in the striatum. Under control conditions NMDA receptor channels are inactivated by the voltage-dependent Mg2+ block and repetitive cortical stimulation induces LTD which does not require activation of NMDA channels. Removal of external Mg2+ deinactivates these channels and reveals a component of the EPSP which is potentiated by repetitive activation. Since the striatum has been involved in memory and in the storage of motor skills, LTD and LTP of synaptic transmission in this structure may provide the cellular substrate for motor learning and underlie the physiopathology of some movement disorders.