Intra-accumbens infusion of quinpirole impairs sensorimotor gating of acoustic startle in rats

Prepulse inhibition (PPI) of the startle reflex is reduced by systemic administration of dopamine (DA) agonists. Since PPI is impaired in patients with schizophrenia, the DA agonist-induced disruption of PPI in rats may be a useful model for studying the pathophysiology of impaired sensorimotor gating in schizophrenia. In the present study, we replicated the observation that PPI is disrupted by systemic administration of the D₂ agonist quinpirole, but not by the D₁ agonist SKF 38393. PPI caused by weak [1–5 dB(A)] or more intense [10 dB(A)] prepulses was also disrupted by quinpirole infusion into the nucleus accumbens (NAC). The effects of intraaccumbens quinpirole on PPI were blocked by pretreatment with the D₂ antagonist haloperidol. These results support the notion that the reduction of PPI after systemic administration of DA agonists is mediated via stimulation of NAC D₂ receptors.     

Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats

Sensorimotor gating of the startle reflex is impaired in humans with schizophrenia and in rats after mesolimbic D₂ dopamine receptor activation. The loss of startle gating after D₂ activation in rats has been used as an animal model of impaired sensorimotor gating in schizophrenia, because the ability of antipsychotics to restore startle gating in D₂-activated rats correlates significantly with antipsychotic clinical potency. Substantial evidence indicates that the pathophysiology of schizophrenia includes structural and functional deficits in prefrontal and temporal regions, particularly the dorsolateral prefrontal cortex and the hippocampus and parahippocampal gyrus. The present study assessed startle gating in adult rats after ibotenic acid lesions of the medial prefrontal cortex or ventral hippocampus. Medial prefrontal cortex lesioned rats exhibited normal startle amplitude and normal sensorimotor gating, as reflected by prepulse inhibition (PPI) of the startle reflex. Hippocampus lesioned rats exhibited elevated startle amplitude, and similar to rats with medial prefrontal cortex lesions, did not show significant changes in basal PPI. Low doses of the mixed dopamine agonist apomorphine did not significantly reduce PPI in sham lesioned rats, but significantly disrupted PPI in both medial prefrontal cortex- and ventral hippo-campus lesioned rats. These data are consistent with the hypothesis that cell damage in frontal and temporal cortex increases the sensitivity to the sensorimotor gating-disruptive effects of dopamine receptor activation.     

Methamphetamine facilitates ethanol-induced depressions in cerebellar purkinje neurons of prazocin- or DSP4-treated rats

Prepulse inhibition (PPI) is the normal reduction in startle reflex that occurs when a startling stimulus is preceded by a weak prepulse. PPI is reduced in patients with schizophrenia and in rats after central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus model some features of impaired sensorimotor gating in schizophrenia. Ascending DAergic and descending glutamatergic fibers converge within the nucleus accumbens (NAC), and interactions at this DA-glutamate interface have been implicated in the pathophysiology of schizophrenia. In this study, we examined the role of NAC DA-glutamate interactions in the regulation of PPI in rats. Intra-NAC infusion of the non-NMDA antagonist, CNQX, attenuated the PPI-disruptive effects ofd-amphetamine (AMPH), but CNQX did not affect PPI when injected alone, nor did it reverse the PPI-disruptive effects of the direct D₂/D₃ agonist quinpirole. Intra-NAC infusion of the non-NMDA agonist AMPA significantly reduced PPI. The PPI-disruptive effects of AMPA were blocked by haloperidol and by 6-hydroxydopamine (6OHDA) lesions of the NAC. These data suggest that the PPI-disruptive effects of AMPH are dependent on tonic non-NMDA receptor activation in the NAC, and that non-NMDA receptor activation in the NAC results in a DA-dependent reduction in PPI. The parsimonious interpretation of these data is that non-NMDA glutamate receptors in the NAC facilitate presynaptic DA function, and that this DA-glutamate interaction is a critical regulatory substrate of sensorimotor gating.     

DOI-induced deficits in prepulse inhibition in Wistar rats are reversed by mGlu2/3 receptor stimulation

Prepulse inhibition (PPI) of the acoustic startle response (ASR) provides a measure of sensorimotor gating mechanisms that are impaired in schizophrenia patients. Interactions of the serotonin (5-hydroxytryptamine, 5-HT) and glutamatergic systems, especially via the 5-HT_2A receptor subtype, have been implicated in the regulation of PPI. The present study investigated the involvement of interactions between 5-HT_2A and metabotropic glutamate (mGlu)2/3 receptors in modulating PPI in Wistar and Lister Hooded rats. Systemic administration of the 5-HT_2A/2C receptor agonist DOI ((+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride; 3 mg/kg) reduced PPI and ASR magnitude in Wistar but not in Lister Hooded rats. In Wistar rats, pre-treatment with the mGlu2/3 receptor agonist LY379268 (1 mg/kg) attenuated the DOI-induced disruption of PPI as well as the DOI-elicited reductions of ASR magnitude. LY379268 itself did not alter PPI in both strains and only slightly increased ASR magnitudes in Wistar rats. Taken together, these findings support the notion of functionally antagonistic interactions between 5-HT_2A and mGlu2/3 which might be involved in regulating sensorimotor gating mechanisms. Additionally, the data suggest that stimulation of mGlu2/3 receptors may be useful to ameliorate sensorimotor gating deficits resulting from an overstimulation of 5-HT_2A receptors.     

Altered prepulse inhibition in rats treated prenatally with the antimitotic Ara-C: an animal model for sensorimotor gating deficits in schizophrenia

Rationale Sensorimotor gating disruption is one of many neurocognitive deficits seen in schizophrenia. Disorganized thought is one of the cardinal symptoms associated with sensorimotor gating. In an attempt to model sensorimotor gating deficits in rats relevant to the neurodevelopmental hypothesis for schizophrenia, we have used prenatal injections of the antimitotic drug, cytosine arabinoside (Ara-C) to subtly perturb the development of the rat CNS and disrupt sensorimotor gating.Objective To produce rats with either basal sensorimotor gating deficits or increased vulnerability to the disruption of sensorimotor function by apomorphine or phencyclidine (PCP). Prepulse inhibition (PPI) of the acoustic startle response was used to assess sensorimotor gating.Methods Three different cohorts of pregnant Sprague Dawley female rats were injected with Ara-C (30 mg/kg in saline) or saline at embryonic days 19.5 and 20.5. The Ara-C and control rats were tested for acoustic startle response and PPI at preadolescent and post-adolescent ages; postnatal day (Pnd) 35 and 56, respectively. Apomorphine (2.0 mg/kg) or phencyclidine (3.0 mg/kg), was given prior to PPI sessions in order to disrupt PPI.Results At Pnd 35, Ara-C treatment did not significantly affect acoustic startle amplitudes or PPI. However, at PND 56, Ara-C treated rats had significantly lower acoustic startle amplitudes and significantly diminished sensorimotor gating. Pharmacological challenge with the dopamine agonist apomorphine and the glutamate antagonist PCP significantly disrupted sensorimotor gating in the control subjects. Apomorphine did not further disrupt the existing deficit in the Ara-C treated rats. Ara-C treatment did not cause gross loss of neuronal tissue, although there was a subtle and variable disorganization of the pyramidal cell layer in the hippocampal CA_2/3 region.Conclusion The results provide evidence to suggest that late embryonic exposure to Ara-C disrupts the circuitry involved in mediating PPI. While the dopamine agonist apomorphine caused a significant disruption in the control rats it did not further disrupt the existing deficit in the Ara-C treated rats. These data provide evidence to support the contention that modest neurodevelopmental insults can significantly affect sensorimotor gating processes in an adult onset dependent manner.     

The 5-HT<Subscript>1A</Subscript> receptor agonist MKC-242 reverses isolation rearing-induced deficits of prepulse inhibition in mice

Rationale Prepulse inhibition (PPI) of startle provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. PPI deficits observed in schizophrenia patients can be modeled in rats by individual housing from weaning until adulthood. The deficits in PPI produced by isolation rearing can be reversed by antipsychotics. We previously found that (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a highly potent 5-HT_1A receptor agonist, reduced aggressive behavior selectively in isolation-reared mice. Objective This study examines whether isolation rearing of mice produces PPI deficits and whether PPI deficits are attenuated by 5-HT_1A receptor activation. Methods Male ddY mice, 4 weeks old, were housed for more than 6 weeks singly or in groups of five or six. The PPI of the acoustic startle response was measured using SR-LAB systems. Results The PPI was less in isolation-reared mice than in group-reared mice. Oral administration of MKC-242 at 0.1–0.3 mg/kg reversed PPI deficits in isolation-reared mice, although it did not affect PPI in group-reared mice. MKC-242 did not affect MK-801-induced and apomorphine-induced PPI deficits in group-reared mice. The reversal by MKC-242 of isolation-induced PPI deficits was antagonized by the 5-HT_1A receptor antagonist WAY100635 at low doses. Conclusion These results suggest that isolation rearing produces deficits in sensorimotor gating in mice that are reversible by activation of 5-HT_1A receptors, probably somatodendritic 5-HT_1A autoreceptors.     

Antipsychotics possessing antidepressive efficacy increase G<Subscript>olf</Subscript> protein in rat striatum

Rationale Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects. Objectives In this study, we measured striatal and extrastriatal dopamine D₂ receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose. Materials and methods Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [¹¹C]raclopride and one with [¹¹C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D₂ receptor occupancy was calculated. Results The dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride and the temporal cortex measured with [¹¹C]FLB 457 were 54.2–85.5% and 34.5–87.3%, respectively. ED₅₀ values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D₂ receptor occupancy between the striatum and the temporal cortex. Conclusions The data from this study suggest that paliperidone ER at 6–9 mg provides an estimated level of dopamine D₂ receptor occupancy between 70–80% and that the magnitude of dopamine D₂ receptor occupancy is similar between the striatum and temporal cortex.     

Imaging apomorphine stimulation of brain arachidonic acid signaling <Emphasis Type="Italic">via</Emphasis> D<Subscript>2</Subscript>-like receptors in unanesthetized rats

Rationale and objective Because of the important role of dopamine in neurotransmission, it would be useful to be able to image brain dopamine receptor-mediated signal transduction in animals and humans. Administering the D₁–D₂ receptor agonist apomorphine may allow us to do this, as the D₂-like receptor is reported to be coupled to cytosolic phospholipase A₂ activation and arachidonic acid (AA) release from membrane phospholipid. Methods Unanesthetized adult rats were given intraperitoneally apomorphine (0.5 mg/kg) or saline, with or without pretreatment with 6 mg/kg intravenous raclopride, a D₂/D₃ receptor antagonist. [1–¹⁴C]AA was injected intravenously, then AA incorporation coefficients k*—brain radioactivity divided by integrated plasma radioactivity—markers of AA signaling, were measured using quantitative autoradiography in 62 brain regions. Results Apomorphine significantly elevated k* in 26 brain regions, including the frontal cortex, motor and somatosensory cortex, caudate-putamen, thalamic nuclei, and nucleus accumbens. Raclopride alone did not change baseline values of k*, but raclopride pretreatment prevented the apomorphine-induced increments in k*. Conclusions A mixed D₁–D₂ receptor agonist, apomorphine, increased the AA signal by activating only D₂-like receptors in brain circuits containing regions with high D₂-like receptor densities. Thus, apomorphine might be used with positron emission tomography to image brain D₂-like receptor-mediated AA signaling in humans in health and disease.     

Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors

In this study, the behavioural response to dopamine D₁-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D₂-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1 and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion (activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration of a D₁-like agonist plus a D₂-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement of dopamine function by repeated ECS requires concomitant stimulation of both D₁-like and D₂-like receptors, and that this effect is long-lasting. Received: 24 January 1997 /Final version: 5 March 1997     

Decreased prepulse inhibition and increased sensitivity to muscarinic,but not dopaminergic drugs in M<Subscript>5</Subscript> muscarinic acetylcholine receptor knockout mice

Rationale Schizophrenic patients show decreased measures of sensorimotor gating, such as prepulse inhibition of startle (PPI). In preclinical models, these measures may be used to predict antipsychotic activity. While current antipsychotic drugs act largely at dopamine receptors, the muscarinic acetylcholine receptors offer promising novel pharmacotherapy targets. Of these, the M₅ receptor gene was recently implicated in susceptibility to schizophrenia. Due to the lack of selective ligands, muscarinic receptor knockout mice have been generated to elucidate the roles of the five receptor subtypes (M₁–M₅). Objectives Here, we used M₅ receptor knockout (M₅−/−) mice to investigate the involvement of M₅ receptors in behavioral measures pertinent to schizophrenia. We tested the hypothesis that disruption of M₅ receptors affected PPI or the effects of muscarinic or dopaminergic agents in PPI or psychomotor stimulation. Materials and methods We measured PPI in M₅−/−, heterozygous and wild-type mice without drugs, and with clozapine (0.56–3.2 mg/kg) or haloperidol (0.32–3.2 mg/kg) alone, and as pretreatment to d-amphetamine. In addition, we evaluated locomotor stimulation by the muscarinic antagonist trihexyphenidyl (0.56–56 mg/kg) and by cocaine (3.2–56 mg/kg). Results The M₅−/− mice showed decreased PPI relative to wild-type mice, and clozapine appeared to reduce this difference, while haloperidol increased PPI regardless of genotype. The M₅−/− mice also showed more locomotor stimulation by trihexyphenidyl than wild-type mice, while cocaine had similar effects between genotypes. Conclusions These data suggest that disruption of the M₅ receptor gene affected sensorimotor gating mechanisms, increased sensitivity to clozapine and to the psychostimulant effects of muscarinic antagonists without modifying the effect of dopaminergic drugs.     

Repeated quinpirole treatments produce neurochemical sensitization and associated behavioral changes in female hamsters

Rationale Repeated stimulation of dopaminergic pathways with dopamine receptor agonists can produce both neurochemical and behavioral sensitization.Objectives The present study was designed to examine whether repeated treatment with the D₂-like dopamine receptor agonist, quinpirole, would produce neurochemical sensitization of D₁ dopamine receptor-mediated processes and associated behavioral changes in female hamsters in a manner analogous to that previously used to sensitize heterologous dopamine signaling pathways in derived cell lines.Materials and methods Female hamsters received two injections of quinpirole (1.5 mg/kg) or saline each week for 7 weeks, during which time pouching behavior and body weight were monitored. Over the next 2 weeks, hamsters were tested for differences in prepulse inhibition of the acoustic startle response (PPI) and sexual behavior. Adenylate cyclase activation assays were then performed on dissected tissue from the nucleus accumbens and caudate–putamen.Results Repeated treatment with quinpirole increased pouching behavior and body weight and disrupted PPI. No changes in sexual activity in response to repeated quinpirole were found. Prior quinpirole treatment enhanced D₁ dopamine receptor-stimulated adenylate cyclase activity in the caudate–putamen that was blocked by co-incubation with the D₁ dopamine antagonist, SCH23390.Conclusions These results show that repeated activation of D₂-like receptors in vivo can produce changes in feeding behavior and sensory processing that is associated with sensitization of D₁ dopamine receptor-mediated signaling in the caudate–putamen.     

Disruption of prepulse inhibition of the startle reflex by the preferential D<Subscript>3</Subscript> agonist ropinirole in healthy males

Rationale Emerging evidence from agonist–antagonist studies suggests a role for the dopamine D₃ receptor subtype in the regulation of PPI in animals, but such evidence is lacking for human subjects. Objectives This study examines the effect of the preferential D₃ agonist ropinirole on PPI in humans. Methods PPI was tested in 12 healthy men in three sessions associated with ropinirole 0.25 mg, ropinirole 0.5 mg, or placebo according to a balanced, crossover, double-blind design. Two prepulses (75- and 85-dB white noise bursts) and two lead intervals (50 and 80 ms) were employed. Results Ropinirole 0.5 mg significantly reduced prepulse inhibition (PPI) with both prepulses at the 80-ms lead intervals. There was no effect of treatment on startle amplitude and habituation. Conclusions These results suggest a role for the dopamine D₃ receptor in the mediation of human PPI, although a contribution from ropinirole’s agonistic activity at the D₂ receptor cannot be entirely excluded. Firm conclusions on the role of the D₃ receptor in the modulation of human PPI can only be drawn with the use of genetic approaches or more selective ligands for this receptor.     

Role of the strychnine-insensitive glycine binding site in the nucleus accumbens and anterodorsal striatum in sensorimotor gating: a behavioral and microdialysis study

This study examined the role of the strychnine-insensitive glycine binding site of the NMDA receptor in prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. PPI is an operational measure of gating processes which normally lead to a diminished ASR when a startling stimulus is preceded by a weak prepulse. PPI is impaired in schizophrenics and, therefore, experimentally induced PPI deficits in rats can be regarded as a model for gating deficits in schizophrenia. Local administration of 7-chlorokynurenate (7-CLKYN), an antagonist of the strychnine-insensitive glycine site of the NMDA receptor, into the nucleus accumbens reduced PPI. This sensorimotor gating deficit was antagonized by systemic pretreatment of the rats with the glycine site agonist D-cycloserine, indicating that the effect of 7-CLKYN was due to a blockade of the NMDA receptor associated glycine binding site. A similar deficit in PPI was observed after intra-accumbal administration of the competitive NMDA receptor antagonist AP-5. PPI was normal after injecting these drugs into the anterodorsal striatum. The hypothesis that the PPI deficit is accompanied by a change in dopamine release was tested by a neurochemical analysis of the effects of local injection of 7-CLKYN. Microdialysis data showed no increase of accumbal and striatal dopamine release after blockade of the glycine site with 7-CLKYN. Our data demonstrate that the glycine/NMDA receptor in the nucleus accumbens plays a important role in sensorimotor information processing that depends not on a hyperactive dopamine system. Received: 24 May 1996/Final version: 26 September 1996     

Effects of haloperidol and SCH 23390 on acoustic startle in animals depleted of dopamine as neonates: implications for neuropsychiatric syndromes

Animals depleted of dopamine (DA) in the neonatal period and tested in adulthood exhibit some similarities to patients with schizophrenia, including increased sensitivity to DA agonists, altered sensitivity to DA receptor antagonists, and abnormalities of the acoustic startle response (ASR). In this study, we examined the contributions of D₁-like and D₂-like DA receptors to ASR measures in animals depleted of DA as neonates. Male rat pups received intracerebroventricular injections of 6-hydroxydopamine (DA depleted) or its vehicle (controls) at 3 days of age. Animals underwent startle testing ad adults (60–75 days of age) after administration of DA antagonists (haloperidol: 0.1 or 0.3 mg/kg, SCH 23390: 0.01 or 0.05 mg/kg) with and without DA agonist administration (apomorphine 0.5 mg/kg). ASR amplitude and prepulse inhibition (PPI: percentage decrease in startle amplitude due to a low intensity prepulse) were measured. DA depleted animals showed increased ASR amplitude and reduced PPI compared to controls. Administration of D₁-like or D₂-like DA antagonists significantly reduced overall ASR and increased PPI in both control and DA depleted animals, with DA depleted animals showing a relatively greater sensitivity to the D₁-like antagonist SCH 23390. Findings are discussed in terms of the role of residual DA in mediating ASR phenomena in depleted animals, differences between D₁/D₂ DA receptor mediation of ASR compared to other behaviors in DA depleted animals, and potential implications for neuropsychiatric syndromes such as schizophrenia.     

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Rationale

Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct (dopamine D1 receptor-expressing) and indirect (D2 receptor-expressing striatal output) pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia.

Objectives

To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia.

Results

Our results indicate that, in rats: (1) PDE10A inhibition (TP-10, 0.32–10.0 mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5 mg/kg), confirming previous report; (2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5 mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005 mg/kg).

Conclusions

These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.     

Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition

 Recent evidence suggests that the dopamine D₄ receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D₄ dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1–5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D₄-selective compounds, CP-293,019 (5.6–17.8 mg/kg), U-101,387 (3–30 mg/kg) and L-745,870 (1–10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D₄ dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D₂ receptor antagonists. Received: 13 May 1997/Final version: 15 July 1997     

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.     

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.     

Effects of daily SKF 38393, quinpirole,and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine

In three experiments, male Wistar rats (250–350 g) were injected (SC) daily with the D₁-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D₂-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D₁-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8–10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D₁ receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D₂ receptor stimulation also contributes to the effect.Portions of this paper were presented at the 1991 Society for Neuroscience meetings, New Orleans, La, USA.     

Monoamine oxidase inhibitor-induced blockade of locomotor sensitization to quinpirole: role of striatal dopamine uptake inhibition

Previous studies have shown that the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D₂/D₃ dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. However, clorgyline is also an inhibitor of striatal dopamine uptake, and this mechanism could account for the effect of clorgyline on quinpirole sensitization. To investigate this possibility, the effects of clorgyline and pargyline were examined. Of these two MAOIs, only clorgyline inhibits dopamine uptake in the striatum. Rats received subcutaneous injections of clorgyline (1 mg/kg), pargyline (10 mg/kg) or vehicle 90 min prior to each injection of quinpirole (0.5 mg/kg, s.c., ×8, twice weekly) or saline. Clorgyline and pargyline blocked the development of quinpirole-induced locomotor sensitization and sensitized self-directed mouthing behaviors in quinpirole rats. Thus, it is unlikely that clorgyline blocks locomotor sensitization to quinpirole via an inhibition of striatal dopamine uptake. Both MAOIs increased dopamine metabolism in the striatum, showed opposite effects in the prefrontal cortex, and eliminated the correlation between prefrontal dopamine and striatal DOPAC content found in quinpirole sensitized rats. We suggest that clorgyline and pargyline may affect the behavioral and neurochemical response to quinpirole via a previously reported MAOI-displaceable quinpirole binding site, a site which we hypothesize serves as a ‘switch’ to select what motor output becomes sensitized to repeated injections of quinpirole.