Evidence for the independent role of GABA synapses of the zona incerta-lateral hypothalamic region in haloperidol-induced catalepsy

Bicuculline (0.5-50 ng), injected bilaterally into the zona incerta-lateral hypothalamus (ZI-LH) of the rat, inhibited catalepsy evoked by haloperidol (1 mg/kg s.c.) in a dose-dependent manner. The same effect was obtained by injections of bicuculline directed towards the ventromedial thalamic nucleus (Vm), but then higher doses of the drug were necessary (10-50 ng). Muscimol (10-50 ng), injected into the ZI-LH, evoked a state of catalepsy almost identical to that of haloperidol. Bicuculline (50 ng) abolished the catalepsy evoked by muscimol (25 ng). Bicuculline injected into ZI-LH in doses of 0.5-2.5 ng did not change locomotor activity of rats as measured in photoresistor actometers, whereas it had a slightly stimulating effect at a dose of 5 ng. A comparison between the doses of bicuculline injected into the ZI-LH and Vm suggests that, irrespective of Vm synapses, GABA synapses of this region are involved in the mediation of haloperidol-induced catalepsy. A similar conclusion regarding the catalepsy and rigidity induced by morphine was drawn previously. It seems, therefore, that the catalepsy antagonism of bicuculline is independent of the action of the drug which promotes the locomotor stimulation.     

Discrimination of morphine- and haloperidol-induced muscular rigidity and akinesia/catalepsy in simple tests in rats

The present study was conducted to establish a simple method for measuring muscular rigidity in rats, which could be used for screening and is able to discriminate between rigidity and akinesia/catalepsy. Therefore, we treated rats with morphine (30 mg/kg i.p.), since large doses of morphine lead to muscular rigidity and akinesia. We measured muscular rigidity with a new method by determining the resistance of the hindlimb to passive flexion in the 'balance test' and also checked haloperidol (3 mg/kg i.p.) treated rats for muscular rigidity. Furthermore, catalepsy was also tested after administration of each of these drugs. Then, the influence of D(1)-like and D(2)-like dopamine receptor stimulation on muscular rigidity and catalepsy was studied. Therefore, the partial D(1) agonist SKF 38393 (3 and 8 mg/kg s.c.), the D(2)/D(1) agonist pergolide (0.25 and 0.5 mg/kg i.p.) and the dopamine precursor L-DOPA (50 and 100 mg/kg i.p.) were administered up to 30 min before muscular rigidity was measured in morphine-treated rats. The results showed that morphine, but not haloperidol led to muscular rigidity, whereas both drugs led to positive scores in the catalepsy test. The dopaminergic drugs partly antagonized the morphine-induced muscular rigidity in the doses applied, but not the catalepsy. Apparently, rigidity, akinesia/catalepsy produced by morphine can be discriminated from that produced by haloperidol in simple and quick tests.     

Repeated pre-exposure to morphine into the ventral pallidum enhances morphine-induced place preference: involvement of dopaminergic and opioidergic mechanisms

In the present study, the effect of repeated administration of morphine into the ventral pallidum (intra-VP) on the conditioned place preference (CPP) induced by systemic morphine injection was investigated in male Wistar rats. Subcutaneous (s.c.) administration of morphine (2.5, 5 and 7.5mg/kg), during conditioning, induced conditioned place preference (CPP). The maximum response was obtained with 5mg/kg of morphine. Lower dose of morphine (0.5mg/kg) did not induce CPP, but in the animals which had previously, received 3 days intra-VP repeated injections of morphine (3 or 5microg/rat) followed by 5 days free of the drug, elicited a significant CPP. Moreover, 3 days intraperitoneal (i.p.) pretreatment with different doses of naloxone (0.5, 1 and 2mg/kg), SCH 23390 (0.012, 0.025 and 0.05mg/kg) or sulpiride (6.2, 12.5 and 25mg/kg) in combination with repeated injections of morphine (5microg/rat), blocked the opioid response on the acquisition of morphine (0.5mg/kg) CPP. On the other hand, our results showed that 3 days single repeated administration of different doses of naloxone (0.5, 1 or 2mg/kg, i.p.), SCH 23390 but not sulpiride followed by 5 days free of the drug, significantly decreased the acquisition of morphine (0.5mg/kg) CPP and also induced place aversion. Furthermore, the drugs' injections had no effect on locomotor activity on the testing phase of CPP. It is concluded that repeated intra-VP injections of morphine induces behavioral sensitization, which may be due to the opioidrgic and/or dopaminergic mechanism(s).     

Repeated administration of dopaminergic agents in the nucleus accumbens and morphine-induced place preference

In the present study, the effects of repeated intra nucleus accumbens (intra-NAc) injections of dopamine receptor agents on morphine-induced conditioned place preference (CPP) in rats were investigated by using an unbiased 3-days schedule of place conditioning design. The animals receiving once daily subcutaneous (s.c.) injections of morphine (0.5-7.5mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner. The maximum response was observed with 5mg/kg of the opioid. Three days intra-NAc injections of apomorphine (0.5 and 1 microg/rat) followed by 5 days free of the drug, increased or decreased, respectively CPP induced by the lower dose of morphine (0.5mg/kg, s.c.). Morphine-induced CPP was also significantly increased in the animals that had previously received the 3-days intra-NAc injections of SKF 38393 (4 and 8 microg/rat) or quinpirole (2 and 4 microg/rat, intra-NAc). The CPP induced by a higher dose of morphine (5mg/kg, s.c.) was significantly decreased in the animals that had previously received the 3-days SCH 23390 (0.005 and 0.01 microg/rat; intra-NAc). On the other hand, the CPP induced by morphine (5mg/kg, s.c.) was significantly increased in the animals that had previously received the 3-days sulpiride administration (5 microg/rat, intra-NAc). The 3-days administration of apomorphine, SKF 38393 or quinpirole, but not SCH 23390 and sulpiride reduced the locomotor activity in the test session. It is concluded that repeated injections of dopamine receptors agents followed by 5 days free of the drugs in the NAc can affect morphine reward.     

Morphine-induced place preference: involvement of the central amygdala NMDA receptors

In the present study, the effects of bilateral injections of N-methyl-d-aspartate (NMDA) receptor agonist and/or antagonist into the central amygdala (CeA) on the acquisition and expression of morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Animals that received 3 daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg) indicated a significant preference for compartment paired with morphine in a dose dependent manner. Intra-CeA administration of the NMDA (0.01, 0.1 or 1 microg/rat) with an ineffective dose of morphine (1 mg/kg, s.c.) elicited a significant CPP. Administration of the non-competitive NMDA receptor antagonist, MK-801 (0.1, 0.3 or 0.5 microg/rat), into the central amygdala dose-dependently inhibited the morphine (6 mg/kg, s.c.)-induced place preference. Furthermore, intra-CeA administration of MK-801 (0.25, 0.5 or 1 microg/rat) reduced the response induced by NMDA (1 microg/rat, intra-CeA) plus morphine (1 mg/kg, s.c.). Neither NMDA nor MK-801 alone produce a significant place preference or place aversion. Moreover, intra-CeA injection of NMDA but not MK-801 before testing significantly increased the expression of morphine (6 mg/kg, s.c.)-induced place preference. NMDA or MK-801 injections into the CeA had no effects on locomotor activity on the testing sessions. These results suggest that the NMDA receptor mechanisms in the central amygdala may be involved in the acquisition and expression of morphine-induced place preference.     

Effect of central and peripheral administration of a nitric oxide synthase inhibitor on morphine hyperthermia in rats

The effect of central and peripheral administration of a nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), on morphine hyperthermia was studied in male Sprague-Dawley rats. The first series of experiments examined the effect of subcutaneous (s.c.) administration of L-NAME on the hyperthermia induced by morphine given s.c. in doses of 4 and 15 mg/kg. L-NAME, at a s.c. dose of 50 mg/kg, per se, had no influence on body temperature (T(b)). Coadministration of L-NAME (50 mg/kg, s.c.) with the higher dose of morphine (15 mg/kg, s.c.) caused a significant suppression of morphine hyperthermia during the first 30 min and then produced hypothermia. In contrast, s.c. injection of L-NAME (50 mg/kg, s.c.) failed to alter the hyperthermic response induced by the lower dose of morphine (4 mg/kg). In the second series of experiments, we investigated the effect of intracerebroventricular (i.c.v.) administration of L-NAME on the hyperthermia induced by morphine given s.c. L-NAME, itself, given i.c.v. at a dose of 1 mg did not evoke any change in T(b). Intracerebroventricular administration of L-NAME (1 mg) blocked the hyperthermia induced by 15 mg/kg morphine during the first 30 min and induced a slight hypothermia but did not alter the hyperthermia induced by 4 mg/kg morphine. The results indicate that either central or peripheral NO synthesis is required for the production of hyperthermia induced by 15 mg/kg of morphine. However, NO synthesis does not seem to be involved in the hyperthermic process induced by 4 mg/kg of morphine.     

Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates striatal macrophage invasion and neurodegeneration following local endotoxin infusion in gerbils

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) induced catalepsy in mice is modified by dopaminergic, adenosinergic and GABAergic agents. In light of serotonergic agents being implicated in antipsychotic-induced catalepsy and their ability to increase brain neurosteroid content, the present study was undertaken to investigate the effect of various 5-HT agents on catalepsy induced by 3alpha,5alpha-THP in mice. Pretreatment with selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), 5-HT releaser, fenfluramine (10 mg/kg, i.p.), 5-HT(1A) receptor agonist, 8-OH-DPAT (0.3 mg/kg, s.c.), 5-HT1B/1C receptor agonist, TFMPP (3 mg/kg, i.p.), 5-HT2A/1C receptor agonist, DOI (1.5 mg/kg, s.c.) and 5-HT3 agonist, 2-methylserotonin (5 mg/kg, i.p.) potentiated the catalepsy induced by exogenous administration of 3alpha,5alpha-THP. Furthermore, FGIN 1-27, an MDR agonist that increases endogenous content of 3alpha,5alpha-THP although per se failed to exhibit any cataleptic effect but enhanced the cataleptic response in combination with these serotonergic agents. The potentiating action of 5-HT1A, 5-HT2A/1C or 5-HT3 receptor agonist on 3alpha,5alpha-THP induced catalepsy was not blocked by prior administration of sub-effective dose (1 mg/kg, s.c.) of their respective receptor antagonists pindolol, ritanserin or ondansetron or by pretreatment with serotonergic neurotoxin 5,7-DHT (100 microg/mouse, i.c.v.). However this effect of different serotonergic agents was antagonized by the GABA(A) receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3alpha-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). The 5-HT agents enhance neurosteroid-induced catalepsy by increasing GABAergic tone, likely as a consequence of increased brain content of 3alpha,5alpha-THP.     

Glucocorticoids attenuate haloperidol-induced catalepsy through adrenal catecholamines

Summary To examine the influence of adrenal secretions on neuroleptic induced catalepsy, we studied the effect of adrenocorticoids, noradrenaline (NA) or adrenaline (AD) on haloperidol (HAL) induced catalepsy in adrenalectomised (ADX) and sham-adrenalectomised (sham-ADX) rats. HAL (1 mg/kg, i.p.) induced a greater degree of catalepsy in ADX rats as compared to sham-ADX rats. Corticosterone (CORT, 1–2 mg/kg, s.c.) or dexamethasone (1–2 mg/kg, s.c.) attenuated the HAL catalepsy in sham-ADX but not in ADX rats. Further, when the HAL (1 mg/kg) catalepsy score was maximal (at 120 min), the rats were subjected to cold stress (3 °C for 10 min) or treated with NA, AD (2 g/kg, i.v.) or CORT (2 mg/kg, s.c.). After cold stress procedure or CORT treatment, the catalepsy was significantly reduced in sham-ADX but not in ADX rats, whereas NA or AD infusion caused an immediate but short lasting significant decrease in HAL catalepsy in both sham-ADX and ADX rats. The anticataleptic effect of NA or glucocorticoids was blocked by an ₁adrenoceptor blocker, prazosin.These findings suggest that peripheral noradrenergic and adrenergic mechanisms play an important role in the neuroleptic induced catalepsy. Such mechanisms may mediate the anticataleptic action of glucocorticoids.     

Lateral hypothalamus-zona incerta region as an output station for the catalepsy induced by the blockade of striatal D1 and D2 dopamine receptors

Our previous study reported that the blockade of GABAA receptors of the lateral hypothalamus-zona incerta region (LH-ZI) by local injections of bicuculline methiodide inhibited the haloperidol-induced catalepsy. The aim of the present study was to determine (1) whether the blockade of GABAA receptors of the LH-ZI may counteract the catalepsy evoked by SCH 23390 and by sulpiride, and (2) whether the GABAA receptors of the LH-ZI affect the function of the striatal dopaminergic system. Bicuculline methiodide (2.5 and 5 ng/side) injected bilaterally into the LH-ZI inhibited in a dose-dependent manner the catalepsy induced by SCH 23390 administered peripherally (0.2 mg/kg s.c.). SCH 23390 (2 micrograms/side) and sulpiride (1 microgram/side) injected bilaterally into the rostroventral part of the striatum induced potent catalepsy. The catalepsy induced by injection of SCH 23390 (2 micrograms) and sulpiride (1 microgram) into the striatum was inhibited by bicuculline methiodide (2.5 ng and 5 ng) injected into the LH-ZI. Neither bicuculline (5 ng/side) nor muscimol (50 ng/side) injected bilaterally into the LH-ZI changed the levels of dopamine and its intraneuronal metabolite, 3,4-dihydroxyphenyl-acetic acid, or the concentration of noradrenaline and 5-hydroxyindole-acetic acid measured in the striatum and nucleus accumbens by HPLC with an electrochemical detection. It is concluded that GABAA receptors of the LH-ZI are an output station for the catalepsy induced by the blockade of the striatal D2 and D1 dopamine receptors.     

A possible participation of gonadotropin-releasing hormone in the neuroleptic and cataleptic effect of haloperidol

Haloperidol, an antipsychotic agent, stimulates the release of gonadotropin-releasing hormone (GnRH), and this hormone is known to mimic some of the behavioral effects of haloperidol. Hence, the present study was carried out to find out the contribution of GnRH in the behavioral effects of haloperidol. The studies revealed that haloperidol (0.15, 0.25 and 0.5 mg/kg, i.p.) and leuprolide (GnRH agonist; 50, 100, 200 and 400 μg/kg, s.c.) dose-dependently inhibited conditioned avoidance response (CAR) in male Sprague–Dawley rats. In higher doses, haloperidol (0.5, 1 mg/kg, i.p.) and leuprolide (200, 400 μg/kg, s.c.) produced catalepsy in rats. Co-administration of sub-effective dose of leuprolide (50 or 100 μg/kg, s.c.) and haloperidol (0.15 or 0.5 mg/kg, i.p.) similarly inhibited CAR and induced catalepsy. Pre-treatment of rats with antide (GnRH antagonist; 10 μg/rat, s.c.), attenuated the inhibitory effect of both the agents on CAR; blocked leuprolide-induced catalepsy; and attenuated the intensity and reduced the duration of haloperidol-induced catalepsy. In conclusion, the studies suggest a possible role of GnRH in the neuroleptic and cataleptic effect of haloperidol.     

Effects of calcium channel antagonists on the motivational effects of nicotine and morphine in conditioned place aversion paradigm

The motivational component of drug withdrawal may contribute to drug seeking and relapse through the negative reinforcement-related process; thus, it is important to understand the mechanisms that mediate affective withdrawal behaviors. The present study was undertaken to examine the calcium-dependent mechanism of negative motivational symptoms of nicotine and morphine withdrawal using the conditioned place aversion (CPA) paradigm. Rats were chronically treated with nicotine (1.168 mg/kg, free base, s.c., 11 days, three times daily) or morphine (10 mg/kg, s.c., 11 days, twice daily). Then, during conditioning, rats pre-treated with nicotine or morphine received a nicotinic receptor antagonist mecamylamine (3.5 mg/kg) or an opioid receptor antagonist naloxone (1 mg/kg) to precipitate withdrawal in their initially preferred compartment, or saline in their non-preferred compartment. Our results demonstrated that after three conditioning sessions, mecamylamine induced a clear place aversion in rats that had previously received nicotine injections, and naloxone induced a significant place aversion in rats that had previously received morphine injections. Further, the major findings showed that calcium channel antagonists, i.e., nimodipine, verapamil and flunarizine (5 and 10 mg/kg, i.p.), injected before the administration of mecamylamine or naloxone, attenuated nicotine or morphine place aversion.As an outcome, these findings support the hypothesis that similar calcium-dependent mechanisms are involved in aversive motivational component associated with nicotine a morphine withdrawal. We can suggest that calcium channel blockers have potential for alleviating nicotine and morphine addiction by selectively decreasing the incentive motivational properties of both drugs, and may be beneficial as smoking cessation or opioid dependence pharmacotherapies.     

The effect of morphine on the potassium evoked release of tritiated 5-hydroxytryptamine from spinal cord slices in the rat

The effect of morphine on the potassium (40 mM) evoked release of exogenous [3H]5-HT from slices of the dorsal spinal cord of the rat was studied. The effects of in vitro applied morphine on the slices were compared to those produced by systemic morphine applied to the animals before preparation of the slices. The in vitro application of morphine (10(-6) to 10(-5) M) did not affect the release of [3H]5-HT. By contrast, it was observed that the potassium evoked release of [3H]5-HT from the slices of the spinal cord of rats which had received 10 mg/kg s.c. of morphine 30 min beforehand was significantly increased. The effect of systemic morphine was dose-dependent (in the range of 1.5-10 mg/kg s.c.) and could be blocked by prior administration of naloxone (1 mg/kg i.m.) 2 min before the morphine. The acute administration of 10 mg/kg s.c. of morphine, which did not induce analgesia in rats rendered tolerant to morphine, did not modify the [3H]5-HT release. Higher doses of morphine, which have been shown to restore analgesia in these rats, induced an increase in the release which was significant for a dose of 100 mg/kg s.c. These results demonstrating a specific and dose-dependent increase in the potassium evoked release of [3H]5-HT from spinal dorsal cord slices after systemic administration of morphine, emphasize the role of serotonergic systems in such analgesia. The lack of effect of the drug directly applied in vitro favours a supraspinal site of action of the drug and is in good agreement with recent results in the literature.     

Ethanol enhances naloxone sensitization and disrupts morphine discrimination--comparison to dizocilpine and pentobarbital: explanation of enhancing acute and attenuating chronic effects

1. Ethanol affects ligand-gated ion channels as a positive modulator of gamma-aminobutyric acid (GABA(A)) receptor function and an N-methyl-D-aspartate (NMDA) antagonist. NMDA antagonists attenuate chronic drug effects. Accordingly, we found that ethanol decreased morphine dependence and locomotor sensitization. We now test whether ethanol alters sensitization to the disrupting effects of naloxone on schedule-controlled responding after morphine administration or affects the acute stimulus effects of morphine. 2. Groups of rats, trained to lever-press for food, were co-administered ethanol (1 g/kg; i.p.), the NMDA antagonist dizocilpine (DZ; 0.05 mg/kg; i.p.), the GABA(A) agonist pentobarbital (PB; 3 mg/kg i.p.), or vehicle with morphine (5 mg/kg s.c.). Separate groups received naloxone (0.1-1 mg/kg s.c.) 4-hrs later, prior to food sessions (FR15; 30 min) on three consecutive days. Ethanol enhanced the suppressive effects of higher naloxone doses on all three days. DZ and PB altered this behavior differentially by day and naloxone dose. 3. Next, we examined the effects of ethanol, DZ, PB, and naloxone (0.3 mg/kg; s.c.) on morphine discrimination. Rats, trained to discriminate morphine (3.2 mg/kg s.c.) from saline in a two-lever, food-reinforced procedure, were tested with morphine (0, 1-5.6 mg/kg) after vehicle and drug administrations. Naloxone blocked dose-related responding to morphine, demonstrating pharmacological specificity, and altered response rates. Both ethanol and DZ, but not PB, disrupted morphine-appropriate responding. 4. The paradox that ethanol and DZ attenuate chronic morphine effects while enhancing acute effects may reflect a temporal pattern of primary mu opiate receptor function followed by secondary NMDA-mediated processes induced by morphine administration.     

Stress or drug priming induces reinstatement of extinguished conditioned place preference

To construct a model for the relapse of drug use, we investigated the reinstatement of morphine-induced conditioned place preference (CPP) in rats. After the morphine CPP paradigm was established, rats were left extinguishing for 9 days, then exposed to 15 min of random foot shock or s.c. drug priming with different doses of morphine or amphetamine, respectively. Foot shock or a higher dose (0.25 mg/kg) of both drugs could reinstate the CPP induced by 4 mg/kg of morphine after a 9-day extinction, while a lower dose (0.125 mg/kg) of both drugs had no effect. It is concluded that the CPP extinction-reinstatement paradigm might be used as a model to investigate the mechanism of relapse in addicts.     

Mecamylamine effects on haloperidol-induced catalepsy and defecation.

Recent clinical experience with Tourette syndrome (TS) patients suggests that the nicotinic receptor antagonist, mecamylamine (Inversine), may be a useful adjunct to neuroleptic therapy for controlling tic symptom. This is consistent with previous preclinical findings demonstrating that mecamylamine can potentiate the cataleptic effects of neuroleptics in rats. However, these earlier preclinical studies employed high doses (1-2.5 mg/kg) of mecamylamine that may not be clinically relevant since human doses of mecamylamine used to treat TS have been much lower (0.03-0.1 mg/kg). In order to test the potential therapeutic properties of mecamylamine preclinically, we conducted catalepsy experiments in rats employing both a low and high dose of mecamylamine in combination with haloperidol. Sixty-four male Sprague Dawley rats were randomized into four treatment groups (n = 16/group). Each rat received an injection of either saline or mecamylamine (0.1 or 3.0 mg/kg s.c.) followed one hour later with a second injection of either saline or haloperidol (0.4 mg/kg s.c.). The bar test was used to measure duration of catalepsy at 3 hrs following the second injection. The results demonstrated that only the mecamylamine treated rats showed statistically significant haloperidol-induced catalepsy when measured at 3 hrs. In addition, haloperidol-induced defecation was not affected by the 0.1 mg/kg mecamylamine dose, but completely abolished by the 3.0 mg/kg dose. These findings suggest that a clinically relevant dose of mecamylamine (0.1 mg/kg) can affect the duration of haloperidol-induced catalepsy without having significant effects on gastrointestinal function.     

Involvement of the ventral tegmental area (VTA) in morphine-induced memory retention in morphine-sensitized rats

In the present study, the effects of intra-ventral tegmental area (VTA) injections of morphine on memory retention of a one-trial passive avoidance task have been investigated in morphine-sensitized rats. Retrieval was examined 24h after training and used as memory retention. Sensitization was obtained by subcutaneous (s.c.) injections of morphine, once daily for 3 and 5 days free of the opioid before training. Post-training administration of the both systemic (2.5, 5 and 7.5mg/kg, s.c.) and intra-VTA (5 and 7.5microg/rat) of morphine, dose-dependently decreased memory retention. The response induced by post-training administration of intra-VTA morphine (7.5microg/rat) was significantly reversed in morphine-sensitized rats. The inhibition of morphine-induced amnesia in morphine-sensitized rats was decreased by once daily injections of naloxone (0.5, 1 and 2mg/kg, s.c.), SCH 23390 (0.025, 0.05 and 0.1mg/kg, s.c.) or sulpiride (25, 50 and 100mg/kg, s.c.), during the sensitization. The results suggest that VTA has an important role in morphine-induced amnesia and morphine sensitization affects this process through opioid and dopamine receptors.     

Effect of GABA receptor agonists or antagonists on morphine-induced Straub tail in mice

The effects of GABA receptor agents on Straub tail induced by morphine were investigated in mice. Subcutaneous injection of different doses of morphine (10-60 mg/kg) induced a dose-dependent Straub tail in mice. Maximum response was obtained with 40 mg/kg of the drug, 30 min after the drug administration. The morphine response was decreased by subcutaneous injection of naloxone (0.5-2 mg/kg). Intraperitoneal administration of different doses of baclofen (2-8 mg/kg) reduced Straub tail induced by morphine (40 mg/kg). The response of baclofen was decreased by Intraperitoneal injection of CGP35348 (150 mg/kg). CGP35348 by itself did not elicit any response. Different Intraperitoneally doses of muscimol (1-4 mg/kg) bicuculline (1-3 mg/kg), or picrotoxin (1-3 mg/kg) also reduced morphine effect. The effect of muscimol was not altered by bicuculline pretreatment. It is concluded that both GABAA and GABAB receptor activation reduced Straub tail induced by morphine.     

The NMDA receptor antagonist MK-801 prevents long-lasting non-associative morphine tolerance in the rat.

Several studies have demonstrated that the N-methyl-D-aspartate (NMDA) antagonist MK-801 attenuates the development of morphine tolerance and withdrawal. These studies employed repeated morphine injections to induce tolerance, a procedure in which learning has been suggested to play a significant role in tolerance development. MK-801 has been reported to block some types of learning, and it is unclear, therefore, whether the effect of MK-801 on tolerance development is due to its antagonism of associative (learning) or non-associative factors. Moreover, previous studies have tested the effects of MK-801 on morphine tolerance only up to 48 h after its induction; yet morphine tolerance can persist for many months, and it is not known whether MK-801 can block long-lasting tolerance. In the present study, therefore, we adopted a model of morphine tolerance in which the involvement of learning is minimized by using a single injection of morphine in a sustained-release preparation, and we tested tolerance for up to 56 days. In the first experiment, simultaneously administering MK-801 (0.2 mg/kg, s.c.) and morphine (60 mg/kg, s.c.), each in a sustained-release preparation, abolished tolerance that lasted at least 12 days. Analgesia was measured in the hot-plate test following a test dose of morphine (15 mg/kg, i.p.). In the second experiment, delivering MK-801 and morphine as before, the duration of morphine-induced catalepsy and analgesia was prolonged. Nevertheless, 24 h later one symptom of naloxone-precipitated withdrawal was significantly attenuated in these same animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cataleptic effect of neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice: modulation by serotonergic agents

The neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) induced catalepsy in mice is modified by dopaminergic, adenosinergic and GABAergic agents. In light of serotonergic agents being implicated in antipsychotic-induced catalepsy and their ability to increase brain neurosteroid content, the present study was undertaken to investigate the effect of various 5-HT agents on catalepsy induced by 3α,5α-THP in mice. Pretreatment with selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), 5-HT releaser, fenfluramine (10 mg/kg, i.p.), 5-HT_1A receptor agonist, 8-OH-DPAT (0.3 mg/kg, s.c.), 5-HT_1B/1C receptor agonist, TFMPP (3 mg/kg, i.p.), 5-HT_2A/1C receptor agonist, DOI (1.5 mg/kg, s.c.) and 5-HT₃ agonist, 2-methylserotonin (5 mg/kg, i.p.) potentiated the catalepsy induced by exogenous administration of 3α,5α-THP. Furthermore, FGIN 1–27, an MDR agonist that increases endogenous content of 3α,5α-THP although per se failed to exhibit any cataleptic effect but enhanced the cataleptic response in combination with these serotonergic agents. The potentiating action of 5-HT_1A, 5-HT_2A/1C or 5-HT₃ receptor agonist on 3α,5α-THP induced catalepsy was not blocked by prior administration of sub-effective dose (1 mg/kg, s.c.) of their respective receptor antagonists pindolol, ritanserin or ondansetron or by pretreatment with serotonergic neurotoxin 5,7-DHT (100 μg/mouse, i.c.v.). However this effect of different serotonergic agents was antagonized by the GABA_A receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3α-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). The 5-HT agents enhance neurosteroid-induced catalepsy by increasing GABAergic tone, likely as a consequence of increased brain content of 3α,5α-THP.     

Sensitization does not develop to cocaine-induced potentiation of the antinociceptive effect of morphine

Repeated intermittent cocaine administration produces a progressive increase (sensitization) in the motor stimulatory action of cocaine. Previous studies have shown that cocaine produces antinociception and also enhances the antinociceptive effect of opioid analgesics. The present study was designed to investigate if sensitization to these effects of cocaine develops. In the first part of the study, we determined if acute cocaine administration (3, 10, 30 mg/kg, intraperitoneal [i.p.]) increases the antinociceptive effect of morphine (5 mg/kg, subcutaneous [s.c.]) in rats using the hot plate test. Cocaine (30 mg/kg, i.p.), alone, produced a small but significant antinociceptive effect at 15 min after drug administration. When administered 15 min prior to morphine, cocaine dose-dependently enhanced the effect of morphine (5 mg/kg, s.c.) at the time (45 min post-cocaine) when cocaine by itself did not significantly change the hot plate latency. In the second part of the study, we examined if sensitization develops to cocaine-induced antinociception and its ability to increase the antinociceptive effect of morphine. Na?ve rats were injected with either saline or cocaine (30 mg/kg) once daily for 3 days and tested on the hot plate apparatus either 24 h or 1 wk after the last cocaine injection. Some of the rats from each group were also tested for motor stimulation induced by cocaine (5 mg/kg, i.p.) 24 h after the hot plate test to confirm that sensitization had occurred to the motor stimulatory action of the drug. Additional rats were treated with saline or cocaine for 3 days, but neither treated with morphine nor tested on the hot plate apparatus, and tested for behavioral sensitization to the motor stimulatory action of cocaine (5 mg/kg, i.p.) 24 h or 1 wk later. Sensitization developed to the motor stimulatory effect of cocaine in both groups, regardless of morphine treatment on the prior day. Sensitization also developed to the antinociceptive effect of cocaine 24 h but not 1 wk after the last cocaine injection. No sensitization was observed in the ability of cocaine to enhance the antinociceptive effect of morphine. Overall, our data suggest that while cocaine enhanced the antinociceptive effect of morphine, sensitization did not develop to this action of cocaine.