Fatty acid derivatives of clozapine: prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat.
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Stable amides of clozapine derived from fatty acids prominent in cerebral tissue might enhance the central activity of clozapine and reduce its exposure to peripheral tissues. Such derivatives might enhance the safety of this unique drug, which is the only agent with securely established superior antipsychotic effectiveness, but with a risk of potentially lethal systemic toxicity. Amide derivatives of clozapine were prepared from structurally varied fatty acid chlorides and evaluated for ability to inhibit behavioral arousal in rat induced by dopamine agonist apomorphine and to induce catalepsy. Their duration-of-action and potency were compared to free clozapine, and concentrations of clozapine were assayed in brain and blood. Selected agents were also evaluated for affinity at dopamine receptors and other potential drug-target sites. Clozapine-N-amides of linoleic, myristic, oleic, and palmitic acids had moderate initial central depressant activity but by 6 h, failed to inhibit arousal induced by apomorphine. However, the docosahexaenoic acid (DHA) derivative was orally bioavailable, 10-times more potent (ED(50) 5.0 micromol/kg) than clozapine itself, and very long-acting (>/= 24 h) against apomorphine, and did not induce catalepsy. DHA itself was inactive behaviorally. Clozapine showed expected dopamine receptor affinities, but DHA-clozapine was inactive at these and other potential target sites. After systemic administration of DHA-clozapine, serum levels of free clozapine were very low, and brain concentrations somewhat lower than after administering clozapine. DHA-clozapine is a long-acting central depressant with powerful and prolonged antidopaminergic activity after oral administration or injection without inducing catalepsy, and it markedly reduced peripheral exposure to free clozapine. It lacked the receptor-affinities shown by clozapine, suggesting that DHA-clozapine may be a precursor of free, pharmacologically active clozapine. Such agents may represent potential antipsychotic drugs with improved central/peripheral distribution, and possibly enhanced safety. (+info)
Neurotensin gene expression and behavioral responses following administration of psychostimulants and antipsychotic drugs in dopamine D(3) receptor deficient mice.
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Exposure to psychostimulants and antipsychotics increases neurotensin (NT) gene expression in the striatum and nucleus accumbens. To investigate the contribution of D(3) receptors to these effects we used mice with targeted disruption of the D(3) receptor gene. Basal NT mRNA expression was similar in D(3) receptor mutant mice and wild-type animals. Acute administration of haloperidol increased NT gene expression in the striatum in D(3)+/+, D(3)+/- and D(3)-/- mice. Similarly, acute cocaine and amphetamine induced NT mRNA expression in the nucleus accumbens shell and olfactory tubercle to a comparable extent in D(3) mutants and wild-type mice. Daily injection of cocaine for seven days increased NT mRNA in a restricted population of neurons in the dorsomedial caudal striatum of D(3)+/+ mice, but not in D(3)-/- and D(3)+/- animals. No differences were observed between D(3) receptor mutant mice and wild-type littermates in the locomotor activity and stereotyped behaviors induced by repeated cocaine administration. These findings demonstrate that dopamine D(3) receptors are not necessary for the acute NT mRNA response to drugs of abuse and antipsychotics but appear to play a role in the regulation of NT gene induction in striatal neurons after repeated cocaine. In addition, our results indicate that the acute locomotor response to cocaine and development of psychostimulant-induced behavioral sensitization do not require functional D(3) receptors. (+info)
Haloperidol-induced catalepsy is influenced by calcium channel antagonists.
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The effect of pretreatment of some voltage-dependent calcium channel antagonists was studied on haloperidol-induced catalepsy in male Wistar rats. Cataleptogenic effect of haloperidol (0.25 mg/kg, i.p.) was enhanced dose-dependently by nitrendipine (5, 10 and 20 mg/kg, i.p.) and the highest dose of nimodipine (20 mg/kg, i.p.). Neither verapamil (10 and 20 mg/kg, i.p.) nor diltiazem (10 and 20 mg/kg, i.p.) influenced the score of haloperidol-induced catalepsy in rats. These results suggest the involvement of calcium-dependent mechanisms in the generation of haloperidol-induced catalepsy. The possible involvement of dopaminergic mechanisms and modification by calcium channel antagonists are discussed. (+info)
Effects of amantadine on modification of dopamine dependent behaviours by molindone.
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Amantadine, a dopamine agonist is reported to act by releasing dopamine from the dopaminergic nerve terminals as an anti-Parkinsonian drug. In the present behavioural study in the rat, molindone-induced catalepsy and ptosis, which are dopamine dependent-behaviors are reversed by amantadine. Amantadine has also revered molindone-induced inhibition of traction response in mice. Our study indicates that amantadine, like other DA agonists, e.g. amphetamine and apomorphine can antagonize or even reverse the neuroleptic induced dopaminergic behaviors. (+info)
The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice.
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The A(2A)R is largely coexpressed with D(2)Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A(2A)R antagonizes D(2)R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A(2A)R-D(2)R interaction. However, whether the D(2)R is required for the A(2A)R to exert its neural function is an open question. In this study, we examined the role of D(2)Rs in A(2A)R-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A(2A)Rs or D(2)Rs or both). Behavioral analysis shows that the A(2A)R agonist 2-4-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D(2) KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A(2A)R antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D(2)R, although the stimulation was significantly attenuated. At the cellular level, A(2A)R inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D(2)R deficiency. Consistent with the D(2) KO phenotype, A(2A)R inactivation partially reversed both acute D(2)R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A(2A)Rs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D(2)Rs. Thus, A(2A)R-mediated neural functions are partially independent of D(2)Rs. Moreover, endogenous adenosine acting at striatal A(2A)Rs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D(2)R neurotransmission. (+info)
Comparison of 12-chloroscoulerine enantiomers on animal behavior to dopamine receptors.
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AIM: To compare the pharmacological characteristics of 12-chloroscoulerine (CSL) enantiomers to dopamine (DA) receptors. METHODS: Radioligand receptor binding assay with calf striatum and behavioral tests of mice or rats were used. RESULTS: In the competitive binding assay, the affinities (Ki) of l-CSL to D1 and D2 receptors were 5.7 nmol.L-1, while those of d-CSL for D1 and D2 receptors were 135 and 9150 nmol.L-1, respectively. The Ki of dl-CSL to D1 and D2 receptors were 8.9 and 9.6 nmol.L-1, respectively, which were slightly weaker than that of l-CSL. In the behavioral experiments, CSL enantiomers 5-60 mg.kg-1 antagonized the stereotypy induced by apomorphine in rats, and 5-150 mg.kg-1 produced catalepsy. The enantiomers 10-60 mg.kg-1 reduced the mice jumping behavior induced by amphetamine + levodopa. l-CSL 10-80 mg.kg-1 antagonized the spontaneous locomotor activity of normal or amphetamine-treated mice. CONCLUSION: CSL enantiomers are antagonists to DA receptors: l-CSL > dl-CSL >> d-CSL. (+info)
Behavioral characteristics of olanzapine: an atypical neuroleptic.
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AIM: To assess the atypical neuroleptic properties of a novel antipsychotic agent, olanzapine (Ola). METHODS: The action of Ola on apomorpine (Apo)-induced climbing behavior, 5-hydroxy-dl-tryptophan (5-HTP)-induced head twitch response, oxotremorine-induced tremor, and the conditioned avoidance behavior in mice were observed. The catalepsy of mice induced by Ola was also investigated. The single unit extracellular recording technique was used to compare the spontaneous firing rate changes of dopamine (DA) cells in the ventral tegmental area (VTA, A10) and the substantia nigra pars compact (SNC, A9) in rats after i.v. Ola. RESULTS: Ola antagonized the climbing behavior (ED50 1.8 mg.kg-1, p.o.), head twitch behavior (ED50 0.3 mg.kg-1, p.o.), and tremor (ED50 5.2 mg.kg-1, p.o.) in mice. In a conditioned avoidance paradigm in mice, Ola inhibited the avoidance response with an ED50 of 2.72 mg.kg-1 (p.o.). However, the catalepsy was not induced by Ola in mice even under a very high dose of 100 mg.kg-1 (p.o.). Ola selectively increased the firing rate of DA cells in the VTA, but failed to affect that of SNC DA cells. CONCLUSION: Ola distinguished itself from the typical neuroleptic (e.g. haloperidol, Hal) and took resemblance of the atypical neuroleptic (e.g. clozapine, Clo) in 3 aspects: 1) the multiple receptor pharmacodynamics involving D1/D2, 5-HT2 and M-ACh receptors; 2) dose-response separation between the block of conditioned avoidance response and catalepsy induction; and 3) the specificity of action sites of firing rates upon acute drug challenge. (+info)
Endomorphin-1: induction of motor behavior and lack of receptor desensitization.
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The endomorphins are recently discovered endogenous agonists for the mu-opioid receptor (Zadina et al., 1997). Endomorphins produce analgesia; however, their role in other brain functions has not been elucidated. We have investigated the behavioral effects of endomorphin-1 in the globus pallidus, a brain region that is rich in mu-opioid receptors and involved in motor control. Bilateral administration of endomorphin-1 in the globus pallidus of rats induced orofacial dyskinesia. This effect was dose-dependent and at the highest dose tested (18 pmol per side) was sustained during the 60 min of observation, indicating that endomorphin-1 does not induce rapid desensitization of this motor response. In agreement with a lack of desensitization of mu-opioid receptors, 3 hr of continuous exposure of the cloned mu receptor to endomorphin-1 did not diminish the subsequent ability of the agonist to inhibit adenylate cyclase activity in cells expressing the cloned mu-opioid receptor. Confirming the involvement of mu-opioid receptors, the behavioral effect of endomorphin-1 in the globus pallidus was blocked by the opioid antagonist naloxone and the mu-selective peptide antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7) amide (CTOP). Furthermore, the selective mu receptor agonist [d-Ala(2)-N-Me-Phe(4)-Glycol(5)]-enkephalin (DAMGO) also stimulated orofacial dyskinesia when infused into the globus pallidus, albeit transiently. Our findings suggest that endogenous mu agonists may play a role in hyperkinetic movement disorders by inducing sustained activation of pallidal opioid receptors. (+info)