Persistent alterations in dendrites, spines, and dynorphinergic synapses in the nucleus accumbens shell of rats with neuroleptic-induced dyskinesias.
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Chronic treatment of humans or experimental animals with classical neuroleptic drugs can lead to abnormal, tardive movements that persist long after the drugs are withdrawn. A role in these neuroleptic-induced dyskinesias may be played by a structural change in the shell of the nucleus accumbens where the opioid peptide dynorphin is upregulated in treated rats that show vacuous chewing movements (VCMs). The shell of the nucleus accumbens normally contains a dense plexus of dynorphinergic fibers especially in its caudomedial part. After 27 weeks of haloperidol administration and 18 weeks of withdrawal, the immunoreactive labeling of this plexus is intensified when compared with that after vehicle treatment. In addition, medium spiny neurons here show a significant increase in spine density, dendritic branching, and numbers of terminal segments. In the VCM-positive animals, the dendritic surface area is reduced, and dynorphin-positive terminals contact more spines and form more asymmetrical specializations than do those in animals without the syndrome (VCM-negative and vehicle-treated groups). Persistent, neuroleptic-induced oral dyskinesias could therefore be caused by incontrovertible alterations, involving terminal remodeling or sprouting, to the synaptic connectivity of the accumbal shell. (+info)
"Early" and "late" effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits.
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Both dopamine (DA) agonists and NMDA antagonists produce prepulse inhibition (PPI) deficits in rats that model PPI deficits in schizophrenia patients. While DA agonist effects on PPI are reversed by acute treatment with either "typical" high-potency D2 DA antagonists or "atypical" antipsychotics, PPI deficits produced by phencyclidine (PCP) are preferentially reversed by acute treatment with "atypical" antipsychotics. Acute effects of antipsychotics may not accurately model the more clinically relevant effects of these drugs that emerge after several weeks of continuous treatment. In the present study, sustained treatment with haloperidol via subcutaneous minipumps blocked the PPI-disruptive effects of apomorphine and attenuated the PCP-induced disruption of PPI. Restoration of PPI in apomorphine-treated rats was evident within the first week of sustained haloperidol administration. A partial reversal of PCP effects on PPI did not develop until the second week of sustained haloperidol treatment, followed a fluctuating course, but remained significant into the seventh week of sustained haloperidol administration. The delayed emergence of anti-PCP effects of haloperidol suggests that the brain substrates responsible for the DAergic and NMDA regulation of PPI are differentially sensitive to acute and chronic effects of antipsychotics. (+info)
Dopamine D(2) receptor blockade by haloperidol. (3)H-raclopride reveals much higher occupancy than EEDQ.
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Two techniques are commonly used to measure antipsychotic induced dopamine D(2) occupancy in animals: competition with a reversible radioligand (3H-raclopride) or with an irreversible receptor inactivator (EEDQ). While both of these techniques have been used in the past, there is no direct and systematic comparison. In the first direct comparison of these two methods we find that the dose of haloperidol required for blocking 50% of the dopamine D(2) receptors was 0.02 mg/kg/sc (95% CI 0.018-0.022 mg/kg) as measured using 3H-raclopride method; but was significantly higher with the EEDQ method 0.14 mg/kg/s.c. (95% CI 0.048-0.224 mg/kg). The 3H-raclopride method showed significantly lesser variance (p = 0.02) despite the higher sensitivity. This seven-fold difference in the sensitivity of the two techniques to measure antipsychotic-induced D(2) occupancy explains discrepancies in the previous studies which have used these two methods and also suggest that for future studies the 3H-raclopride method is a more sensitive and, likely, a more valid reflector of true receptor occupancy. (+info)
Characterization of inhibition by risperidone of the inwardly rectifying K(+) current in pituitary GH(3) cells.
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The effects of risperidone on ionic currents in rat pituitary GH(3) cells were investigated with the aid of the patch-clamp technique. Hyperpolarization-activated K(+) currents in GH(3) cells bathed in high-K(+) Ca(2+)-free solution were studied to determine the effect of risperidone and other related compounds on the inwardly rectifying K(+) current (I(K(IR))). Risperidone (0.1-10 microM) suppressed the amplitude of I(K(IR)) in a concentration-dependent manner. The IC(50) value for the risperidone-induced inhibition of I(K(IR)) was 1 microM. Risperidone (3 microM) was found to slow the rate of activation. An increase in current deactivation by the presence of risperidone was also observed. Haloperidol (10 microM) and thioridazine (10 microM) inhibited the amplitude of I(K(IR)) effectively, and clozapine slightly suppressed it; however, metoclopramide (10 microM) had no effect on it. Risperidone (10 microM) had no effect on voltage-dependent K(+) and L-type Ca(2+) currents. However, in the inside-out configuration, risperidone (10 microM) did not alter the single-channel conductance, but reduced the activity of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels. Under the current-clamp mode, risperidone (3 microM) depolarized the membrane potential and increased the firing rate. With the aid of the spectral analysis, cells that exhibited an irregular firing pattern were also converted to those displaying a regular firing pattern after addition of risperidone (3 microM). The present study provides evidence that risperidone, in addition to the blockade of dopamine receptors, can produce a depressant effect on I(K(IR)) and BK(Ca) channels, and implies that the blockade of these ionic currents by risperidone may affect membrane excitability and prolactin secretion in GH(3) cells. (+info)
Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions.
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The dopamine D2 receptor (D2) system has been implicated in several neurological and psychiatric disorders, such as schizophrenia and Parkinson's disease. There are two isoforms of the D2 receptor: the long form (D2L) and the short form (D2S). The two isoforms are generated by alternative splicing of the same gene and differ only by 29 amino acids in their protein structures. Little is known about the distinct functions of either D2 isoform, primarily because selective pharmacological agents are not available. We generated D2L receptor-deficient (D2L-/-) mice by making a subtle mutation in the D2 gene. D2L-/- mice (which still express functional D2S) displayed reduced levels of locomotion and rearing behavior. Interestingly, haloperidol produced significantly less catalepsy and inhibition of locomotor activity in D2L-/- mice. These findings suggest that D2L and D2S may contribute differentially to the regulation of certain motor functions and to the induction of the extrapyramidal side effects associated with the use of typical antipsychotic drugs (e.g., haloperidol). Quinpirole induced a similar initial suppression of locomotor activity in both D2L-/- and wild-type mice. In addition, the D2S receptor in the mutant mice functioned approximately equally well as did D2L as an impulse-modulating autoreceptor. This suggests that the functions of these two isoforms are not dependent on the formation of receptor heterodimers. Our findings may provide novel information for potentially developing improved antipsychotic drugs. (+info)
NMDA and glutamate evoke excitotoxicity at distinct cellular locations in rat cortical neurons in vitro.
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The development of cortical neurons in vivo and in vitro is accompanied by alterations in NMDA receptor subunit expression and concomitant modifications in the pharmacological profile of NMDA-activated ionic currents. For example, we observed that with decreasing NR2B/NR2A subunit expression ratio, the block of NMDA receptor-mediated whole-cell responses by the NR2B-selective antagonist haloperidol was also decreased. In mature cultures (>22 d in vitro), however, NMDA responses obtained from excised nucleated macropatches, which comprised a large portion of the soma, remained strongly antagonized by haloperidol. These results suggest that in more mature neurons NR1/NR2B receptors appear to be preferentially expressed in the cell body. As predicted from the whole-cell recording pharmacological profile, NMDA-induced toxicity was largely unaffected by haloperidol in mature cultures. However, haloperidol effectively blocked glutamate toxicity in the same cultures, suggesting that the neurotoxic actions of this amino acid were mostly due to the activation of somatic NMDA receptors. In experiments in which the potency of glutamate toxicity was increased by the transport inhibitor l-trans-pyrrolidine-2,4-dicarboxylic acid, the neuroprotective effects of haloperidol were significantly diminished. This was likely because of the fact that glutamate, now toxic at much lower concentrations, was able to reach and activate dendritic receptors under these conditions. These results strongly argue that exogenous glutamate and NMDA normally induce excitotoxicity at distinct cellular locations in mature mixed neuronal cultures and that NR1/NR2B receptors remain an important component in the expression of glutamate, but not NMDA-induced excitotoxicity. (+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)