S.K. Long

Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum.

Dose-effect curves were established for the effects of the antipsychotic drugs haloperidol, clozapine, olanzapine, risperidone and ziprasidone on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex, and of dopamine in the striatum. Haloperidol was more effective in stimulating the release of dopamine in the striatum, whereas clozapine was much more effective in the medial prefrontal cortex. The efficacy of risperidone, olanzapine and ziprasidone did not differ for the two brain areas. The benzamides sulpiride and raclopride increased dopamine release in the striatum but did not affect the release of dopamine and noradrenaline in the medial prefrontal cortex. In the presence of dopamine/noradrenaline reuptake inhibitors, the benzamides strongly increased the release of dopamine-but not of noradrenaline-in the medial prefrontal cortex. The 5-HT(2) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (MDL100,907) (800 nmol/kg) and the dopamine D(2) receptor antagonist raclopride (2 micromol/kg) displayed a clear synergism in increasing the release of dopamine in the medial prefrontal cortex. No such synergism was seen in the case of noradrenaline. Co-administration of the 5-HT(2) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine HCl (DOI) (850 nmol/kg) with clozapine (10 micromol/kg) or haloperidol (800 nmol/kg) blocked the increase in dopamine as well as noradrenaline in the medial prefrontal cortex. It is concluded that typical and non-benzamide atypical antipsychotics increase extracellular dopamine in the medial prefrontal cortex via a synergistic interaction by blocking 5-HT(2) as well as dopamine D(2) receptors. The increase in extracellular noradrenaline in the medial prefrontal cortex that was observed after administration of antipsychotics is explained by inhibition of 5-HT(2) receptors and not dopamine D(2) receptors. Finally, the significance of the classification of antipsychotic drugs based on their selective action on the release of dopamine and noradrenaline in the medial prefrontal cortex is discussed. In particular, the position of the benzamides is discussed.

Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat brain.

In the present study we have compared the effects of the classical antipsychotic drug haloperidol and four different atypical antipsychotics (clozapine, risperidone, olanzapine, ziprasidone) on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex (MPFC) of conscious rats. Haloperidol (10, 100 and 800 nmol/kg), clozapine (0.3, 1, 10 and 30 micromol/kg), risperidone (100, 500 and 5000 nmol/kg), olanzapine (10, 100 and 500 nmol/kg) and ziprasidone (10, 100 and 1000 nmol/kg) were administered subcutaneously to rats. All compounds induced increases in dialysate levels of dopamine and noradrenaline in the medial prefrontal cortex. The increases induced by the four antipsychotic agents in extracellular levels of dopamine and noradrenaline displayed a striking co-variation both in dose and time. A similar co-variation was seen in the decrease of dopamine and noradrenaline, after administration of a low dose (30 nmol/kg, s.c.) of the dopamine D2/3 receptor agonist (+)-7-hydroxy-2-(N,N-di-n-propylamino) tetralin ((+)-7-OH-DPAT). It is concluded that there is a close coupling between the release of dopamine and noradrenaline in the medial prefrontal cortex. The mechanism of action of this interaction, that might be of importance for a better understanding of the mechanism of action of antipsychotic drugs, is discussed.

Effect of 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX) on dorsal root-, NMDA-, kainate- and quisqualate-mediated depolarization of rat motoneurones in vitro

1 Mature in vitro rat spinal cord preparations have been used to compare the depressant effects of 6‐cyano‐2,3‐dihydroxy‐7‐nitroquinoxalinedione (CNQX) and kynurenate on transmission from low threshold myelinated primary afferents in dorsal roots. EC50 values ± s.e.mean (number of preparations in parentheses) for depression of the monosynaptic ventral root reflex were respectively 1.0 ± 0.3 μm (5) and 135 ± 15μm (3) for CNQX and kynurenate. Transmission through superior cervical ganglia was not significantly affected by concentrations of CNQX up to 100 μm or kynurenate up to 5 mm. 2 Immature in vitro rat spinal cord preparations were used to measure dose‐ratios for antagonism of depolarizations induced by N‐methyl‐d‐aspartate (NMDA), kainate or quisqualate by 4, 10 and 25 μm CNQX. In the presence of 0.75 mm Mg2+ pA2 values + s.e.mean were respectively 4.62 ± 0.05 (16), 5.79 ± 0.01 (4) and 5.59 ± 0.05 (16) for each agonist. These values were not significantly altered in the absence of added Mg2+. The mean pA2 values for kainate were significantly higher than those for quisqualate (P < 0.01). 3 Antagonism of NMDA‐induced depolarizations was evident at 10 and 25 but not 4 μm CNQX. The antagonism of NMDA was reversed by d‐serine (100 and 200 μm). 4 A similarity between the relative potencies of both CNQX and kynurenate for depression of synaptic transmission and antagonism of amino acid‐induced depolarizations indicates that monosynaptic transmission from myelinated primary afferents to motoneurones is mediated by kainate and/or quisqualate sub‐types of non‐NMDA receptors.

SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4- [5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride): a novel dopamine D2 receptor antagonist and 5-HT1A receptor agonist potential antipsychotic drug.

Combined dopamine D2 receptor antagonism and serotonin (5-HT)1A receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D2/3 antagonist and 5-HT1A agonist. SLV313 possessed high affinity at human recombinant D2, D3, D4, 5-HT2B, and 5-HT1A receptors, moderate affinity at 5-HT7 and weak affinity at 5-HT2A receptors, with little-no affinity at 5-HT4, 5-HT6, α1, and α2 (rat), H1 (guinea pig), M1, M4, 5-HT3 receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT1A receptors (pEC50=9.0) and full antagonist activity at hD2 (pA2=9.3) and hD3 (pA2=8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT1A syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT1A antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT1A-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT1A receptor agonist and full D2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.

New 1-aryl-4-(biarylmethylene)piperazines as potential atypical antipsychotics sharing dopamine D2-Receptor and serotonin 5-HT1A-Receptor affinities

This paper describes the syntheses of several 1-aryl-4-(biarylmethylene)piperazines and the results of the determination of their affinity for D(2) and 5-HT(1A) receptors. A selection of these compounds was evaluated in vivo, resulting in the identification of a drug candidate which is being clinically evaluated as a potential atypical antipsychotic with reduced extrapyrimidal side effects.

The effect of centrally acting myorelaxants on NMDA receptor‐mediated synaptic transmission in the immature rat spinal cord in vitro

1 The effect of the myorelaxant drugs baclofen, diazepam and tizanidine have been compared on in vitro preparations of baby rat spinal cord and adult rat superior cervical ganglion. 2 Dorsal root‐elicited long duration (time to half decay 9.71 ± 0.29 s.e.mean, n = 31) ipsilateral ventral root reflexes (DR‐VRP), measured as integrated area, of immature rat spinal cord preparations were abolished by RS‐2‐amino‐5‐phosphonopentanoate (AP5) (EC50 8.13 ± 0.92 μm, n = 3). The initial short latency component of DR‐VRP was resistant to AP5. 3 Baclofen abolished both components of the DR‐VRP. Respective EC50 values for the AP5‐insensitive and AP5‐sensitive components were 237 ± 68 nm (n ± 7) and 57 ± 10 nm (n = 7). These effects of baclofen were reversed by the GABAB antagonist, CGP35348. The apparent Kd values (16.7 ± 6.4 μm, n = 3 and 14.3 ± 3.9 μm, n = 6 respectively) for this reversal were not significantly different. 4 Tizanidine, clonidine and diazepam had no effect on the AP5‐insensitive component of the DR‐VRP. 5 The AP5‐sensitive long duration component of the DR‐VRP was depressed to respective maximal levels of 23.2 ± 1.4% (n = 7), 18.8 ± 3.8% (n = 4) and 47.6 ± 1.6% (n = 5) of control (100%) levels by tizanidine (EC50 135 ± 33 nm), clonidine (EC50 26.0 ± 2.2 nm) and diazepam (EC25 114 ± 12 nm, n = 4). The depressant effects of tizanidine and clonidine were reversed by idazoxan (1 μm). Flumazenil (1 μm) failed to reverse the depressant effect of tizanidine. The depressant effect of diazepam was reversed by flumazenil (1 μm) but not by idazoxan (1 μm). Naloxone 1 μm did not reverse the effects of either tizanidine or diazepam. 6 In the presence of tetrodotoxin (0.1 μm) which abolished synaptic activity, clonidine, tizanidine or diazepam (10, 100 and 10 μm respectively) produced no significant antagonism of NMDA‐induced depolarizations recorded from ventral roots. 7 Control (100%) synaptic responses of rat superior cervical ganglion preparations were depressed respectively to near maximal levels of 60.0 ± 5.2% (n = 4) and 60.7 ± 5.6% (n = 5) by clonidine (0.5 μm, EC25 15.3 ± 3.0 nm) and tizanidine (1 μm, EC25 227 ± 83 nm). These depressant effects were reversed by idazoxan (1 μm). Baclofen (EC25 28.7 ± 10.0, n = 3) depressed the postganglionic response to a maximum level of 71.8 ± 2.4% (n = 4) control at a concentration of 100 μm. The latter depressant action was reversed by the GABAB receptor antagonist, CGP35348 (1 mm). Diazepam (1 μm) had no significant effect on ganglionic transmission. 8 It is concluded that the activation of benzodiazepine or α2‐noradrenaline receptors can modulate NMDA receptor‐mediated excitatory synaptic pathways whereas synaptic excitation from primary afferent terminals, mediated by non‐NMDA receptors, appears to lack the propensity for this type of modulation. The results show also that the isolated spinal preparation can be used to identify central myorelaxant actions that are mediated through functional benzodiazepine or α2‐noradrenaline receptors.

Preferential blockade of cholecystokinin-8S-induced increases in aspartate and glutamate levels by the CCKB receptor antagonist, L-365,260, in rat brain

In the present studies, the ability of a locally delivered cholecystokinin (CCK) receptor agonist and systemically delivered antagonists to modulate extracellular levels of aspartate and glutamate in the frontal cortex of anaesthetised rats and frontal cortex and caudate-putamen of freely moving rats was investigated using an in vivo microdialysis technique. In the anaesthetised rats, local application of sulphated CCK octapeptide (CCK-8S, 10 microM) into the frontal cortex enhanced extracellular aspartate levels to a maximum of 265+/-16% of the basal levels, whereas glutamate levels were increased to a maximum of 168+/-7% of the basal levels. Given 40 min prior to the cortical perfusion of 10 microM of CCK-8S, the CCK(B) receptor antagonist, L-365,260 (20 mg/kg, s.c.), limited the rise in cortical aspartate by over half to 170+/-10% of the basal levels. However, this same dose of L-365,260 still allowed CCK-8S to increase glutamate by 44+/-15% above the basal levels. Whereas the enhanced glutamate levels were totally unaffected by systemic administration of the CCK(A) receptor antagonist, L-364,718 (20 mg/kg, -40 min, s.c.), this treatment was able to limit the elevation in aspartate to 220+/-4% of the basal levels. In the freely moving rats, local perfusion of CCK-8S (10 microM) increased aspartate and glutamate levels to maxima of 275+/-12% and 225+/-14% of the basal levels, respectively, in the frontal cortex. In the caudate-putamen, aspartate and glutamate levels were also elevated by CCK-8S (10 microM) to 248+/-15% and 185+/-12% of the basal levels, respectively. The respective increase in aspartate and glutamate induced by CCK-8S (10 microM) were limited to 140+/-10% and 124+/-6% (frontal cortex), of the basal levels, and 162+/-15% and 143+/-8% (caudate-putamen), by 40 min pretreatment with L-365,260 (20 mg/kg, s.c.). In conclusion, CCK-8S was able to enhance both aspartate and glutamate overflow in the frontal cortex of anaesthetised rats, and frontal cortex and caudate-putamen of freely moving rats. These increases were preferentially offset by the selective CCK(B) receptor antagonist, L-365,260, since no influence could be discerned using the selective CCK(A) receptor antagonist, L-364,718.

Potentiation of synaptic reflexes by D-serine in the rat spinal cord in vitro

6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) depressed dorsal root-evoked ventral and dorsal root potentials of the in vitro immature rat spinal cord to 26.3 +/- 5.2 S.E.M. and 40.8 +/- 2.7% of control values respectively. These depressant effects of CNQX were partially reversed by D-serine (EC50 values 39.7 microM +/- 8.7 S.E.M. N = 6 and 34.9 +/- 12.5 microM, N = 5 for ventral root potential and dorsal root potential respectively). Under our experimental conditions, which included the presence of Mg2+ (0.75 mM) in the bathing medium, no measurable potentiation of these synaptic reflexes by D-serine was recorded in the absence of CNQX. These data indicate that CNQX, in addition to its depressant effect at non-NMDA receptors, depresses an NMDA receptor-mediated component of segmental transmission through its action at the glycine site of the NMDA receptor complex.