Effekten av Dopamin D-1 og D-2 receptor agonister på aber: Et adfærdsmæssigt korrelat til D-1 og D-2 receptor stimulation. Dopamin D-1 og D-2 agonister hos aber

The effect of dopamine (DA) D-1 and D-2 receptor agonists was evaluated in five Cebus monkeys previously treated with haloperidol for two years. Three monkeys had developed oral tardive dyskinesia. The behavioural effects of the D-1 agonist SKF 38393, the D-2 agonist LY 171555 and apomorphine, a combined D-1/D-2 agonist, were investigated. Apomorphine induced oral hyperkinesia, non-oral stereotyped, repetitive movements of head, limbs and trunk and increased reactivity. SKF 38393 induced oral hyperkinesia and slight sedation. No non-oral stereotyped, repetitive movements were seen. Conversely LY 171555 produced non-oral stereotyped, repetitive movements, increased reactivity and inhibited the oral movements. Pretreatment with SKF 38393 produced an inhibition of the LY 171555-induced non-oral stereotyped, repetitive movements, and conversely, the SKF 38393-induced oral movements were inhibited by LY 171555. Pretreatment with SKF 38393 produced an inhibition of the apomorphine-induced stereotyped, repetitive movements and oral hyperkinesia. D-1 and D-2 DA receptor agonists appeared to have opposite effects and to antagonize each other. The results indicate that oral hyperkinesia are more related to D-1 receptor stimulation and to a less degree related to D-2 receptor supersensitivity.     

Hippocampal modulation of locomotor activity induced by focal activation of postsynaptic dopamine receptors in the core of the nucleus accumbens

The locomotor effects of intra-NAcc injection of dopamine receptor agonists following discrete lesion or inhibition of the DH or the VH have been poorly investigated using only the indirect dopamine receptor agonist amphetamine. In the present study, we investigated how lidocaine in the DH or the VH modulated hyperlocomotion induced by focal injection into the NAcc core of the selective D1-like receptor agonist, SKF 38393, or coinjection of SKF 38393, and the selective D2-like receptor agonist, LY 171555; the latter pharmacological condition being required for the full expression of the postsynaptic effects of D2-like receptor agonists, and recognized to produce a locomotor response mainly mediated by D2-like postsynaptic receptors. Rats were given the D1-like receptor agonist SKF 38393 alone or in combination with the D2-like receptor agonist LY 171555 into the NAcc core, and lidocaine into the DH or the VH. Then, locomotor activity was recorded. Focal injection into the NAcc core of SKF 38393 alone or in combination with LY 171555 resulted in an increase of locomotor activity. Administration of lidocaine into the DH further potentiated the increase in locomotor activity induced by activation of D1-like receptors or co-activation of D1-like and D2-like receptors in the NAcc core. Administration of lidocaine into the VH also potentiated the increase in locomotor activity induced by D1-like receptor activation, but decreased that produced by co-activation of D1-like and D2-like receptors in the NAcc core. Taken together, these results suggest that under lidocaine-free conditions the DH may exert a tonic inhibitory modulation on hyperlocomotion mediated by D1-like and D2-like postsynaptic receptors in the NAcc core, while the VH may exert a tonic inhibitory on hyperlocomotion mediated by D1-like receptors and a tonic facilitatory control on hyperlocomotion mediated by D2-like postsynaptic receptors.     

Synergistic effects of D1 and D2 dopamine agonists on turning behaviour in rats

In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, a specific D1 dopamine receptor agonist, SKF 38393A, at a dose that does not itself produce turning, significantly increased the contralateral rotation observed following a low dose of the specific D2 agonist LY 171555. Doses of SKF 38393A or the D2 agonist bromocriptine, which would themselves not induce turning, in combination produced a high rate of turning. These results suggest a synergistic interaction between D1 and D2 dopamine receptors in this system.     

Local cerebral glucose utilization after D1 receptor stimulation in 6-OHDA lesioned rats: Effect of sensitization (priming) with a dopaminergic agonist

In rats bearing unilateral 6-hydroxydopamine (6-OHDA) lesions of the dopaminergic nigro-striatal neurons, a single administration of a D-2 agonist (LY 17155) potentiates the contralateral turning induced by a D-1 agonist (SKF 38393). To identify the neural substrate of this form of sensitization (priming), we studied the local cerebral glucose utilization (lCMR_glc) in 6-OHDA lesioned animals treated, 3 days apart, as follows: (1) saline-saline, (2) LY 171555-saline, (3) saline-SKF 38393 and (4) LY 171555-SKF 38393. The unilateral 6-OHDA lesion per se (Sal-Sal) produced increases in lCMR_glc in the globus pallidus (GP) and in the lateral habenula (LH) of the lesioned hemisphere. lCMR_glc in LY-Sal group were similar to those measured in the Sal-Sal group. Administration of SKF 38393 to drug-naïve rats (Sal-SKF) abolished the lesion-induced metabolic asymmetry in the LH but did not have any effect on the GP; furthermore, it increased lCMR_glc in the substantia nigra pars reticulata (SNr) of the lesioned side. After priming with LY 171555, administration of SKF 38393 (LY-SKF) produced marked metabolic asymmetries by increasing lCMR_glc in the SNr and entopeduncular nucleus (EP), and decreasing it in the LH of the lesioned side. These changes were also significant when compared to the corresponding values of the other experimental groups. Again, in LY-SKF group no modification of the lesion-induced metabolic asymmetry in the GP was found. These results indicate that priming exerts a facilitatory influence on the ability of D-1 receptors to stimulate the striato-nigral and striato-entopeduncular pathway, suggesting that changes in the effectiveness of dopamine in activating its postsynaptic target elements might contribute to the mechanism of sensitization to drugs stimulating dopaminergic transmission. © 1993 Wiley-Liss, Inc.     

Acute effects of lithium on dopaminergic responses: iontophoretic studies in the rat visual cortex

The interactions between lithium and cortical dopaminergic receptors were investigated using the iontophoretic technique to record and apply dopaminergic compounds, GABA, acetylcholine and LiCl on neurons in the primary visual cortex of the rat. The main responses to dopamine (DA) or to the D1 agonist (+/- )SKF38393 on spontaneously-active (SA) or visually-driven (VD) units was a prolonged decrease in firing and a reduction in the responsiveness to pulses of acetylcholine. The D1 antagonist SCH23390, applied iontophoretically or intravenously, blocked or attenuated the inhibitory responses to both DA and (+/- )SKF38393. The D2 agonist quinpirole (LY171555) either produced only slight excitations or had no effects on both VD and SA units. The concomitant application of lithium blocked the inhibitory responses to DA and to (+/- )SKF38393 but did not modify the responsiveness to LY171555. In addition, the DA- and (+/- )SKF38393-induced decreases in responsiveness to acetylcholine were also suppressed by lithium. These effects were on dopaminergic mechanisms, since the excitatory responses to acetylcholine alone as well as the inhibitions caused by GABA were unchanged by the application of lithium. These results imply that the modifications in sensitivity to dopaminergic agents induced by lithium are mediated by dopamine D1 receptors and are discussed in relation to adenylate-cyclase.     

Effects of dopamine agonists on excitatory inputs to nucleus accumbens neurons from the amygdala: modulatory actions of cholecystokinin

The interaction of the cholecystokinin octapeptide (CCK-8) with dopamine (DA) and dopamine agonists on neurons in the nucleus accumbens was investigated using single unit recording and iontophoretic techniques in urethane-anaesthetized rats. Neurons in the nucleus accumbens were activated by single pulse stimulation of amygdala. Using seven-barrel microelectrodes, the effects of iontophoretic application of CCK-8, DA, dopamine D1 and/or D2 receptor agonists (SKF 38393 and LY 171555 respectively) were compared. The iontophoretic application of DA, LY 171555 and LY 171555 + SKF 38393 attenuated by 50-60% the excitatory responses of accumbens neurons to electrical stimulation of basolateral amygdala whereas SKF 38393 attenuated the response by less than 30%. The iontophoretic application of CCK reduced these attenuating effects of DA, LY 171555 and SKF 38393 + LY 171555. With CCK there was a rather small reduction of the attenuating effect of SKF 38393. These observations provide additional electrophysiological evidence of the interaction of CCK and dopamine and suggest that the interaction is associated mainly with dopamine D2 mechanisms.     

Dopaminergic grafts in the striatum reduce D1 but not D2 receptor-mediated rotation in 6-OHDA-lesioned rats.

Rats received fetal dopaminergic neuronal grafts in the striatum and/or substantia nigra ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). Dopaminergic grafts in the striatum substantially and significantly reduced turning elicited by the selective D1 agonist SKF 38393, but did not reduce turning elicited by the selective D2 agonist LY 171555. Thus, reduced turning in such grafted animals in response to non-selective dopaminergic agonists may be the result of diminished D1 supersensitivity. Fetal dopaminergic grafts in the ipsilateral substantia nigra (SN) did not augment the decreases in turning produced by concomitant ipsilateral dopaminergic grafts in the striatum in response to SKF 38393. LY 171555, D-amphetamine or L-DOPA. Dopaminergic grafts in the SN increased, while dopaminergic grafts in the striatum or in striatum and SN decreased, the facilitatory effect of D-amphetamine on rotation elicited by subsequent injection of dopamine agonists.     

The group I metabotropic glutamate receptor antagonist S-4-CPG modulates the locomotor response produced by the activation of D1-like, but not D2-like, dopamine receptors in the rat nucleus accumbens

Functional interactions between dopamine (DA) and glutamate neurotransmissions in both the dorsal and the ventral striatum have been described for long time. However, there is much controversy as to whether glutamate transmission stimulates or attenuates DA release and locomotor activity. We investigated the functional interactions on locomotor activity between group I metabotropic glutamatergic receptors (mGlu receptors) and both D1-like and D2-like DA receptors in the rat nucleus accumbens. Intra-accumbens administration of the selective group I mGlu receptor antagonist S-4-CPG (0.2 or 2 microg per side), which had no effect when injected alone, prevented the increase in locomotor activity produced by the selective D1-like receptor agonist SKF 38393 (1 microg per side). Co-administration with S-4-CPG of the group I mGlu receptor agonist DHPG, but not of the group II mGlu receptor agonist APDC or the group III mGlu receptor agonist AP4, reversed the antagonistic effect of S-4-CPG on the SKF 38393-induced increase in locomotor activity. This indicates that the antagonistic effect of S-4-CPG could result from an action at the group I mGlu receptors. In contrast, administration of S-4-CPG showed no effect on the locomotor responses produced by either the selective D2-like receptor agonist LY 171555 (1 microg per side) or a mixed solution of SKF 38393 + LY 171555 (1 microg per side each). Altogether, these results confirm that glutamate transmission may control locomotor function through mGlu receptors in a DA-dependent manner, and further indicate that group I mGlu receptors would interact with D1-like receptors, but not D2-like receptors, to modulate DA transmission and locomotor activity.     

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

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

Adfærdsmæssig interaktion mellem en ny glutamat-antagonist,FG 9065, og dopamin-agonister hos aber

Lublin H, Gerlach J. Behavioral interaction between a new glutamate antagonist, FG 9065, and dopamine agonists in monkeys.

Glutamatergic mechanisms have been found to be involved in regulation of the dopaminergic system. The effects of glutamate are mediated by two groups of receptors: the N-rnethyl-D-aspartate (NMDA) receptors and the non-NMDA receptors, one of the latter being of the quisqualate type. FG 9065 (a quisqualate antagonist) was evaluated in eight Cebus monkeys, which previously had received haloperidol for 2 years. Five monkeys had mild oral tardive dyskinesia, consisting of tongue protrusions and/or chewing movements. FG 9065 was evaluated alone and in combination with methylphendiate (dopamine-releasing and uptake-inhibiting drug), SKF 38393 (partial dopamine D-1 agonist), and quinpirole (LY 171555, selective dopamine D-2 agonist). FG 9065 induced/aggravated oral tardive dyskinesia. Otherwise no behavioral effects were found. Methylphenidate increased locomotor activity, stereotypy, and reactivity. SKF 38393 increased oral tardive dyskinesia and grooming, whereas locomotor activity was reduced, probably due to sedation. Quinpirole increased locomotor activity, stereotypy, and reactivity, whereas oral hyperkinesia and grooming were decreased. Pretreatment with FG 9065 inhibited the methylphenidate-induced stereotypy and reactivity, aggravated SKF 38393-induced grooming behavior and reduced the quinpirole-induced locomotor activity, repetitive movements, and reactivity. The results confirm the existence of an interaction between the glutamatergic and dopaminergic systems. FG 9065 antagonized the effect of methylphenidate and the D-2 agonist. If these results can be confirmed in following studies, they might indicate neuroleptic and therefore therapeutic properties of this group of drugs.     

D1-dopamine receptor agonists selectively activate striatal c-fos independent of rotational behaviour

L-Dopa and dopaminergic agonists selective for the D1- or D2-dopamine receptor subtype induce contraversive rotation in rats which have been unilaterally lesioned with injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra. D-Amphetamine, which releases dopamine from neurones on the unlesioned side of the animal, causes ipsiversive rotation. These increases in rotational behaviour are mediated, at least in part, by dopamine receptors in the striatum. In unilaterally lesioned animals, L-dopa and the D1-selective agonists SKF 38393 and CY 208-243 produce contralateral rotation and induction of the nuclear proto-oncogene c-fos in the lesioned striatum. D-Amphetamine induces both ipsilateral rotation and c-fos activation in the intact striatum. Three lines of evidence, however, dissociate fos induction and rotation. First, LY 171555, a selective D2-dopamine receptor agonist, also induces contraversive rotation but this rotation is not accompanied by c-fos activation in striatum. Second, D1-dopamine agonists produce activation of striatal c-fos even if rotation is prevented by an anaesthetic. Third, rotation induced by injection of SKF 38393 into substantia nigra is not accompanied by c-fos induction. These results suggest a mechanism by which D1-dopamine receptor mechanisms may regulate long-term changes in dopaminergic systems.     

Modulation of GABA release by dopamine in the substantia nigra

The role of specific dopamine receptor subtypes in the regulation of GABA release in the substantia nigra was investigated using microdialysis in the awake rat. Both basal and potassium-stimulated changes in the extracellular concentrations of GABA were examined in response to the local perfusion of tetrodotoxin (TTX), the D1 agonist SKF 38393, or the D2 agonist LY 171555 through the microdialysis probe in the substantia nigra. Although TTX (1 microM) did not alter the basal extracellular concentrations of GABA in the substantia nigra, it attenuated the potassium-stimulated (80 mM K+) release of GABA. SKF 38393 had no effect on basal extracellular concentrations of GABA, but did potentiate K+ -stimulated release of GABA in a concentration-dependent manner. The potentiated response at the highest concentration of SKF 38393 (100 microM) was blocked by the D1 antagonist SCH 23390. In contrast to the effect of the D1 agonist, the D2 agonist LY 171555 attenuated the stimulated release of GABA. These data indicate that although basal extracellular concentrations of GABA in the substantia nigra may not be derived from neuronal pools, K+ -stimulated release of GABA is impulse-mediated and is modulated by the D1 and the D2 receptors. Local interactions between dopamine and GABA in the substantia nigra may have important implications for the direct regulation of basal ganglia efferent activity and motor behavior.     

Effects of administration of dopamine D2 agonist quinpirole on exploratory locomotion.

Injections of the dopamine D2 agonist quinpirole (LY 171555) into the nucleus accumbens reduced exploratory locomotion in a dose-dependent manner. Injections of the dopamine D1 agonist SKF 38393 had no effect on exploratory locomotion. The results are consistent with observations from recent electrophysiological and behavioral experiments which suggest a presynaptic action of the D2 agonist. It is proposed that quinpirole activates D2 receptors on the axon terminals of glutamatergic hippocampal-accumbens neurons that are associated with exploratory locomotion.     

Selective D-1 dopamine receptor agonist treatment of parkinson's disease

Summary Preclinical evidence suggests that the D-1 dopamine receptor contributes to the generation of behaviors used as models for human extrapyramidal disorders. To evaluate the potential of D-1 receptor stimulation in neurologic disease, SKF 38393, a selective D-1 dopamine receptor agonist, was administered to seven patients with idiopathic Parkinson's disease in a double-blind, placebo controlled study. SKF 38393 was found to be rapidly absorbed when administered orally, and to occur in micromolar concentrations in spinal fluid. No change in scores of parkinsonian severity were noted when SKF 38393 was administered alone, or when the drug was combined with intravenous levodopa. The results support the view that the pathophysiology of Parkinson's disease may relate exclusively to the D-2 subclass of dopamine receptors.     

Independent in vitro regulation by the D-2 dopamine receptor of dopamine-stimulated efflux of cyclic AMP and K-stimulated release of acetylcholine from rat neostriatum

Two types of dopamine receptors whose stimulation affect cAMP efflux (and by inference formation) could be identified in rat neostriatum. One type of receptor, called D-1 receptor, increased cAMP efflux whereas stimulation of a second type of dopamine receptor, called D-2 receptor, was followed by a reduction in cAMP efflux induced by stimulation with a D-1 receptor agonist. D-2 receptor agonists inhibited the effects of D-1 receptor agonists on cAMP efflux in a non-competitive way. These inhibiting effects of D-2 receptor agonists occured also in the absence of Ca²⁺-ions which could imply that some of the D-2 receptors are located on cells possessing D-1 receptors.

The dopamine receptor mediating inhibition of the release of radiolabeled acetylcholine (ACh) in the neostriatum appeared to have the same pharmacological characteristics as the D-2 dopamine receptor mediating the inhibition of the D-1 receptor agonist induced cAMP efflux. Selective D-2 receptor agonists like LY 141865 and RU 24926 stimulated this receptor while the D-1 receptor agonist SKF 38393 was inactive. Effects of the selective D-2 receptor agonists could be antagonized by (—)-sulpiride, a selective D-2 receptor antagonist. Although the pharmacological characteristics of the dopamine receptors mediating inhibition of both ACh release and (D-1 dopamine receptor agonist induced) cAMP efflux appeared to be similar, drugs stimulating cAMP efflux did not affect ACh release or LY 141865 induced inhibition of ACh release from rat neostriatum. Therefore it is still questionable whether the dopamine receptor mediating inhibition of both ACh release and cAMP efflux is one and the same functional entity.     

Neurophysiological investigation of effects of the D-1 agonist SKF 38393 on tonic activity of substantia nigra dopamine neurons

The effects of the D-1 agonist SKF 38393 on tonic activity of rat substantia nigra pars compacta dopamine neurons were studied using extracellular, single-unit recording techniques. Unlike nonselective D-1/D-2 dopamine agonists or the D-2 agonist quinpirole, SKF 38393 did not inhibit dopamine neuronal activity when applied iontophoretically or when administered intravenously in doses up to 20 mg/kg to chloral hydrate-anesthetized rats. Moreover, pretreatment with SKF 38393 did not alter the inhibitory response of these neurons to apomorphine or the D-2 agonist quinpirole. However, in locally anesthetized, gallamine-treated, artificially respired rats, dopamine cell activity was significantly altered by i.v. administration of SKF 38393; firing rate increases and decreases were observed. Administration of the inactive enantiomer of SKF 38393, S-SKF 38393, did not induce similar changes in parallel experiments. These results support the idea that unlike D-2 autoreceptor stimulation, D-1 receptor stimulation does not exert a direct local effect on dopamine neurons in the substantia nigra pars compacta and suggest that D-1 receptor stimulation at sites postsynaptic to the dopamine cells may indirectly affect the activity of some dopamine neurons through long-loop feedback mechanisms.     

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D2 receptor agonist, SKF 38393, a selective D1 receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed by L-sulpiride, a D2 antagonist, and by a combination of reserpine with alpha-methyltyrosine (alpha-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D1 antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D2 receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D1 receptor level.     

LY293558, an AMPA glutamate receptor antagonist, prevents and reverses levodopa-induced motor alterations in Parkinsonian rats.

To evaluate the possible involvement of glutamate AMPA receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of LY293558, a competitive AMPA receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of LY293558 was studied to evaluate the possible reversion or prevention of these levodopa effects. In the first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 LY293558 (5 mg/kg, i.p.) was administered immediately before levodopa. In the second set of experiments, rats were treated daily for 22 days with levodopa and LY293558 (5 mg/kg, twice daily, i.p.). In the third set of experiments, the effect of LY293558 (5 mg/kg, i.p.) administration on selective dopamine D-1 (SKF38393, 1.5 mg/kg, s.c.) and D-2 agonist (quinpirole, 0.1 mg/kg, i.p.)-induced rotational behavior after daily levodopa treatment was studied. The duration of the rotational behavior induced by chronic levodopa decreased by 30% after 22 days. Acute administration of LY293558 on day 23 reversed this effect. The group of animals that were chronically treated with levodopa and LY293558 did not show the decrease in this motor response duration. Chronic levodopa treatment attenuated the rotational response to the D-1 agonist SKF38393 and increased the response to the D-2 agonist quinpirole. LY293558 did not reverse the effect of levodopa on rotational behavior induced by the D-1 agonist but significantly reduced the rotational response to the D-2 agonist in levodopa-treated animals by 40%. Our results demonstrate that an AMPA receptor antagonist reverses and prevents levodopa-induced motor alterations in parkinsonian rats and that this effect on motor fluctuations induced by chronic levodopa is probably due to a modulation of the indirect output pathway of the basal ganglia.     

Anticonvulsant effects of ipsilateral but not contralateral microinjections of the dopamine D2 agonist LY 171555 into the nucleus accumbens of amygdala-kindled rats.

Recent radioligand binding studies demonstrated an increase in the density of dopamine D2 receptors in the nucleus accumbens ipsilateral to the stimulating electrode in amygdala- or hippocampal-kindled rats. In the present study we examined the anticonvulsant effect of dopamine agonists by unilateral microinjections into the nucleus accumbens in rats kindled from the right basolateral amygdaloid nucleus. Microinjections of the D2 agonist LY 171555 into the ipsilateral nucleus accumbens 15 min prior to the kindling stimulation in fully kindled rats decreased significantly kindling parameters such as seizure severity, seizure duration and afterdischarge duration, whereas the D1 agonist SKF 38393 had no anticonvulsant effects. After ipsilateral microinjection of 40 pmol LY 171555 focal and generalized kindled seizures were totally blocked in almost 50% of the rats. The anticonvulsant effect of LY 171555 could be completely antagonised by systemic administration of the D2 antagonist sulpiride. Microinjection of the D1 or D2 agonist into the nucleus accumbens contralateral to the stimulating electrode had no anticonvulsant effects. In accordance with other reports our data indicate a possible topographic limitation of D2 receptor mediated anticonvulsant effects to specific regions of the basal ganglia.     

Possible role of dopamine D1 receptor in the behavioural supersensitivity to dopamine agonists induced by chronic treatment with antidepressants

The effect of chronic treatment with antidepressants (ADs) on the behavioral responses to LY 171555, a selective D₂ receptor agonist, SKF 38393, a selective D₁ receptor agonist, and B-HT 920, a selective DA autoreceptor agonist, was studied in rats. In normal rats small, intermediate and high doses of LY 171555 produced hypomotility, hyperactivity and stereotypies, respectively. Chronic but not acute pretreatment with imipramine (IMI) greatly potentiated the motor stimulant effect of LY 171555, but failed to modify its stereotypic and sedative effect. The potentiation of the motor stimulant effect of LY 171555 was observed also after chronic, but not acute, treatment with desmethylimipramine (DMI), mianserin (MIA) or repeated electroconvulsive shock (ECS). Chronic treatment with IMI failed to modify the effect of SKF 38393 (motor stimulation, grooming and penile erection), but reversed the sedative effect of B-HT 920 into a motor stimulant response. The motor stimulant response to LY 171555 in IMI-pretreated animals was suppressed byl-sulpiride, a D₂ antagonist, and by a combination of reserpine with α-methyltyrosine (α-MT), but it was only partially antagonized by high doses of SCH 23390, a selective D₁ antagonist. The results indicate that chronic treatment with ADs potentiates the behavioural responses mediated by the stimulation of postsynaptic D₂ receptors in the mesolimbic system and suggest that this behavioural supersensitivity is due to enhanced neurotransmission at the D₁ receptor level.