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Mechanisms of action of novel antipsychotic agents
216 MECHANISMS B. Costall,
OF ACTION A.M.
OF NOVEL
Domeney
and
ANTIPSYCHOTIC R.J.
Postgraduate School of Studies Bradford, Bradford, West Yorkshire
AGENTS
Naylor in Pharmacology, BD7 1DP. UK
University
of
The hyperactivity which results from a slow, persistent infusion of dopamine into the rat or primate mesolimbic nucleus accumbens is sensitive to blockade by neuroleptic agents (1,2). It has recently been reported that an ability to inhibit a mesolimbic dopamine excess is also a property of a number of 5-HTI antagonists of which GR38032F is an example (3, and these proceedings). In the present studies we show that the dopamine response can also be antagonized by Org 5222 (a tetracyclic dopamine antagonist structurally related to the antidepressant mianserin. It is also a potent serotonin antagonist and lacks cataleptogenic or extrapyramidal effects at doses which block dopamine receptors (4) and by Org 5878 (des-enkephalin-r-endorphin, DErE, P-endorphin-LG-17) which has neuroleptic-like activity in some experimental models and appears to be antipsychotic without extrapyramidal effects in schizophrenic patients (5). In assessing whether the ability to inhibit a mesolimbic dopamine excess in animals may be extrapolated to an antipsychotic action in the clinic, novel agents such as GR38032F and Org 5878 may be given to patients previously receiving neuroleptic treatment. Our studies show that abrupt withdrawal from classical neuroleptic therapy used to suppress the hyperactivity resulting from mesolimbic dopamine infusion can lead to a marked rebound hyperactivity response. This rebound response was sensitive to inhibition by both GR38032F and Org 5878 which would indicate that prior exposure to a neuroleptic agent should not comprise the actions of the novel compounds. In establishing these results, both rats and marmosets were used which had been subject to bilateral intracerebral implantation of chronically indwelling guide cannulae for the bilateral infusion of dopamine (25 pg/24 h) into the nucleus accumbens of rat, or the ventral striatum of marmoset. In the marmoset studies animals were selected prior to the infusion of dopamine as low or high activity responders to the dopamine agonist (-)N-n-propylnorapomorphine [(-I mg/kg S.C. In order to inhibit the dopamine response NPAI r 0.05 during infusion fluphenazine was given at a dose of 10 ug/kg b.d., GR38032F at 10 ug/kg b.d., Org 5222 at 25 ug/kg b-d. and Org 5878 at Spontaneous locomotor activity of marmosets was 50 ug/kg t.d.s. measured in cages equipped with infrared photocell units to measure activity between the perches and the floor of the cage. Animals were also challenged with (-INPA at weekly intervals after the infusion and changes in hyperactivity induced by (-INPA recorded. Marmosets initially selected as high activity responders to (-INPA changed, over a period of 21-28 days post-infusion, to low responders. This long-term consequence of a period of mesolimbic dopamine excess in the marmoset was prevented in animals in which the dopamine response had been suppressed by GR38032, Org 522 or DErE, but not in those which had received fluphenazine.
217
In the rat studies a rebound hyperactivity was induced by withdrawing from a mesolimbic dopamine infusion where haloperidol, 0.15 mg/kg i.p. b.d., had been used to suppress the behavioral hyperactivity. This rebound response could be inhibited by fluphenazine (100 pg/kg, sedative dose), GR38032F (100 ug/kg) and Org 5878 (DErE, 100 ug/kg). These studies indicate that the immediate and longer-term consequences of a mesolimbic dopamine excess may be inhibited by agents acting on dopamine receptors, 5-HT receptors, or undefined sites influenced by a peptide. New possibilities are therefore revealed for drug action to ameliorate the symptoms of psychosis. 1.
Barnes, N.J.G. et al. Neuropharmacoloqv
2.
Costall,
B. et al. Neuropharmacoloqy
3.
Costall,
B. et al. Brit. J. Pharmacol.
4.
Kelder, J. et al. Pharm. Weekbl.
26:1327-1335,
21:327-335,
1982
91:335, 1987
Sci. Ed, 6:261, 1984
Van Ree, J.M. et al. Proqr. Brain Res. 65:221-235,
DOPANINE INFUSION AND INTRACEREBRAL DETECTION OF POTENTIAL ANTIPSYCHOTIC B. Costall, A.M. Domeney
1987
INJECTION ACTIVITY
MODELS:
1986
VALUE
FOR THE
and R.J. Naylor
Postgraduate School of Studies Bradford, Bradford, West Yorkshire
in Pharmacology, BD7 lDP, UK
University
of
The cerebral dopamine disturbance in psychosis is believed to be discrete, confined primarily to the limbic system. We have attempted to mimic this by discrete intracerebral injection or infusion into selected mesolimbic nuclei of rat or marmoset brain using amphetamine or dopamine. The present studies show that the behavioral consequences of a mesolimbic dopamine excess so induced can be inhibited by fluphenazine, sulpiride and the novel potential antipsychotic agent GR38032F. Rats were subjected to standard stereotaxic surgery for the implantation of chronically indwelling cannulae for acute injection of amphetamine (10 ug) bilaterally into the nucleus accumbens: potential antagonists were injected into the same nucleus 30 min prior to amphetamine. Both rats and marmosets were prepared as above for persistent infusion, via osmotic minipumps, of dopamine (25 ug/24 h, 0.48 ul/h), or vehicle (0.1% NazSOs), bilaterally into the nucleus accumbens/ventral striatum in rat and marmoset and central nucleus of the amygdala in rat. Neuroleptic agents or GR38032F were injected into the rat nucleus accumbens prior to amphetamine, into the rat infusion at the same brain site, and amygdala during dopamine systemically (twice daily injections) in rat and marmoset throughout the 13 days of dopamine infusion into the nucleus accumbens. In all tests the behavioral measure was hyperactivity, assessed in cages equipped with photocell units.
OF ACTION A.M.
OF NOVEL
Domeney
and
ANTIPSYCHOTIC R.J.
Postgraduate School of Studies Bradford, Bradford, West Yorkshire
AGENTS
Naylor in Pharmacology, BD7 1DP. UK
University
of
The hyperactivity which results from a slow, persistent infusion of dopamine into the rat or primate mesolimbic nucleus accumbens is sensitive to blockade by neuroleptic agents (1,2). It has recently been reported that an ability to inhibit a mesolimbic dopamine excess is also a property of a number of 5-HTI antagonists of which GR38032F is an example (3, and these proceedings). In the present studies we show that the dopamine response can also be antagonized by Org 5222 (a tetracyclic dopamine antagonist structurally related to the antidepressant mianserin. It is also a potent serotonin antagonist and lacks cataleptogenic or extrapyramidal effects at doses which block dopamine receptors (4) and by Org 5878 (des-enkephalin-r-endorphin, DErE, P-endorphin-LG-17) which has neuroleptic-like activity in some experimental models and appears to be antipsychotic without extrapyramidal effects in schizophrenic patients (5). In assessing whether the ability to inhibit a mesolimbic dopamine excess in animals may be extrapolated to an antipsychotic action in the clinic, novel agents such as GR38032F and Org 5878 may be given to patients previously receiving neuroleptic treatment. Our studies show that abrupt withdrawal from classical neuroleptic therapy used to suppress the hyperactivity resulting from mesolimbic dopamine infusion can lead to a marked rebound hyperactivity response. This rebound response was sensitive to inhibition by both GR38032F and Org 5878 which would indicate that prior exposure to a neuroleptic agent should not comprise the actions of the novel compounds. In establishing these results, both rats and marmosets were used which had been subject to bilateral intracerebral implantation of chronically indwelling guide cannulae for the bilateral infusion of dopamine (25 pg/24 h) into the nucleus accumbens of rat, or the ventral striatum of marmoset. In the marmoset studies animals were selected prior to the infusion of dopamine as low or high activity responders to the dopamine agonist (-)N-n-propylnorapomorphine [(-I mg/kg S.C. In order to inhibit the dopamine response NPAI r 0.05 during infusion fluphenazine was given at a dose of 10 ug/kg b.d., GR38032F at 10 ug/kg b.d., Org 5222 at 25 ug/kg b-d. and Org 5878 at Spontaneous locomotor activity of marmosets was 50 ug/kg t.d.s. measured in cages equipped with infrared photocell units to measure activity between the perches and the floor of the cage. Animals were also challenged with (-INPA at weekly intervals after the infusion and changes in hyperactivity induced by (-INPA recorded. Marmosets initially selected as high activity responders to (-INPA changed, over a period of 21-28 days post-infusion, to low responders. This long-term consequence of a period of mesolimbic dopamine excess in the marmoset was prevented in animals in which the dopamine response had been suppressed by GR38032, Org 522 or DErE, but not in those which had received fluphenazine.
217
In the rat studies a rebound hyperactivity was induced by withdrawing from a mesolimbic dopamine infusion where haloperidol, 0.15 mg/kg i.p. b.d., had been used to suppress the behavioral hyperactivity. This rebound response could be inhibited by fluphenazine (100 pg/kg, sedative dose), GR38032F (100 ug/kg) and Org 5878 (DErE, 100 ug/kg). These studies indicate that the immediate and longer-term consequences of a mesolimbic dopamine excess may be inhibited by agents acting on dopamine receptors, 5-HT receptors, or undefined sites influenced by a peptide. New possibilities are therefore revealed for drug action to ameliorate the symptoms of psychosis. 1.
Barnes, N.J.G. et al. Neuropharmacoloqv
2.
Costall,
B. et al. Neuropharmacoloqy
3.
Costall,
B. et al. Brit. J. Pharmacol.
4.
Kelder, J. et al. Pharm. Weekbl.
26:1327-1335,
21:327-335,
1982
91:335, 1987
Sci. Ed, 6:261, 1984
Van Ree, J.M. et al. Proqr. Brain Res. 65:221-235,
DOPANINE INFUSION AND INTRACEREBRAL DETECTION OF POTENTIAL ANTIPSYCHOTIC B. Costall, A.M. Domeney
1987
INJECTION ACTIVITY
MODELS:
1986
VALUE
FOR THE
and R.J. Naylor
Postgraduate School of Studies Bradford, Bradford, West Yorkshire
in Pharmacology, BD7 lDP, UK
University
of
The cerebral dopamine disturbance in psychosis is believed to be discrete, confined primarily to the limbic system. We have attempted to mimic this by discrete intracerebral injection or infusion into selected mesolimbic nuclei of rat or marmoset brain using amphetamine or dopamine. The present studies show that the behavioral consequences of a mesolimbic dopamine excess so induced can be inhibited by fluphenazine, sulpiride and the novel potential antipsychotic agent GR38032F. Rats were subjected to standard stereotaxic surgery for the implantation of chronically indwelling cannulae for acute injection of amphetamine (10 ug) bilaterally into the nucleus accumbens: potential antagonists were injected into the same nucleus 30 min prior to amphetamine. Both rats and marmosets were prepared as above for persistent infusion, via osmotic minipumps, of dopamine (25 ug/24 h, 0.48 ul/h), or vehicle (0.1% NazSOs), bilaterally into the nucleus accumbens/ventral striatum in rat and marmoset and central nucleus of the amygdala in rat. Neuroleptic agents or GR38032F were injected into the rat nucleus accumbens prior to amphetamine, into the rat infusion at the same brain site, and amygdala during dopamine systemically (twice daily injections) in rat and marmoset throughout the 13 days of dopamine infusion into the nucleus accumbens. In all tests the behavioral measure was hyperactivity, assessed in cages equipped with photocell units.