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     

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958

  Rationale: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D₁ and D₂ receptors. Objectives: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D₁ receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D₁ and D₂ receptor using a varied range of startle-eliciting intensities. Methods: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D₁ receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D₁ or D₂ receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). Results: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. Conclusions: These data suggest that dopamine D₁ receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D₁/D₂ receptor interaction whereby D₂ receptor activation is necessary for the full expression of the D₁ receptor-mediated enhancement of startle. Received: 10 October 1998 / Final version: 11 January 1999     

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     

The substantia nigra pars reticulata mediates the enhancement of startle by the dopamine D<Subscript>1</Subscript> receptor agonist SKF 82958 in rats

Rational and objectives Several studies have shown that the substantia nigra pars reticulata (SNr) is a critical site of action mediating dopamine agonist effects on motor behaviors. Because dopaminergic and GABAergic mechanisms may interact in the SNr, we tested the contribution of both dopamine and GABA receptors in the SNr on the enhancement of startle by the dopamine D₁ agonist SKF 82958.Methods Male Sprague-Dawley rats were implanted with cannulae into the SNr and 1 week later infused with either the D₁ antagonist SCH 23390 (0.1, 1 µg) or the GABA_A antagonist bicuculline (0.1 µg), followed by a systemic challenge with the D₁ agonist SKF 82958 (1 mg/kg). Other rats were infused with the GABA_A agonist muscimol (0.1 µg) or SKF 82958 (0.1, 1, 5 µg).Results Both SCH 23390 and bicuculline infused into the SNr completely blocked the enhancement of startle by systemic SKF 82958. Muscimol infused into the SNr produced a significant increase in startle by itself, whereas SKF 82958 had no effect.Conclusions These results suggest that activation of D₁ receptors in the SNr is necessary for the enhancement of startle by SKF 82958, but that activation of these receptors alone is not sufficient to increase startle. These results also suggest that GABA transmission in the SNr may be involved in the enhancement of startle by SKF 82958. Based on these data, we propose that activation of striatonigral neurons by D₁ receptor agonists facilitates GABA release in the SNr to produce the observed enhancement of startle.     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D₁ receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3–300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100–300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D₁ receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D₁ receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D₁ agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D₁ receptor subtype.     

Enhancement of dopamine-mediated behaviour by the NMDA antagonists MK-801 and CPP: similarities with repeated electroconvulsive shock

The behavioural effect of dopamine D₁-like receptor agonists (SKF 38393, SKF 81297) and a D₂-like receptor agonist (quinpirole), administered alone and in combination, was tested in rats pretreated with a single injection of an NMDA antagonist (MK-801, CPP) or vehicle. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Pretreatment with MK-801 (0.05 mg/kg, SC, 30 min) had no significant effect (compared to controls) on the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC) or quinpirole (0.1 and 0.25 mg/ kg SC) administered alone. In contrast, MK-801 markedly increased locomotion (activity counts and scores) induced by co-administration of a D₁-like plus a D₂-like agonist [SKF 38393 (7.5 mg/kg) plus quinpirole (0.25 mg/kg), SKF 81297 (0.2 mg/kg) plus quinpirole (0.1 mg/kg)]. The behavioural response to the non-selective dopamine agonist apomorphine (0.5 mg/ kg SC) was also enhanced by MK-801. Pretreatment with CPP (0.1 mg/kg SC, 30 min) also significantly increased the locomotor response to co-administration of SKF 38393 plus quinpirole administered alone, but had no effect on the behavioural response to separate injection of these agonists. MK-801 (0.05 mg/kg SC, 30 min) also enhanced the behavioural response to bilateral injection into the nucleus accumbens of SKF 38393 plus quinpirole (1.0 plus 0.4 μg/side, respectively). These data suggest that in the intact rat, the enhancement of dopamine-mediated behaviour by either MK-801 or CPP requires concomitant stimulation of D₁-like and D₂-like receptors, possibly located within the nucleus accumbens. The effect of these NMDA antagonists on dopamine function is similar to that of repeated electroconvulsive shock (ECS), indicating that one of the actions of ECS may be to reduce NMDA receptor function. Received: 24 January 1997/Final version: 21 March 1997     

The D1 dopamine agonist SKF 38393 functions as a discriminative stimulus in rats

Rats (N=11) were trained to discriminate SKF 38393 (8.0 mg/kg, IP), a D₁ dopamine receptor agonist, from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. The discrimination was acquired by nine rats within an average of 77±6 (SEM) sessions. Subsequently, various doses of SKF 38393 as well as SKF 82526, a potent, selective D₁ agonist that does not readily penetrate the blood-brain barrier, were injected prior to test sessions. SKF 38393 (2–16 mg/kg) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. On the other hand, SKF 82526 (0.125 and 1.0 mg/kg) induced no drugappropriate responding. This experiment establishes that SKF 38393 can serve as a discriminative stimulus in rats. Furthermore, the observation that SKF 82526 did not substitute for SKF 38393 in this paradigm makes it unlikely that this effect involves a peripheral site of action. The results suggest the existence of a functional, behaviorally relevant D₁ dopamine receptor in the CNS of rats.     

Synergistic enhancement of the acoustic startle reflex by dopamine D1 and 5-HT1A agonists and corresponding changes in c-Fos expression in the dorsal raphe of rats

Rationale: Although there is evidence that central opioid receptors are involved in immunomodulation, it has been only recently that an endogenous agonist, designated endomorphin-1, possessing high selectivity and affinity for the mu opioid receptor has been identified. Objective: The present study assesses the immunomodulatory effects of endomorphin-1 in the rat and provides further evaluation of the antinociceptive effects of endomorphin-1. Methods: Rats were surgically implanted with cannulae directed at the lateral cerebral ventricle. Animals received vehicle or endomorphin-1 at doses of 31.63 or 56.23 μg (ICV) and were tested for antinociception in two different assays, the warm water tail withdrawal procedure and the hotplate assay. Additional studies assessed the effect of naltrexone on the antinociception produced by endomorphin-1 in both antinociceptive assessments. Assessments of immune status following endomorphin-1 treatment included measurements of splenic natural killer cell activity, production of interferon-γ, and lymphocyte proliferative responses to mitogenic stimulation by Con-A, LPS, and the microbial superantigen, TSST-1. Results: Endomorphin-1 induced significant and naltrexone reversible antinociception 30 and 60 min following drug administration, as measured by the hotplate assay and warm water tail withdrawal procedure. In marked contrast, endomorphin-1 did not produce immunomodulatory effects up to 120 min following ICV administration. Conclusions: Endomorphin-1 produces antinociception but does not induce immunomodulatory effects in the rat. These findings suggest that it is possible to develop therapeutic strategies for separating antinociception and immunomodulatory properties through the mu opioid receptor. Electronic Publication     

Selective attenuation of the antinociceptive effects of μ opioids by the putative dopamine D3 agonist 7-OH-DPAT

Rationale: The purpose of the present investigation was to evaluate the effects of the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of μ opioids. Methods: Antinociception was assessed using a warm-water tail-withdrawal procedure in rats. Results: The μ opioids morphine (0.3–10 mg/kg) and dezocine (0.03–3.0 mg/kg) produced dose-dependent increases in antinociception with maximal effects obtained at the higher doses tested. Pretreatment with the putative D₃ agonist 7-OH-DPAT (1.0–10 mg/kg) produced a dose-dependent attenuation of the antinociceptive effects of morphine and dezocine. At the highest dose of 7-OH-DPAT tested, the morphine dose-effect curve was shifted rightward by approximately 1.5 log units and the dezocine curve by greater than 2.3 log units. The (+)-isomer of 7-OH-DPAT (1.0 and 3.0 mg/kg) also shifted the morphine dose-effect curve to the right in a dose-dependent manner. The DA D₃/D₂ agonist (−)-quinpirole (0.1–10 mg/kg) attenuated the effects of morphine, but these effects were small in magnitude, not dose-dependent and observed only under a limited set of conditions. The DA D₂/D₃ antagonist spiperone failed to alter the morphine dose-effect curve, but reversed the effects of 7-OH-DPAT on morphine antinociception. Pretreatment with the DA D₁ agonist (±)-SKF38393 (1.0 and 10 mg/kg) and the D₁ antagonist (+)-SCH23390 (0.1 and 1.0 mg/kg) failed to alter the morphine dose-effect curve. Conclusion: The finding that 7-OH-DPAT markedly attenuated the effects of morphine and that these effects were reversed with spiperone suggests that activity at the D₃, and possibly the D₂, receptor can modulate μ agonist-induced antinociception. Received: 30 June 1998/Final version: 12 January 1999     

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.     

Potentiation of prepulse inhibition of the startle reflex in rats: pharmacological evaluation of the procedure as a model for detecting antipsychotic activity

Prepulse inhibition (PPI) of the startle reflex – whereby presentation of a weak prepulse preceding a startling pulse diminishes the amplitude of the startle reflex – is disrupted by dopamine (DA) agonists; this disruption can be reversed by antipsychotics. There are also some indications in the literature that a few antipsychotics (most notably clozapine and haloperidol) may, on their own, have effects opposite to those of DA agonists, i.e. may enhance PPI. In order to explore these antipsychotic-induced potentiations of PPI more thoroughly, we assessed, in Sprague-Dawley rats, the effects of IP administration of various clinically effective antipsychotics in a PPI procedure with levels of PPI (ranging from 5 to about 40%) low enough to facilitate detection of PPI-potentiating effects of drugs. Both clozapine (5–20 mg/kg) and haloperidol (0.25–1 mg/kg) robustly and dose-dependently potentiated PPI. A similar effect was not seen with risperidone (0.1–1 mg/kg) or with the three substituted benzamides amisulpride (10–60 mg/kg), raclopride (0.1–3 mg/kg) and remoxipride (1–10 mg/kg). As risperidone is known to have prominent 5-HT₂ antagonistic activity, these results do not indicate a role for 5-HT₂ receptors in the clozapine and haloperidol PPI-enhancing effects. The absence of effects with the benzamides and with risperidone, at doses with known anti-dopaminergic activity, suggests that DA antagonist activity is not involved. The demonstration that prazosin (3–20 mg/kg), a non-antipsychotic with α₁ adrenoceptor antagonistic properties, dose-dependently potentiated PPI indicates that α₁ receptors might mediate the clozapine and haloperidol PPI-enhancing activity. Additionally, the finding that diazepam (1–10 mg/kg) did not enhance, but on the contrary reduced PPI, argues against a sedation- or general depressant-mediated effect of clozapine, haloperidol and prazosin. The negative results with four clinically active antipsychotics (risperidone and the benzamides), and the positive result with the non-antipsychotic prazosin, indicate that this PPI-enhancing procedure has poor predictive validity as a screening tool for potential antipsychotics. Received: 14 November 1996/Final version: 6 February 1997     

Effects of dopamine D1 receptor agonists in rats trained to discriminate dihydrexidine

Rationale The full D₁ receptor agonist dihydrexidine (DHX) [(+/−)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson’s disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. Methods: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D₁ receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D₁ agonist, fenoldopam, was evaluated.Results SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958<ABT-431<SKF 75670A≤dinapsoline<SKF 81297<DHX. Fenoldopam (10 and 30 mg/kg) did not substitute and was without effect on rates of responding.Conclusions DHX produces prominent dopamine D₁ receptor agonist effects in vivo and is likely to produce subjective effects in humans similar to other D₁ receptor agonists.     

Serotonin1B receptor stimulation enhances dopamine-mediated reinforcement

The effect of 5-HT_1B receptor stimulation on dopamine-mediated reinforcement in rats was investigated using intravenous self-administration of the selective dopamine uptake inhibitor GBR-12909 on an FR5 schedule of reinforcement. Pretreatment with the 5-HT_1A/1B receptor agonist CGS-12066B (1–10 mg/kg, IP) dose-dependently reduced the self-administration of GBR-12909 (83 μg/injection) by increasing the interval between drug injections, consistent with a enhancement of the reinforcing effects of GBR-12909. Additionally, CGS-12066B pretreatment (3 mg/kg, IP) shifted the dose-effect function for GBR-12909 self-administration to the left. Pretreatment with the selective 5-HT_1A receptor agonist 8-OH-DPAT (0.03– 1.0 mg/kg, SC) had no significant effect on GBR-12909 self-administration (83 μg/injection), indicating that the effect of CGS-12066B is not mediated by the 5-HT_1A receptor. Finally, CGS-12066B pretreatment (1–10 mg/kg, IP) did not alter the self-administration of cocaine (0.03–0.5 mg/injection), suggesting that the simultaneous stimulation of multiple 5-HT receptor subtypes by the indirect 5-HT agonist properties of cocaine may mask the effect of 5-HT_1B receptor stimulation on DA-mediated reinforcement. Received: 5 February 1996/Final version: 20 June 1996     

Repeated administration of amphetamine induces sensitisation to its disruptive effect on prepulse inhibition in the rat

 Male Sprague-Dawley rats were repeatedly treated with amphetamine (AMP, 1 mg/kg, SC) at 3- day intervals for 15 days and tested for prepulse inhibition of acoustic startle after each treatment. This treatment regimen induced sensitisation in the animals as evidenced by a progressive increase in the disruptive effect of AMP on prepulse inhibition. Persistent changes in brain function was indicated, since an increase in disruptive effect was observed in sensitised animals also after a 22-day-long drug- and test-free period. The development of sensitisation was blocked by pretreatment with haloperidol (HPD, 0.1 mg/kg, SC), which suggests that sensitisation to the disruptive effect of AMP was dependent on dopamine (DA) D₂ receptor activation. Furthermore, the development of sensitisation was blocked by adrenalectomy, which suggests that sensitisation was dependent also on circulating adrenal hormones. Increased DA-ergic activity has been implicated in the pathophysiology of schizophrenia and AMP-induced sensitisation to the neuronal functions that modulate prepulse inhibition may be an experimental model to investigate this hypothesis. Received: 20 May 1997 / Final version: 14 August 1997     

Effects of Dopamine D1 and D2 Receptor Agonists and Antagonists on Seizures Induced by Chemoconvulsants in Mice

Abstract: Dopamine agonists and antagonists with different affinities for D₁ and D₂ receptors in the brain were assessed for their ability to affect clonic seizures in mice induced by chemoconvulsants. The dopamine D₂ antagonists remoxipride (5-20 mg/kg) and raclopride (5-20 mg/kg), haloperidol (2.5 and 5 mg/kg) and the D₁ antagonist SCH 23390 (0.3, 1.5 mg/kg) did not markedly modify seizures induced by pentylenetetrazole, picrotoxin or bicuculline. The dopamine D₂ agonist quinpirole only weakly blocked the action of pentylenetetrazole while the D₁ agonist SKF 38393 (1-10 mg/kg subcutaneously) caused a dose-dependent blockade of pentylenetetrazole-induced seizures. The D₁/D₂ agonist apomorphine given at “postsynaptic” doses (1 and 2 mg/kg) blocked pentylenetetrazole-induced seizures. The protection afforded by apomorphine against pentylenetetrazole seizures appeared to be associated with its activation of both D₁ and D₂ receptors since both raclopride and SCH 23390 blocked the action of apomorphine. Reserpine and the two partial dopamine autoreceptor agonists, (—)3-PPP and HW-165, at high (non-autoreceptor selective) doses induced seizures in animals treated with the subconvulsive dose of pentylenetetrazole. The overall results suggest that dopamine receptor blockade has a minor or limited effect on seizures caused by GABA inhibition. The anticonvulsant effect of dopamine agonists such as apomorphine appears to be mediated by postsynaptic dopamine D₁ and D₂ receptors. Stimulation of dopamine D₁ receptors can reduce seizure activity caused by GABA receptor blockade possibly by facilitation of GABA transmission in the striatum and substantia nigra.     

PHNO, a selective dopamine D2 receptor agonist, does not reduce prepulse inhibition of the startle reflex in rats

RATIONALE: Dopamine agonists nonselective for dopamine receptor subtypes, such as apomorphine, reduce prepulse inhibition of the startle reflex. It has been suggested that either D2 or D3 dopamine receptors mediate this action of apomorphine. OBJECTIVE: The present study investigated whether a selective D2 agonist with relatively low affinity for D3 receptors can reduce prepulse inhibition. METHODS: Rats (n=48) were treated with vehicle or one of three doses ( 15, 30 or 60 microg/kg, s.c.) of the specific dopamine D2 receptor agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) for 11 days. On days 1, 6 and 11 of treatment, the rats (n=12 in each group) were tested for their acoustic startle reflexes (105-dB, 40-ms white noise) and for prepulse inhibition (5-kHz tone, 5 dB above a 65 dB background white noise). Prepulses were presented with a range of stimulus onset asynchronies (SOAs: 5-160 ms) or lead times between the onset of the prepulse and the onset of the startle stimulus. In a second experiment, two groups of rats (n=10 in each group) were tested in a similar manner after vehicle or apomorphine (0.8 mg/kg, s.c.) to verify the sensitivity of the present procedure to agonist-induced reductions in prepulse inhibition. RESULTS: At doses that increased motor activity, PHNO increased prepulse inhibition at SOAs less than 80 ms and had no effect on prepulse inhibition at SOAs of 80 ms or above. However, all doses decreased startle amplitudes on trials in which only the startle-eliciting stimulus was presented. Apomorphine reduced prepulse inhibition under the same conditions. CONCLUSIONS: These findings with PHNO are in contrast to the less-specific D2 agonist, quinpirole, which has been reported to decrease prepulse inhibition. It is concluded that activation of D2 dopamine receptors alone is not sufficient to attenuate prepulse inhibition of the startle reflex.     

Genetics, haloperidol-induced catalepsy and haloperidol-induced changes in acoustic startle and prepulse inhibition

The acoustic startle response (ASR), prepulse inhibition (PPI) of the ASR and the effects of haloperidol on the ASR and PPI were examined in C57BL/6J (B6) and DBA/2 (D2) inbred mouse strains and their F₁ and F₂ progeny. The startle stimulus was a 60-ms, 110-dB, 10-kHz tone; the prepulse stimuli were 20-ms white noise bursts at 56, 68 and 80 dB against a 50-dB background presented 100-ms before the startle pulse. The B6 strain showed modest PPI (25–40%); in contrast, the D2 strain showed on average no PPI and numerous individuals showed prepulse augmentation (PPA). The F₂ progeny showed an intermediate PPI; however, the extreme values ranged from 200% PPA to essentially 100% PPI. Haloperidol in dose-dependent fashion, increased PPI in both the B6 and D2 strains; the threshold dose was in the range of 0.1–0.2 mg/kg. Raclopride (0.3 mg/kg), clozapine (2 mg/kg) and risperidone (0.4 mg/kg) also increased PPI in both strains. The effects of haloperidol (0.4 mg/kg) on PPI in 140 F₂ progeny were examined. For all prepulse intensities, there were highly significant (r > 0.80) and negative correlations between baseline PPI and the haloperidol-induced change in PPI. Thus, those animals that showed the greatest PPA showed the greatest haloperidol-induced increase in PPI. There was, however, significant variance in the haloperidol response; plots of the regression residuals showed the most and least responsive animals differed by almost 100% in effect on PPI. The F₂ progeny were subsequently phenotyped for haloperidol-induced catalepsy. There was no association between the variation in effects on catalepsy and PPI. However, it was observed that those individuals with the poorest baseline PPI were catalepsy non-responsive. Received: 11 February 1997 /Final version: 20 May 1997     

Reinforcing effect of the D1 dopamine agonist SKF 81297 in rhesus monkeys

Rhesus monkeys with IV catheters were allowed to self-administer cocaine for 1 h/day. When responding was stable, saline or the D₁ dopamine agonist SKF 81297 (SKF; 0.001–0.3 mg/kg/inj) was substituted for cocaine. At least two doses of SKF maintained responding above saline levels in all monkeys. The D₁ antagonist SCH 39166 (0.001–0.03 mg/kg, IM) was then administered 30 min before sessions of self-administration of the lowest dose of SKF that maintained behavior (0.01 mg/kg/inj). SKF-maintained responding decreased in a dose-related manner, suggesting antagonism of the reinforcing effect. These results suggest that stimulation of D₁ receptors can initiate a reinforcing effect and further implicate D₁ receptors in the reinforcing effects of drugs that increase dopamine neurotransmission.     

A D2 dopamine receptor agonist disrupts sensorimotor gating in rats. Implications for dopaminergic abnormalities in schizophrenia

Prepulse inhibition of acoustic startle is deficient in schizophrenic patients and in animals injected with either direct or indirect dopamine (DA) agonists. The present experiments confirmed the hypothesis that the dopaminergic blockade of prepulse inhibition is attributable to the activation of D2 DA receptors. After systemic administrations of the D1 agonist SK&F 38393, the D2 agonist quinpirole, or a combination of the two, rats were tested for prepulse inhibition of the startle response by presenting acoustic stimuli or acoustic stimuli preceded by weak prepulses that inhibit startle. Although the D1 agonist SK&F 38393 had no effect on prepulse inhibition [0.3 to 30.0 mg/kg (1.03 to 102.82 mumols/kg)], the D agonist, quinpirole, blocked prepulse inhibition at doses of 0.3 mg/kg (1.17 mumols/kg) and 0.9 mg/kg (3.51 mumols/kg). Lower doses of quinpirole, 0.03 mg/kg (0.12 mumols/kg) and 0.1 mg/kg (0.39 mumols/kg), were ineffective. When an ineffective dose of quinpirole (0.1 mg/kg) was coadministered with 10.0 mg/kg SKF 38393, prepulse inhibition was reduced relative to saline controls. This reduction of prepulse inhibition is consistent with the synergistic effect of D1 and D2 DA receptor stimulation noted in studies of dopaminergic influences on stereotyped behavior in rats. These findings confirm that a disruption of sensorimotor gating results from D2 dopaminergic stimulation in the rat and extend the applicability of this animal model for the similar behavioral deficits exhibited by schizophrenic patients.     

Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics

Quantitative in vitro receptor autoradiography was used to examine changes in three ionotropic glutamate receptor subtypes using ³H-MK801 (NMDA-R antagonist), ³H-CNQX (AMPA-R antagonist) and ³H-kainic acid (kainate-R agonist) following subchronic (28 days) and chronic (8 months) treatment of rats with a typical antipsychotic, haloperidol (1.5 mg/kg per day), atypical antipsychotic, clozapine (25 mg/kg per day), the dopamine D₂/D₃ receptor antagonist, raclopride (10 mg/kg per day), and the dopamine D1 (D₁/D₅) receptor antagonist SCH23390 (0.5 mg/kg per day). Subchronic and chronic drug treatments did not significantly alter ³H-CNQX or ³H-kainate binding in any of brain regions examined. Subchronic SCH23390 treatment elevated ³H-MK801 binding in the hippocampal formation with significant increases in the CA₁ and dentate gyrus, suggesting a specific role for dopamine D1 receptors in the regulation of hippocampal NMDA receptor function. Subchronic, but not chronic, haloperidol and clozapine treatment significantly reduced ³H-MK801 binding in the medial prefrontal cortex. This suggests that typical and atypical antipsychotics may exert some of their clinical effects by affecting NMDA receptors in the medial prefrontal cortex. Both subchronic and chronic clozapine treatment decreased ³H-MK801 binding in the caudate putamen. The minimal extrapyramidal side effects produced by clozapine may result, in part, from the reduction in NMDA receptor binding in the caudate putamen. Received: 29 February 1996 /Final version: 15 July 1996