Facilitation of brain stimulation reward by MK-801 (dizocilpine) may be independent of D<Subscript>2</Subscript>-like dopamine receptor stimulation in rats

Rationale Dopamine (DA) and glutamate (Glu) interactions in the mesocorticolimbic pathway may regulate motivation and reward and contribute to schizophrenia and drug abuse. We have recently demonstrated synergistic effects of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor blockade and D_2/3 DA receptor stimulation in brain stimulation reward (BSR). Objectives This study was conducted to explore interactions between DA and Glu systems in BSR using the NMDA receptor antagonist MK-801 and the DA receptor agonists 7-OH-DPAT and apomorphine. Methods Systemic effects of these compounds were measured in male Sprague–Dawley rats using rate–frequency threshold analysis of ventral tegmental area (VTA) BSR (n=27). Effects of bilateral applications of MK-801 and 7-OH-DPAT into the nucleus accumbens (NAS) shell subregion were also investigated (n=10). Results MK-801 (0.03 or 0.13 mg kg⁻¹ i.p. or 0.66 μg intra-NAS) reduced reward thresholds while 7-OH-DPAT (0.03 mg kg⁻¹ s.c. or 5.0 μg intra-NAS) or apomorphine (0.05 mg kg⁻¹, s.c.) increased this measure. MK-801 combined with apomorphine or with 7-OH-DPAT, systemically or in the NAS shell, induced additive effects. Conclusions Lack of interaction between DA agonists and MK-801 in this study contrasts with our previous work showing synergistic reward-decreased effects of AMPA/kainate receptor blockade and D_2/3 DA receptor stimulation in the NAS shell, and indicates possible independence of DA and N-methyl-d-aspartate (NMDA) receptor effects in VTA electrical self-stimulation.     

Dopamine D<Subscript>3</Subscript> receptor ligands modulate the acquisition of morphine-conditioned place preference

Rationale The dopamine D₃ receptor has been shown to mediate conditioned effects of psychostimulants such as cocaine. The present work was aimed at determining whether drugs acting at D₃ receptors alter acquisition of conditioned effects of opiates.Methods We have used the conditioned place preference (CPP) in mice, which permits the measurement of approach behaviour to environmental stimuli previously paired with drug effects. To assess the interaction of morphine and D₃ receptor ligands during acquisition of CPP, we have used a particular procedure, in which the animals were given the choice between compartments associated with either morphine alone or the combination of morphine with the tested agent.Results D₃ receptor agonists (7-OH-DPAT, quinelorane, BP 897) did not induce, alone, a significant CPP but, all of them, at the doses tested, and notably BP 897, a highly selective partial agonist, significantly enhanced acquisition of morphine-induced CPP when administered together with morphine at each conditioning session. PNU-99194A, a D₃ receptor-preferring antagonist, induced a CPP itself at the dose of 10 mg/kg but not at 5 or 15 mg/kg and impaired significantly at 10 and 15 mg/kg the morphine-induced CPP. In contrast, BP 897 did not alter morphine-induced analgesia, an unconditioned effect of this drug.Conclusions These results suggest the stimulation of D₃ receptors has no rewarding effect per se, but may synergize upon opiate-induced dopamine release with stimulation of other dopamine receptor subtypes to enhance approach behaviour to morphine-associated environment.     

Differential effects of 7-OH-DPAT and apomorphine on hyperactivity induced by MK-801 (dizocilpine) in rats

Recent experiments from this laboratory demonstrated synergistic locomotor depressant effects of AMPA/kainate receptor blockade and D(2/3) dopamine (DA) receptor stimulation. This study explored functional interactions between DA and glutamate (Glu) systems using the NMDA receptor antagonist MK-801 and the DA receptor agonists 7-OH-DPAT and apomorphine. Using photocell locomotor activity boxes, systemic effects of MK-801 in combination with 7-OH-DPAT (0.03 mgkg(-1) SC, n=8) or a pre-synaptically effective dose of apomorphine (0.05 mgkg(-1) SC, n=6) were measured in male Sprague-Dawley rats. Effects of bilateral applications of MK-801 and 7-OH-DPAT into the nucleus accumbens (NAS) shell subregion were also investigated (n=7). When given alone, MK-801 (0.13 mgkg(-1) or 0.66 microg intra-NAS shell) increased horizontal locomotor activity, while 7-OH-DPAT (0.03 mgkg(-1)) or apomorphine (0.05 mgkg(-1)) decreased this measure. Co-administration of 7-OH-DPAT (systemically or into the NAS shell) completely blocked MK-801 induced hyperactivity. In contrast, MK-801 and apomorphine demonstrated additive effects. Stimulation of D(3) DA receptors may therefore block the hyperactivity induced by NMDA receptor antagonism, and the NAS shell is an important site for this interaction. The differential effects of the DA agonists on hyperactivity induced by NMDA receptor blockade support the proposal that 7-OH-DPAT may induce hypoactivity by stimulation of postsynaptic D(3) DA receptors.     

Effects of AMPA/kainate receptor blockade on responses to dopamine receptor agonists in the core and shell of the rat nucleus accumbens

The present experiments were conducted to investigate effects of α-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA)/kainate receptor blockade (CNQX, NBQX) on locomotor responses to D2/3 (7-OH-DPAT) and D1 [(+)-SKF 38393] dopamine receptor agonists in the nucleus accumbens (NAS) core and shell. CNQX (0.25–0.5 μg) microinjected into the NAS core or shell did not affect baseline locomotor activity. 7-OH-DPAT (2.5–5 μg) decreased locomotor activity. Co- administration of CNQX (0.5 μg) increased the effects of 7-OH-DPAT (5 μg) in the NAS core and shell. A similar increase was observed with NBQX (0.5 μg) in the NAS shell. (+)-SKF 38393 (5 μg) into the NAS core and shell increased locomotor activity after 30 min; this effect was not altered by CNQX (0.5 μg). As the D2/3 dopamine agonist (–)-quinpirole (2 μg) increased effects of (+)-SKF 38393 (5 μg) in NAS shell but not core, lack of site-selective effects of (+)-SKF-38393 and of 7-OH-DPAT within NAS is not attributable to drug diffusion. The previous observation that glutamate effects on locomotor activity depend on the relative involvement of D1 or D2/3 dopamine receptors in the NAS was based on the dopamine-depletion model. The present results demonstrate differential interactions of AMPA receptor blockade with dopamine agonists in ”dopamine-intact” animals. Received: 21 November 1999 / Accepted: 10 January 2000     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.     

Acute dopamine D<Subscript>1</Subscript> and D<Subscript>2</Subscript> receptor stimulation does not modulate mismatch negativity (MMN) in healthy human subjects

Rationale Schizophrenia is commonly associated with an impairment in pre-attentive change detection, as represented by reduced mismatch negativity (MMN), an auditory event related potential. While the neurochemical basis of MMN has been linked to the integrity of the glutamatergic system involving N-methyl-d-aspartate (NMDA) receptors, the role of the dopaminergic system and in particular, the role of D₁ and D₂ receptors on MMN is yet to be determined. Objectives The aim of the present project was to investigate the acute effects of dopamine D₂ (bromocriptine) and D₁/D₂ (pergolide) receptor stimulation on the human MMN in healthy subjects. Methods Fifteen healthy male subjects participated in a double-blind, placebo-controlled, cross-over design in which each subject was tested under three acute treatment conditions separated by a 1-week wash out period; placebo, bromocriptine (2.5 mg) and pergolide (0.1 mg). The subjects were exposed to a duration-MMN paradigm with 50 ms standard tones (91%) and 100 ms deviant tones (9%). Results The results showed that neither D₂ receptor stimulation with bromocriptine, nor simultaneous D₁ and D₂ receptor stimulation with pergolide, modulated MMN. Conclusions These findings suggest that acute D₁ and D₂ receptor stimulation does not modulate MMN. While the role of dopamine cannot be completely ruled out, the findings support the view that the aberrant MMN reported in schizophrenia may be linked primarily to glutamate dysfunction involving NMDA receptors.     

Cocaine-induced locomotor activity and cocaine discrimination in dopamine D<Subscript>4</Subscript> receptor mutant mice

Rationale Previous studies have found a role for dopamine D₂-like receptors in many of the behavioral effects of cocaine, including its stimulation of locomotor activity and interoceptive discriminative-stimulus effects. However, given the lack of selectivity of most of the available pharmacological tools among D₂, D₃ and D₄ dopamine receptors, the roles of these specific receptors remain unclear. Objectives The roles of specific dopamine D₄ receptors in the behavioral effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects were investigated using dopamine D₄ receptor knockout (DA D₄R KO) and wild-type (WT) mice. Methods The mice were trained in daily sessions to discriminate IP injections of saline from cocaine (10 mg/kg). Responses on one of two response keys intermittently produced a food pellet; one response was reinforced in sessions following cocaine injection (10 mg/kg), and the other response was reinforced in sessions following saline injection. Each 20th response produced a food pellet (fixed-ratio, or FR20 schedule of reinforcement). The dose-effects of cocaine and its interaction with the D₂-like antagonist, raclopride, were assessed. Horizontal locomotor activity was also assessed in each genotype. Results As previously shown), cocaine was a more potent stimulant of locomotor activity in the DA D₄R KO mice compared to WT littermate mice. In addition, cocaine was more potent in producing discriminative-stimulus effects in DA D₄R KO mice (ED₅₀ value=0.50 mg/kg) compared to their WT littermates (ED₅₀ value=2.6 mg/kg). Raclopride shifted the cocaine dose-effect curve in both DA D₄R KO and WT mice, though the shift was greater for the DA D₄R KO mice. Conclusions The present results on the stimulation of activity and interoceptive/subjective effects of cocaine are consistent with the previously reported disregulation of dopamine synthesis in DA D₄R KO mice, and further suggest a role of the DA D₄R in vulnerability to stimulant abuse.     

Allopregnanolone does not influence ethanol-induced conditioned place preference in DBA/2J mice

Rationale The neurosteroid allopregnanolone (ALLOP; 3-hydroxy-5-pregnan-20-one) produces behavioral and discriminative characteristics similar to that of ethanol (EtOH) and can modulate some of the behavioral and electrophysiological effects of EtOH.Objective The present experiments investigated ALLOP modulation of the effects of EtOH in a place conditioning procedure in male DBA/2J mice.Methods In a series of experiments examining different EtOH doses (1, 2 g/kg) and ALLOP administration times, ALLOP (0, 3.2, 10, 17 mg/kg, IP) was administered four times with EtOH prior to placement on a distinctive floor (CS+). On alternate days, vehicle was administered prior to a saline injection paired with the other floor stimulus (CS–). In a separate experiment, finasteride (0, 50, 100 mg/kg, IP), a 5-reductase inhibitor that blocks ALLOP synthesis, was administered prior to both CS+ and CS– trials. In a final experiment, animals were place conditioned to EtOH alone, and ALLOP (0, 3.2, 10, 17 mg/kg, IP) was administered prior to the preference test only.Results During conditioning, ALLOP increased and finasteride decreased EtOH-stimulated activity compared with vehicle pretreatment. Acquisition of 2 g/kg EtOH-induced conditioned place preference was observed in all mice, regardless of treatment with either ALLOP or finasteride. Similarly, ALLOP did not modulate the expression of EtOH-induced place preference. EtOH increased brain ALLOP levels compared with saline; however, ALLOP administration produced dose-dependent elevations in brain ALLOP levels that were not further augmented by EtOH (2 g/kg) administration.Conclusions These findings indicate that ALLOP does not modulate EtOH-induced place conditioning in male DBA/2J mice.     

D<Subscript>2</Subscript> but not D<Subscript>1</Subscript> dopamine receptor stimulation augments brain signaling involving arachidonic acid in unanesthetized rats

Rationale and objectives Signal transduction involving the activation of phospholipase A₂ (PLA₂) to release arachidonic acid (AA) from membrane phospholipids, when coupled to dopamine D₁- and D₂-type receptors, can be imaged in rats having a chronic unilateral lesion of the substantia nigra. It is not known, however, if the signaling responses occur in the absence of a lesion. To determine this, we used our in vivo fatty acid method to measure signaling in response to D₁ and D₂ receptor agonists given acutely to unanesthetized rats. Methods [1-¹⁴C]AA was injected intravenously in unanesthetized rats, and incorporation coefficients k* for AA (brain radioactivity/integrated plasma radioactivity) were measured using quantitative autoradiography in 61 brain regions. The animals were administered i.v. the D₂ receptor agonist, quinpirole (1 mg kg⁻¹, i.v.), the D₁ receptor agonist SKF-38393 (5 mg kg⁻¹, i.v.), or vehicle/saline. Results Quinpirole increased k* significantly in multiple brain regions rich in D₂-type receptors, whereas SKF-38393 did not change k* significantly in any of the 61 regions examined. Conclusions In the intact rat brain, D₂ but not D₁ receptors are coupled to the activation of PLA₂ and the release of AA.     

Effect of dopamine D<Subscript>3</Subscript> receptor blockade on renal function and glomerular size in diabetic rats

Dopamine D₂-like receptors, including D₂, D₃, and D₄ receptors, are involved in the regulation of glomerular hyperfiltration due to diabetes mellitus. These hemodynamic alterations represent a risk factor for the later development of diabetic nephropathy. The aim of the present study was to determine whether the D₃ receptor subtype modulates the diabetes-induced increase in glomerular filtration rate (GFR) in rats. Renal function was studied in Sprague–Dawley rats 14 days after induction of a moderate diabetes mellitus (DM) by streptozotocin and in non-diabetic controls (CON). Rats were orally treated either with the peripherally acting, selective dopamine D₃ receptor antagonist BSF 135170 (BSF, 10 mg/kg per day for 2 weeks) or with vehicle (VHC). Perfusion-fixed kidneys were used for estimation of glomerular volume. In conscious rats, which were treated with BSF, the DM-induced increase in fluid intake, urinary output, and renal sodium excretion was significantly less pronounced than in the vehicle group (DM-VHC). In the clearance experiments, GFR in CON was about 0.84±0.04 ml/min per 100 g body weight. The DM-VHC group presented a significant glomerular hyperfiltration (1.09±0.04 ml/min per 100 g body weight). Treatment with BSF significantly lowered GFR towards levels of CON. The estimated glomerular volume was 0.73±0.03×10⁶ m³ in the CON-VHC group and 0.86±0.04×10⁶ m³ in the DM-VHC animals. Interestingly, treatment with BSF decreased the glomerular volume in both groups. Irrespective of BSF treatment, kidney wet weight related to body weight was about 36% higher in DM animals compared with CON animals. We conclude that dopamine D₃ receptors represent a target for the modulation of diabetes-induced glomerular hyperfiltration. Therefore, the results encourage the testing of the possible beneficial effects of long-term D₃ receptor blockade on the development of diabetic nephropathy.     

Locomotor and discriminative-stimulus effects of cocaine in dopamine D<Subscript>5</Subscript> receptor knockout mice

Rationale Dopamine D₁-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D₁ and D₅ receptors, the specific roles of the subtypes have not been determined. Objectives Dopamine D₅ receptor knockout (DA D₅R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D₅ dopamine receptors in the effects of cocaine. In addition, effects of the D₁-like antagonist, SCH 39166 were also studied to further clarify the roles of D₁ and D₅ dopamine receptors in the discriminative-stimulus effects of cocaine. Methods DA D₅R KO, HET and WT mice were treated with cocaine (3–30 mg/kg) or vehicle and their horizontal locomotor activity was assessed. The mice were also trained to discriminate IP injections of saline from cocaine (10 mg/kg) using a two-lever food-reinforcement (FR10) procedure. Doses of cocaine (1.0–10 mg/kg) were administered 5 min before 15-min test-sessions. Results Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D₅R WT mice. Both DA D₅R KO and HET mice showed reduced levels of horizontal activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; doses of 1.0–10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. SCH 39166, at inactive to fully active doses (0.01–0.1 mg/kg) produced predominately saline-appropriate responding. SCH 39166 produced a dose-dependent rightward shift in the cocaine dose-effect curve in all genotypes, with similar apparent affinities. Conclusions The present data suggest an involvement of DA D₅R in the locomotor stimulant effects of cocaine. In addition, the data indicate that there is little involvement of the DA D₅R in the discriminative-stimulus effects of cocaine. In addition, the antagonism data suggest a role of the D₁ receptor in the behavioral effects of cocaine.     

The dopamine D<Subscript>1</Subscript> receptor agonist and D<Subscript>2</Subscript> receptor antagonist LEK-8829 attenuates reinstatement of cocaine-seeking in rats

Various dopaminergic drugs have been studied for their efficacy in the treatment of cocaine addiction. Pretreatment with either selective dopamine D₁ receptor agonists or selective dopamine D₂ receptor antagonists prevents reinstatement of cocaine-seeking in animal models of drug craving and relapse. We tested a novel ergoline derivative with combined D₁ agonistic and D₂ antagonistic effects, 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleate (LEK-8829), for its effects on cocaine-seeking in the intravenous cocaine self-administration model in rats. Pretreatment with systemic injections of LEK-8829 attenuated reinstatement of cocaine-seeking induced by cocaine priming injections and diminished cocaine intake in cocaine self-administration sessions. LEK-8829 itself did not induce reinstatement of cocaine-seeking and did not maintain intravenous self-administration. The results of our study indicate that LEK-8829 is a candidate medication for the treatment of cocaine craving in cocaine addiction.     

Intra-accumbal NMDA but not AMPA/kainate receptor antagonist attenuates WIN55,212-2 cannabinoid receptor agonist-induced antinociception in the basolateral amygdala in a rat model of acute pain

Previous studies showed the role of basolateral amygdala (BLA) in cannabinoid-induced antinociception. Several lines of evidence indicated that the nucleus accumbens (NAc) receives excitatory glutamatergic inputs primarily from limbic-related structures, including the hippocampus, BLA, and various thalamic nuclei. Additionally, it has been shown that the NAc plays an important role in mediating the suppression of animal models of pain. In the present study, we examined the role of NMDA and AMPA/kainate receptors within the NAc in antinociception induced by intra-BLA cannabinoid receptor agonist WIN55,212-2 in rats. 126 adult male albino Wistar rats weighing 230-280 g were unilaterally implanted by two separate cannulae into the BLA and NAc. Dose-response antinociceptive effects of different doses of intra-BLA WIN55,212-2 (5, 10 and 15 μg/0.3 μl/rat) were evaluated in this study. Moreover, animals received intra-accumbal infusions of either NMDA receptor antagonist, AP5 (0.5, 2.5 and 5 μg/0.5 μl saline) or AMPA/kainate receptor antagonist, CNQX (0.1, 0.5 and 2.5 μg/0.5 μl DMSO), just 2 min before microinjection of WIN55,212-2 into the BLA. Antinociceptive responses of drugs were obtained by tail-flick analgesiometer and represented as maximal possible effect (%MPE) at 5, 15, 30, 45 and 60 min after their administrations. Results showed that intra-accumbal AP5 dose-dependently prevented antinociception induced by intra-BLA administration of WIN55,212-2 (15 μg/rat) in time set intervals. Nonetheless, administration of AMPA/kainate receptor antagonist, CNQX, could not affect WIN-induced analgesia. Additionally, solely administration of intra-accumbal injection of CNQX (2.5 μg/0.5 μl DMSO), but not AP5 (5 μg/0.5 μl saline), could significantly change the baseline tail-flick latencies in the rats. It seems that NMDA receptors located in the NAc, in part, mediate the antinociceptive responses of cannabinoid within the BLA in acute model of pain.     

Prolactinemia is uncoupled from central D<Subscript>2</Subscript>/D<Subscript>3</Subscript> dopamine receptor occupancy in amisulpride treated patients

Rationale Atypical antipsychotic drugs are classically associated with lower propensity to extrapyramidal symptoms (EPS) and hyperprolactinemia than typical antipsychotic drugs. It has not been clarified why some atypical antipsychotic drugs, such as amisulpride, induce prolactin plasma concentration (PRL) elevation, but little EPS. Previous studies have found an association between striatal D₂/D₃ receptor occupancy and PRL in typical antipsychotic treated patients suggesting that PRL is a marker of central D₂/D₃ receptors blockade.Objective We have evaluated the relationship between PRL and central (striatum, temporal cortex and thalamus) D₂/D₃ receptor occupancy in amisulpride treated schizophrenic patients.Methods Single photon emission tomography (SPET) and [¹²³I]-epidepride were used to determine D₂/D₃ receptor occupancy in eight amisulpride treated patients. PRL was measured concurrently with the scans.Results The mean PRL was 1166 (range 499–1892 mIU/l) for a mean amisulpride dose of 406 mg/day (range 150–600 mg/day). Amisulpride plasma concentration and central D₂/D₃ receptor occupancy were positively correlated (r=0.83–0.89, df=4, P<0.05). No significant correlations were observed between PRL and amisulpride (daily dose or plasma concentration, P>0.05), or between PRL and central D₂/D₃ receptor occupancy (P>0.05).Conclusions Our findings show that amisulpride-induced hyperprolactinemia is uncoupled from central D₂/D₃ receptor occupancy. Amisulpride has poor blood–brain barrier penetration and reaches much higher concentration at the pituitary, which is outside the blood–brain barrier. Higher D₂/D₃ receptor occupancy at the pituitary gland than at central regions is a possible explanation for amisulpride PRL elevation with low EPS. Further studies evaluating pituitary D₂/D₃ receptor occupancy in vivo are necessary to confirm this hypothesis.This study was partially presented (poster) at the International Congress on Schizophrenia Research, Colorado Springs, USA, 2003 and received the Young Investigator Award.     

The selective dopamine D<Subscript>3</Subscript> receptor antagonists SB-277011A and NGB 2904 and the putative partial D<Subscript>3</Subscript> receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

Rationale We have previously reported that selective antagonism of brain D₃ receptors by SB-277011A or NGB 2904 significantly attenuates cocaine- or nicotine-enhanced brain stimulation reward (BSR). Objective In the present study, we investigated whether the selective D₃ receptor antagonists SB-277011A and NGB 2904 and the putative partial D₃ agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR. Materials and methods Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a rate–frequency curve shift paradigm was used to measure brain-reward threshold (θ ₀). Results METH (0.1–0.65 mg/kg, i.p.) dose-dependently lowered (∼10–50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1–1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1–5 mg/kg) dose-dependently attenuated METH-enhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation–response curve to the right (inhibited BSR itself) in the presence or absence of METH. Conclusions Selective antagonism of D₃ receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D₃ and non-D₃ receptors. These findings support a potential use of selective D₃ receptor antagonists for the treatment of METH addiction.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

Effects of the H<Subscript>3</Subscript> antagonist,thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats

Rationale  Recent studies have raised the possibility that antagonists of H₃ histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia. Objectives  The purpose of this study was to determine if a prototypical H₃ antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia. Methods  The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg). Results  Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment. Conclusions  H₃ receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.     

FAUC 213, a highly selective dopamine D<Subscript>4</Subscript> receptor full antagonist,exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia

Rationale 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213) is a highly selective antagonist at the dopamine D₄ receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay.Objectives In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry.Methods Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study.Results A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D₄ antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D₂ receptor antagonism, but a partial involvement of 5-HT₂- and ₁-receptors cannot be ruled out at present.Conclusions We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.     

The role of dopamine D<Subscript>3</Subscript> compared with D<Subscript>2</Subscript> receptors in the control of locomotor activity: a combined behavioural and neurochemical analysis with novel,selective antagonists in rats

Background The role of dopamine D₃/D₂ receptors in the control of locomotion is poorly understood.Objectives To examine the influence of selective antagonists at D₃ or D₂ receptors on locomotion in rats, alone and in interaction with the preferential D₃ versus D₂ receptor agonist, PD128,907.Methods Affinities of ligands at rat D₂ and cloned, human hD₃, hD_2S, hD_2L and hD₄ sites were determined by standard procedures. Locomotion was monitored automatically in rats pre-habituated for 30 min to an open-field environment. Extracellular levels of dopamine (DA) were determined by dialysis in the nucleus accumbens and striatum. Drugs were given acutely via the systemic route.Results PD128,907, which preferentially recognised D₃ versus D₂ sites, biphasically reduced and enhanced locomotion at low (0.01–0.63 mg/kg) and high (2.5–10 mg/kg) doses, respectively. L741,626 and S23199, which behaved as preferential D₂ versus D₃ receptor antagonists, enhanced the reduction in locomotion evoked by the low dose of PD128,907, blocked the increase provoked by the high dose and suppressed spontaneous locomotion alone. Analogous findings were obtained with haloperidol and raclopride which showed equilibrated affinity at D₂ and D₃ receptors. UH232 and AJ76, which showed a mild preference for D₃ versus D₂ sites, did not modify the effect of a low dose of PD128,907, slightly enhanced the hyperlocomotion elicited by the high dose and exerted little influence on locomotion alone. S14297 and U99194, which acted as preferential D₃ versus D₂ receptor antagonists, abolished the reduction in locomotion elicited by a low dose of PD128,907, potentiated the induction of locomotion by a high dose, and failed to influence locomotion alone. The actions of S14297 were stereoselective inasmuch as they were mimicked by the racemic form, S11566, but not by the inactive enantiomer, S17777. In contrast to S14297, S11566 and U99194, however, S33084, SB269,652, GR218,231 and N-[-4-[-(1-naphtyl)piperazine-1-yl]butyl] anthracene-2-carboxamide (NGB-1), highly selective D₃ versus D₂ receptor antagonists, were inactive under all conditions. PD128,907 (0.01–10.0 mg/kg) suppressed dialysate levels of DA in the nucleus accumbens and striatum, actions blocked by L741,626 and haloperidol, yet unaffected by S14297 and S33084.Conclusions The facilitatory influence of a high dose of PD128,907 upon locomotion is mediated by postsynaptic D₂ receptors and, possibly, countered by their D₃ counterparts. Correspondingly, selective blockade of D₂ but not of D₃ receptors alone suppresses motor function. The reduction in locomotion provoked by a low dose of PD128,907 may be mediated by D₂ autoreceptors, but a role of postsynaptic D₃ receptors cannot be excluded. Finally, mechanisms underlying the contrasting influence of chemically diverse D₃ receptor antagonists upon locomotion remain to be elucidated.     

Chronic lithium chloride administration to rats elevates glucose metabolism in wide areas of brain,while potentiating negative effects on metabolism of dopamine D<Subscript>2</Subscript>-like receptor stimulation

Rationale and objectives The regional cerebral metabolic rate for glucose (rCMR_glc) can be imaged in vivo as a marker of brain functional activity. The effects of chronic lithium administration on baseline values of rCMR_glc and values in response to administration of dopamine D₂-like receptor agonists have not been examined in humans or rats. Knowing these effects may elucidate and localize the therapeutic action of lithium in bipolar disorder.Methods In unanesthetized rats, we used the 2-deoxy-d-glucose (2-DG) technique to image the effects of a 6-week control diet or LiCl diet sufficient to produce a plasma lithium concentration therapeutically relevant to bipolar disorder, on rCMR_glc at baseline and in response to the dopaminergic D₂-like receptor agonist, quinpirole (1 mg/kg i.v.), or to i.v. saline.Results Baseline rCMR_glc was significantly elevated in 30 of 81 brain regions examined, in LiCl diet compared with control diet rats. Affected were visual and auditory structures, frontal cortex, amygdala, hippocampus, nucleus accumbens, caudate–putamen, interpeduncular nucleus, and substantia nigra. Acute quinpirole significantly decreased rCMR_glc in four areas of the caudate–putamen in control diet rats, and in these and 19 additional brain areas in LiCl-fed rats.Conclusions In unanesthetized rats, chronic lithium administration widely upregulates baseline rCMR_glc and potentiates the negative effects on rCMR_glc of D₂-like receptor stimulation. The baseline elevation may relate to lithium’s reported ability to increase auditory and visual evoked responses in humans, whereas lithium’s potentiation of quinpirole’s negative effects on rCMR_glc may be related to its therapeutic efficacy in bipolar disorder.