Cataleptic Response Research Articles

Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation

Subanesthetic doses of N-methyl- d-aspartate (NMDA) receptor antagonists such as ketamine and phencyclidine precipitate psychotic symptoms in schizophrenic patients. In addition, these drugs induce a constellation of behavioral effects in healthy individuals that resemble positive, negative, and cognitive symptoms of schizophrenia. Such findings have led to the hypothesis that decreases in function mediated by NMDA receptors may be a predisposing, or even causative, factor in schizophrenia. The present study examined the effects of the representative atypical (clozapine) and typical (haloperidol) antipsychotic drugs on ketamine- induced increases in [ 14 C] -2-deoxyglucose (2-DG) uptake in the rat brain. As previously demonstrated, administration of subanesthetic doses of ketamine increased 2-DG uptake in specific brain regions, including medial prefrontal cortex, retrosplenial cortex, hippocampus, nucleus accumbens, basolateral amygdala, and anterior ventral thalamic nucleus. Pretreatment of rats with 5 or 10 mg/kg clozapine alone produced minimal or no change in 2-DG uptake, yet clozapine completely blocked ketamine-induced changes in 2-DG uptake in all brain regions studied. In striking contrast, a dose of haloperidol (0.5 mg/kg) that produces a substantial cataleptic response, potentiated, rather than blocked, ketamine-induced activation of 2-DG uptake. These results demonstrate, in a model with potential relevance to schizophrenia, a striking neurobiological difference between the actions of prototypical typical and atypical antipsychotic drugs. The dramatic blockade by clozapine of ketamine-induced brain metabolic activation suggests that antagonism of the consequences of reduced NMDA receptor function could contribute to the superior therapeutic effects of this atypical antipsychotic agent. The results also suggest that this model of ketamine-induced alterations in 2-DG uptake may be extremely useful for understanding the complex neural mechanisms of atypical antipsychotic drug action.

The role of alpha2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat.

1. The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat. 2.The close structural analogues of clozapine, loxapine (0.1 mg kg(-1) s.c.) and iso-clozapine (1 and 3 mg kg(-1) s.c.) induced catalepsy in rats. In contrast, clozapine and the regio-isomer of loxapine, iso-loxapine (up to 10 mg kg(-1) s.c.) did not produce catalepsy, but at a dose of 1 mg kg(-1) significantly inhibited catalepsy induced by loxapine (0.3 mg kg(-1) s.c.). 3. Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D2/5-HT1A, D2/5-HT1B/1D and D2/alpha2-receptor affinity (KD) ratios: i.e. 30-100-fold higher ratios were calculated for loxapine and iso-clozapine, whereas the ratios were less than 1 for clozapine and iso-loxapine. The ratios of affinities for D2 to 5-HT2A, 5-HT2C or D1 did not reflect the grouping of cataleptic and non-cataleptic compounds. 4. Co-treatment with the alpha2-adrenoceptor antagonists, yohimbine (1-10 mg kg(-1) s.c.), RX 821002 (1-10 mg kg(-1) s.c.) and MK-912 (0.3 and 1 mg kg(-1) s.c.) dose-dependently inhibited the cataleptic response to loxapine (0.3 mg kg(-1)). Yohimbine (1-10 mg kg(-1) s.c.) also dose-dependently inhibited the cateleptic response to haloperidol (0.3 mg kg(-1) s.c.). The alpha2-adrenoceptor antagonists had no effect per se. 5. Neither yohimbine (10 mg kg(-1)) nor RX821002 (3 mg kg(-1)) altered the cataleptic response to the D1 receptor antagonist, SCH 23390 (1 mg kg(-1) s.c.), while, like clozapine, both compounds abolished the response to the 5-HT2A receptor antagonist, MDL 100,151 (3 mg kg(-1) s.c.). 6. The present data strongly implicate alpha2-adrenoceptor blockade in the anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side effects in the clinic may also be a consequence of this property.

Modification of cataleptic responses to dopamine receptor antagonists after withdrawal from chronic cocaine or cocaine plus dopamine antagonist administration

1. 1. In mice pretreated chronically with cocaine (indirect dopamine agonist: 10 mg/Kg S.C. on alternating days for 15 days), haloperidol (dopamine D 2 antagonist: 0.3 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (dopamine D 1 antagonist: 0.3 mg/kg i.p.) produced an attenuated response at 24 h, which converted to a supernormal response, when it was administered 15–60 days after withdrawal from cocaine. 2. 2. A challenge dose of SCH23390 exhibited enhanced catalepsy when given 15 days, but not at 24 h, after the last pretreatment dose of SCH23390 (0.1–1.0 mg/kg s.c.). In contrast, haloperidol catalepsy was not affected by the SCH23390 pretreatment. 3. 3. However, in animals chronically pretreated with haloperidol (0.1–1.0 mg/kg s.c.), a challenge dose of SCH23390 as well as haloperidol exhibited attenuated cataleptic effects at 24 h and normal cataleptic responses at 15 days after the last dose of the pretreatment regimen. 4. 4. Challenge doses of haloperidol or SCH23390 given to mice 24 h after chronic cocaine pretreatment produced enhanced and attenuated cataleptic responses, respectively; however, these responses were no longer produced when haloperidol or SCH23390 was given to mice pretreated chronically with a combination of cocaine and either haloperidol or SCH23390. 5. 5. The enhanced catalepsy produced by a challenge dose of SCH23390 (15–60 days after chronic cocaine) was further potentiated when it was administered to animals that had been pretreated chronically with a combination of SCH23390 and cocaine, but was antagonized in animals pretreated chronically with haloperidol and cocaine. In contrast, the degree of enhanced cataleptic responses produced by a challenge dose of haloperidol 30–60 days after pretreatment chronically with a combination of cocaine + SCH23390 was similar to that seen after chronic cocaine alone. However, this enhanced response was antagonized in animals that had been pretreated chronically with the combination of cocaine+haloperidol. 6. 6. The results suggest that the coadministration of SCH23390 with cocaine was able to block indirectly dopamine D 2 receptor inhibition (subsensitivity) induced during the early withdrawal period from chronic cocaine, despite the fact that by itself SCH23390 did not have an effect on haloperidol catalepsy. Accordingly, the stimulatory effects of dopamine D 2 receptors by a single administration of cocaine may be mediated mainly by an indirect stimulation of dopamine D 2 receptor function via its D 1 receptor stimulating action. 7. 7. The coadministration of SCH23390 with cocaine rather aggravate the subsensitive effect of dopamine D 1 receptors (increased SCH23390 catalepsy) produced during long-term withdrawal period from chronic cocaine, but did not affect that of the dopamine D 2 receptor. On the other hand, the coadministration of haloperidol with cocaine normalized both D 1 and D 2 receptor subsensitive effect. 8. 8. These result suggest that a single administration of SCH23390 or haloperidol after long-term withdrawal periods from chronic cocaine may not be effective as antipsychotic drugs because of further aggravation of suppressive behaviors. These results also provide evidence that D 2 receptor antagonists may be more effective as antipsychotic drugs than dopamine D 1 receptor antagonist, since the coadministration of haloperidol with cocaine normalized the abnormal behaviors seen during early and long-term withdrawal periods from chronic cocaine.

Cataleptogenic effect of subtype selective 5-HT receptor antagonists in the rat.

5-HT receptor antagonists with selectivity for 5-HT1A WAY-100635 (N-[2-[-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide), 5-HT1B GR 127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'(5-methyl-1,2, 4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide x HCl), 5-HT2C SB 200646A (N-(1-methyl-5-indolyl)-N'-(3-pyridyl)urea x HCl) and 5-HT2A (ketanserin, fananserin and MDL 100,151 ((+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipe ridinemethanol) receptors were tested for cataleptogenic responses in rats. WAY-100635 (0.1-3 mg/kg, s.c.), ketanserin (0.1-3 mg/kg, s.c.), MDL 100,151 (0.3-3 mg/kg, s.c.) and fananserin (RP 62203; 3 mg/kg, s.c.) induced a significant catalepsy. GR 127935 (1 mg/kg, s.c.), SB 200646A (without effect per se at 10 mg/kg, s.c.) and MDL 100,151 (0.3 mg/kg, s.c.) did not inhibit the cataleptic response to the dopamine D2 receptor antagonist, loxapine (0.3 mg/kg, s.c.). Catalepsy induced by MDL 100,151 (3 mg/kg) was blocked by co-treatment with clozapine, but not by SB 200646A (both at 10 mg/kg, s.c.). Although clozapine displays significant affinity to 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, the present results suggest that blockade of these receptors is not responsible for clozapine's anticataleptic activity.

A role of nitric oxide in WIN 55,212-2 tolerance in mice.

The role of nitric oxide (NO) in the development of cannabinoid tolerance was examined by using N(omega)-nitro-L-arginine methyl ester (L-NAME) as an inhibitor of NO synthase. R(+)-[2,3-Dihydro-5-methyl-3 [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-napht halenyl)methanone mesylate (WIN 55,212-2), a cannabinoid receptor agonist, or L-NAME plus WIN 55,212-2 was acutely or chronically injected i.p. to mice and analgesia, body temperature and immobility were measured. A single injection of WIN 55,212-2 induced time- and dose-dependent analgesia, hypothermia and catalepsy. L-NAME (50 mg/kg), which per se was ineffective, administered 20 min before WIN 55,212-2 did not modify the analgesic, hypothermic and cataleptic responses to the cannabinoid. When WIN 55,212-2 was administered once a day, the animals became completely tolerant to the analgesic, hypothermic and cataleptic effects within five, seven and nine days respectively. L-NAME injected once daily 20 min before WIN 55,212-2 inhibited the development of tolerance to the hypothermic and cataleptic actions but not to the analgesic action of WIN 55,212-2. Since L-NAME given chronically by itself did not modify the analgesia, hypothermia and catalepsy induced by acute administration of WIN 55,212-2, our findings suggest L-NAME acts with some selectivity on the mechanisms involved in cannabinoid tolerance.

Higher Environmental Temperature Potentiates Cataleptic Effect of Fentanyl in Rats

The influence of higher environmental temperature (HET = 30±1°C) on fentanyl-induced behavior was studied in unrestrained rats. Subacute exposure (3 days) of rats to HET significantly (P<0.01) increased the cataleptic effect of fentanyl citrate (0.5 mg/kg), in comparison to the corresponding exposure to normal environmental temperature (NET=22±1°C). Also, the hyperthermic response of rats to a low dose of fentanyl citrate (0.2–0.5 mg/kg) was significantly (P<0.01) potentiated, and the hypothermic response to a high dose of fentanyl citrate (1.5 mg/kg) was significantly (P<0.05) attenuated after exposure to HET. Fentanyl-induced hyperexcitability, loss of righting reflex, loss of corneal reflex and analgesia were not significantly affected by HET. This study provides the first evidence on the influence of environmental temperature on drug-induced catalepsy. HET-induced potentiation of the cataleptic response to fentanyl could be the result of an interference with behavioral thermoregulation.

Dopamine D 1- and D 2-dependent catalepsy in the rat requires functional NMDA receptors in the corpus striatum, nucleus accumbens and substantia nigra pars reticulata

This study investigated the anticataleptic activity of MK-801 versus the D 1 antagonist SCH 23390 and the D 2 antagonist raclopride, using the horizontal bar test in the rat. MK-801, 0.2 mg/kg i.p., strongly opposed the cataleptogenic actions of SCH 23390 and raclopride administered systemically (1 and 3 mg/kg i.p., respectively), or directly into the corpus striatum (CS) or nucleus accumbens (NAc; 1 and 10 μg, respectively). Conversely, intraCS and intraNAc pretreatment with MK-801 (10 μg) markedly attenuated the cataleptic response to a systemic injection of SCH 23390 or raclopride. In the latter experiments the anticataleptic effect of MK-801 was pronounced and sustained (>2 h), except with intraCS MK-801 versus raclopride, where it was initially profound but only short-lived (15 min). Stereotaxic injection of MK-801 (1 μg) into the substantia nigra pars reticulata (SNr) prevented catalepsy developing to either dopamine D 1 or D 2 receptor antagonism. These results indicate there must be unimpeded glutamate neurotransmission in the CS and NAc before catalepsy can develop fully to D 1 and D 2 dopamine receptor blockade in these structures. The weaker glutamate–D 2 interaction in the CS than in the NAc may be related to differences in the N-methyl- d-aspartate receptor subpopulations in these nuclei. Finally, the ability of intranigral MK-801 to diminish both D 1- and D 2-dependent catalepsy suggests the SNr acts as a common output pathway for the expression of both forms of catalepsy in the rat.

Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice.

The antipsychotic drug, haloperidol, elicits the expression of neurotensin and c-fos mRNA in the dorsal lateral region of the striatum and produces an acute cataleptic response in rodents that correlates with the motor side effects of haloperidol in humans. Mice harboring a targeted disruption of the RIIbeta subunit of protein kinase A have a profound deficit in cAMP-stimulated kinase activity in the striatum. When treated with haloperidol, RIIbeta mutant mice fail to induce either c-fos or neurotensin mRNA and the acute cataleptic response is blocked. However, both wild-type and mutant mice become cataleptic when neurotensin peptide is directly injected into the lateral ventricle, demonstrating that the kinase deficiency does not interfere with the action of neurotensin but rather its synthesis and release. These results establish a direct role for protein kinase A as a mediator of haloperidol induced gene induction and cataleptic behavior.

Dopaminergic and Cholinergic Interaction in Cataleptic Responses in Mice

The cataleptogenic effects of haloperidol, a dopamine D2 receptor antagonist; SCH23390, a D1 receptor antagonist; physostigmine, a cholinesterase inhibitor; and pilocarpine, a muscarinic M1 receptor agonist, were challenged by pretreatment of mice with SKF38393, a dopamine D1 receptor agonist; apomorphine, a dopamine D1/D2 receptor agonist (mainly D2 receptor); pirenzepine, a muscarinic M1 receptor antagonist; and scopolamine, a muscarinic M1/M2 receptor antagonist. The effect of physostigmine and pilocarpine on haloperidol and SCH23390 cataleptic responses was also examined. Each of the challenging agents blocked one or more of the cataleptogenic agents, but only scopolamine blocked all four. Pirenzepine blocked cataleptic responses induced by SCH23390 and pilocarpine, but not those by haloperidol and physostigmine. The results of this study suggest that the action of physostigmine (endogenous acetylcholine) on M2 receptors might be more potent than that on muscarinic M1 receptors. A further interesting observation was that the haloperidol-induced catalepsy was enhanced by physostigmine pretreatment, but not by pilocarpine pretreatment, whereas the SCH23390-induced catalepsy showed the opposite spectrum of enhancement by the two cholinergic agonists. We conclude that, although the four cataleptogenic agents act via the dopaminergic-cholinergic systems, their pharmacological differences may be due largely to the different receptor subtypes that are involved in the mediation of catalepsy produced by each agent. Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively. The results suggest that there are, at the least, relationships between muscarinic M1 receptors and dopaminergic D1 receptors, and between muscarinic M2 receptors and dopaminergic D2 receptors. Dopamine D1 and D2 receptors may interact in a synergistic fashion on dopaminergic systems, but act independently of each other in influencing other system such as cholinergic neurons.

The Physiological Role of Dopamine D2 Receptors

Interest lies in the study of the physiological activity of D2 receptors that are abundantly expressed in the striatum, substantia nigra, and hypophysis. Two isoforms of this receptor have been described that differ by their coupling characteristics to G-proteins in vitro . D2 and D1 receptors are the most abundant dopaminergic receptors expressed in the brain. The parallel activation by dopamine of these two receptors in the basal ganglia leads to the activation of two pathways whose synergistic action controls coordinated movements. Unexpectedly, the elimination of D1 receptor expression by homologous recombination, which would be predicted to affect the locomotion-enhancing direct pathway, leads instead of hyperlocomotion in homozygous mice. These results contradict pharmacological studies in which the use of D1 receptor antagonists results in a cataleptic response of treated animals. To study the physiology of the D2 receptor in vivo , mutant mice lacking a functional D2 receptor gene have been generated by homologous recombination. In contrast to D1R, D2R-deficient animals display a phenotype that broadly resembles D2 antagonist treatment, indicating that the effect observed by antagonist treatment is because of the blocking of D2 receptors and not to other members of the dopamine receptor family. The knockout of the D2R gene has evidenced the pleiotropic role of this receptor in the control of physiological functions. The most evident phenotypes are a serious locomotor impairment and abnormal hormonal function. Interestingly, in the D2R knockout animals, there is an increase in enkephalin (ENK) mRNA expression, which could be responsible for the decreased movement of these animals. It is interesting to note that the phenotype exhibited by D2R-deficient mice, at the level of expression of striatal specific peptides, resembles the findings obtained by treatment of 6-OHDA-lesioned animals. This might indicate that the primary target of dopamine depletion in this model is the D2 receptor.

Pharmacological Effects of Aqueous Extract fromValeriana adscendens

A purified aqueous extract of Valeriana adscendens Trel. (Valerianaceae) was investigated for its pharmacological profile. The extract did not exert significant changes on the nociceptive threshold in the hot plate and tail flick test and no effect was registered on the guinea-pig ileum. On the other hand, the extract significantly reduced both the locomotor activity and motor coordination of mice; it also prolonged sleep induced by pentobarbital, whereas no significant cataleptic response was observed. These effects may suggest neuroleptic-like properties.

Prevention by (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin of both catalepsy and the rises in rat striatal dopamine metabolism caused by haloperidol.

1. The influence of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on haloperidol-induced increases in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), was measured in three microdissected brain regions of the rat following a quantitative assessment of catalepsy. 2. Haloperidol alone (2.66 mumol kg-1, i.p.) caused a robust cataleptic response. Given 30 min after haloperidol, 8-OH-DPAT (76 or 760 nmol kg-1, s.c.) prevented catalepsy in 30% and 100% of rats, respectively. 3. Haloperidol significantly increased the DOPAC (by 2 to 4 fold) and HVA (by 3 to 7 fold) contents of the caudate-putamen, nucleus accumbens and medial prefrontal cortex. Given alone, only the lower dose of 8-OH-DPAT caused a significant biochemical change, a doubling of cortical DOPAC. 4. In the cases where catalepsy was prevented by either dose of 8-OH-DPAT, the haloperidol-induced increases in DOPAC and HVA were consistently lower in the caudate-putamen. This pattern was true for the rise in cortical HVA but only in response to the lower dose of 8-OH-DPAT. In contrast, neither dose of 8-OH-DPAT was able to influence the haloperidol-induced rises in cortical DOPAC. In the nucleus accumbens, 8-OH-DPAT did not affect the haloperidol-induced increases in the dopamine metabolites, irrespective of the dose employed or the resulting behaviour. When catalepsy was not prevented, 8-OH-DPAT did not alter the neurochemical responses to haloperidol in any region. 5. These results suggest that part of the mechanism by which 8-OH-DPAT prevents haloperidol-induced catalepsy is reflected by a reversal of the compensatory increase in meso-striatal and/or meso-cortical dopamine neuronal activity that normally accompanies postsynaptic dopamine receptor blockade with haloperidol.

CNS Pharmacological Effects of Aqueous Extract from Iresine herbstii

A purified aqueous extract of Iresine herbstii Hook. f. (Amaranthaceae) was investigated for its CNS pharmacological profile. The extract significantly reduced the locomotor activity, motor coordination and stereotyped behavior of mice. On the other hand, the extract did not exert significant changes on the nociceptive threshold in the hot plate and tail flick test. In addition, no effect was registered on sleep induced by pentobarbital or cataleptic response. The results of the present study suggest that Iresine herbstii induces significative effects on selected aspects of the central nervous system (CNS).

Antinociceptive and behavioral effects of synthetic deltorphin analogs

A possible correlation of behavioral, antinociceptive and cataleptic responses with central δ- and μ-opioid receptor stimulation was tested for in the rat by i.c.v. injections of some synthetic deltorphin analogs. At doses ranging from 0.1 to 3.0 nmol/rat, the selective δ-opioid receptor agonist, [ d-Ala 2,Glu 4]deltorphin (Tyr- d-Ala-Phe-Glu-Val-Val-Gly-NH 2), induced a dose-dependent stereotyped pattern of locomotor activity, reaching the maximum in the first 30 min; doses higher than 30 nmol induced early and fleeting antinociception. The replacement of Glu 4 by Gly, Ala, Val, His or Asn yielded peptides with a lower δ-selectivity because of a gain in μ-affinity. [ d-Ala 2,Ala 4]deltorphin (0.14–4.0 nmol) induced negligible behavioral stimulation but a rapidly appearing and long-lasting analgesia and catalepsy. The other four synthetic peptides induced biphasic effects: low dosages stimulated locomotion whereas higher doses initially suppressed, then increased locomotor activity. At doses ranging from 1 to 70 nmol all the peptides induced analgesia and catalepsy. In experiments examining the locomotor and antinociceptive effects induced by 14 nmol of [ d-Ala 2,Gly 4]deltorphin in rats pretreated with μ and δ antagonists, the non-selective μ-opioid receptor antagonist, naloxone (1 mg/kg i.p.), reduced analgesia and abolished the initial hypolocomotion. The δ-selective antagonist, naltrindole (10 mg/kg i.p.), abolished locomotor activity without affecting analgesia. The μ 1-selective antagonist, naloxonazine (10 mg/kg i.v.), seemed to prolong analgesia and immobility. Hence this peptide appears to activate, in addition to δ-receptors, mainly the opioid receptor μ 2-subtype, which mediates catalepsy in the rat. We suggest that the μ 2- and δ-opioid receptors of the rat brain modulate locomotor behavior by activating functionally opposed responses. [ d-Ala 2,Ala 4]deltorphin had an antinociceptive and cataleptic potency higher than would have been expected from its μ-affinity. A possible explanation might be a μ/δ-opioid receptor interaction.

Alteration of cataleptic responses induced by dopamine receptor antagonists after chronic cocaine administration in mice

The influence of chronic treatment of mice with cocaine, an indirect dopamine receptor agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepin-7ol hydrochloride (SCH23390), a dopamine D 1 receptor antagonist, or haloperidol, mainly a dopamine D 2 receptor antagonist, was investigated. Mice were given cocaine (10 mg/kg s.c.) once every other day for 7 (4 injections), 15 (8 injections) or 21 (11 injections) days. The cataleptic effects of SCH23390 (0.3 mg/kg i.p.) were significantly reduced when it was given 1–7 days after the last dose of a 7- or 15-day pretreatment course of cocaine. When SCH23390 was given 14–21 days after the cocaine the cataleptic effect was increased in the 15-day, but not the 7-day, cocaine-pretreated mice. However, after a 21-day treatment with cocaine, a challenge dose of SCH23390 given 1–3 days thereafter produced a decreased cataleptic response, but an increased response after 7–21 days. The cataleptic effects of haloperidol (0.3 mg/kg i.p.) were reduced when it was given 1–7 days after the last dose of a 7-day pretreatment, but increased 1–3 days after that of a 15-day pretreatment with cocaine (10 mg/kg s.c.). The pretreatment with cocaine for 21 days did not affect the haloperidol catalepsy during a 1- to 3-day withdrawal period. However, haloperidol catalepsy was decreased only 7 days, then reversed 14 days and gradually increased 21 days after the last injection of a 15- or 21-day pretreatment course of cocaine. These results suggest that chronic treatment with the indirect dopamine receptor agonist, cocaine, caused supersensitivity of dopamine D 1 receptors (a decrease in SCH23390 catalepsy) during the early withdrawal period and subsensitivity (an increase in SCH23390 catalepsy) after a longer period of withdrawal. It was apparent that the longer the period and the higher the dose of pretreatment with cocaine, the less were the alterations in initial responses and the greater were the alterations in subsequent responses to the dopamine D 1 receptor antagonists.

IL-1β and TNFα modulate δ9-tetrahydrocannabinol-induced catalepsy in mice

The role of the proinflammatory cytokines interleukin-lα (IL-lα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) in THC-induced catalepsy in mice was examined. Recombinant IL-1β (400 ng/mouse, IV) and TNFα (500 ng/mouse, IV) were effective in potentiating the cataleptic effect of low-dose THC (10 μg/mouse, IV). Recombinant IL-1α and IL-6 did not potentiate catalepsy at any dose tested. Anti-IL-1β and anti-TNFα antibodies were effective in attenuating high-dose (75 μg/ mouse) THC-induced catalepsy. Antibodies to IL-1α and IL-6 had no effect on catalepsy. Early onset catalepsy (10 min postinjection) was potentiated by exogenous recombinant IL-1β and TNFα but only later catalepsy (2 h postinjection) was attenuated by antibodies to endogenous IL-1β or TNFα. This divergence of the cytokine effect suggests that these substances regulate, by different mechanisms, the early and late THC-induced cataleptic response.

Development of tolerance and reverse tolerance to haloperidol- and SCH23390-induced cataleptic effects during withdrawal periods after long-term treatment

The development of tolerance and reverse tolerance and reverse tolerance to the cataleptic effects of selective D 1 antagonist, SCH23390, and the mainly D 2 antagonist, haloperidol, was investigated in mice that had been chronically treated (7 or 30 days) with haloperidol (l mg/kg SC), SCH23390 (0.5 mg/kg SC), or saline (5 ml/kg SC). In control animals, SCH23390 (0.1–1.0 mg/kg IP) and haloperidol (0.1–1.0 mg/kg IP) produced cataleptic responses in a dose-dependent manner, although the responses had different time course profiles. SCH23390 catalepsy had a rapid onset but a short duration, whereas haloperidol catalepsy had a slower onset and longer duration. This could be due to differences in lipid solubility of the drugs, or at least pertly to an action of the drugs on different neuronal pathways. The cataleptic effects of SCH23390 (0.3 mg/kg IP) and haloperidol (0.3 mg/kg IP) were significantly reduced in mice when given 24 h, but not 72 h, after the last dose of a 7 day-pretreatment course (short-term treatment) of SCH23390. However, after long-term treatment (30 days) with SCH23390, a challenge dose of SCH23390 exhibited reverse tolerance (i.e., increased catalepsy) when given 7–21 days, but not 1–3 days, after the last injection of the SCH23390 pretreatment course. In contrast, haloperidol catalepsy was not affected by long-term SCH23390 treatment. However, after the last dose of long-term haloperidol treatment both SCH23390 and haloperidol exhibited tolerance to their cataleptic effects at 1–3 days, a normal response at 7 days, and an exaggerated response (reverse tolerance) at 15–21 days. These results suggest that a prolonged withdrawal period after chronic D 1 antagonist treatment is necessary for the development of reverse tolerance to a D 1 antagonist (an increase in catalepsy), which may be a reflection of a long-lasting subsensitivity of D 1 receptors. Long-term treatment with a D 2 receptor antagonist caused supersensitivity of D 1 and D 2 receptors during the early withdrawal period and subsensitivity after a longer period of withdrawal. These results also provide evidence that the cataleptic effects of SCH23390 may be mediated by indirect blockade of D 2 receptor function through its D 1 blocking action, whereas the cataleptic effects of haloperidol may be affected by supersensitivity of D 1 receptors, but not by their subsensitivity.

Production of antinociception by peripheral administration of [Lys7]dermorphin, a naturally occurring peptide with high affinity for mu-opioid receptors.

1. The opioid activity of the amphibian peptide, [Lys7]dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.c.v.), intravenously (i.v.) or subcutaneously (s.c.) it produced a long lasting analgesia. Its antinociceptive potency exceeded that of morphine 290 times by i.c.v. injection, and 25-30 times by peripheral administration. 2. The dose-response curves of [Lys7]dermorphin antinociception were shifted to the right by the pretreatment with naloxone (0.1 mg kg-1, s.c.) or with the mu 1-selective antagonist, naloxonazine (10 mg kg-1, i.v. 24 h before peptide injection). 3. The peptide also displayed potent antinociceptive effects in a chronic inflammatory pain model (rat Freund's adjuvant arthritis). In this pain model, systemic administration of the peptide raised the nociceptive threshold more in inflamed than in healthy paw. 4. High central and peripheral doses of [Lys7]dermorphin in rats produced catalepsy. The cataleptic response was antagonized by naloxone but left unchanged by naloxonazine pretreatment. 5. In rats and mice, central or peripheral administration of [Lys7]dermorphin induced a significantly slower development of tolerance to the antinociceptive effect than did morphine. 6. Upon naloxone precipitation of the withdrawal syndrome, [Lys7]dermorphin-dependent mice made fewer jumps and lost less weight than the morphine-dependent animals. Withdrawal hyperalgesia did not develop in [Lys7]dermorphin-dependent mice. 7. In conclusion, [Lys7]dermorphin seems to be a unique opioid peptide having a high penetration into the blood-brain barrier despite its low lipid solubility. This peptide causes fewer side-effects than other opioids and appears less likely than morphine to cause physical dependence in rats and mice.

Changes in the central dopaminergic systems in the streptozotocin-induced diabetic rats.

The behavioral response, dopamine metabolism, and characteristics of dopamine subtypes after developing the hyperglycemia were studied in the striata of rats. In animals developed hyperglycemia, the on-set and duration of cataleptic behavior responded to SCH 23390 injection was delayed and shortened, respectively. However, the cataleptic responses to spiperone occurred significantly earlier in on-set and prolonged in duration. Dopamine metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were significantly reduced in the striata of hyperglycemic rats. However, level of DA was significantly increased. It is noted that the ratios of DOPAC and HVA to DA were decreased, suggesting decreased turnover of DA. The affinity of striatal D-1 receptors was significantly increased without changes in the number of binding sites, while the maximum binding number of D-2 receptors was significantly increased without affecting its affinity in the diabetic rats. These results indicate that the dopaminergic activity in the striata was altered in hyperglycemic rats. Furthermore, it suggests that the upregulation of dopamine receptors might be due to the decreased dopamine metabolism.

KF17837: A novel selective adenosine A 2A receptor antagonist with anticataleptic activity

KF17837 is a novel selective adenosine A 2A receptor antagonist. Oral administration of KF17837 (2.5, 10.0 and 30.0 mg/kg) significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A 2A receptor agonist, CGS 21680 (10 μg), in a dose-dependent manner. KF17837 also reduced the catalepsy induced by haloperidol (1 mg/kg i.p.) and by reserpine (5 mg/kg i.p.). These anticataleptic effects were exhibited dose dependently at doses from 0.625 and 2.5 mg/kg p.o., respectively. Moreover, KF17837 (0.625 mg/kg p.o.) potentiated the anticataleptic effects of a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 25 mg/kg i.p.) plus benserazide (6.25 mg/kg i.p.). These results suggested that KF17837 is a centrally active adenosine A 2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A 2A receptor antagonists. Furthermore, KF17837 may be a useful drug in the treatment of parkinsonism.