Effects of prolyl-leucyl-glycinamide and cyclo(leucyl-glycine) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to rats

The effects of melanotropin release-inhibiting factor, a tripeptide (Pro-Leu-Gly-NH₂) derived from the hypothalamus, and its enzymatically stable analog, cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to male Sprague-Dawley rats was determined. Oral administration of haloperidol (1.5 mg/kg per day) for 21 days induced supersensitivity of dopamine receptors as shown by enhanced locomotor activity in response to apomorphine, and an increase in the number of binding sites for [³H]spiroperidol in the striatum. Subcutaneous administration of Pro-Leu-Gly-NH₂ or cyclo(Leu-Gly) in doses of 2 mg/kg per day, given prior to the injection of haloperidol, inhibited both the enhanced response to apormorphine as well as the increase in the number of binding sites for [³H]spiroperidol in the striatum. Chronic administration of either of the peptides alone did not modify either the apomorphine-induced response or the binding of [³H]spiroperidol in the striatum. These studies suggest that the hypothalamic peptide, Pro-Leu-Gly-NH₂ and its long-acting analog, cyclo (Leu-Gly) can prevent the development of both behavioral and biochemical supersensitivity of dopamine receptors in brain induced by neuroleptic drugs and that these peptides may be useful in preventing the development of neuroleptic-induced tardive dyskinesia.     

Difference in catalepsy response in inbred rats during chronic haloperidol treatment is not predictive of the intensity of behavioral hypersensitivity which subsequently develops

An animal model was utilized to explore the observed clinical association between a history of significant neuroleptic-induced parkinsonism and an increased incidence for the subsequent development of tardive dyskinesia. Catalepsy-sensitive Fisher rats and catalepsy-resistant Brown Norway rats were treated for 14 days with haloperidol at a dose of either 1 mg/kg or 5 mg/kg daily. Following a 7-day drug withdrawal period, rats were tested for behavioral hypersensitivity to acute challenge with apomorphine and then striate were assayed for ³H-spiroperidol receptor binding. Despite significant interstrain difference in catalepsy response to either neuroleptic dose, Brown Norway rats treated with 5 mg/kg developed behavioral hypersensitivity and D-2 receptor supersensitivity equivalent to that of the similarly treated Fisher rats. Catalepsy, a possible rat analog for neuroleptic-induced parkinsonism, therefore did not predict the intensity of those subsequent behavioral and receptor changes considered to result from chronic antagonism of striatal dopamine receptors and to possibly underlie tardive dyskinesia. Further studies are required to elucidate the less than obvious relationship between extrapyramidal behavioral effects of chronic neuroleptic treatment.     

Chronic molindone treatment: Relative inability to elicit dopamine receptor supersensitivity in rats

Chronic treatment of rats with the antipsychotic drug molindone (2.5 mg/kg) did not elicit behavioral supersensitivity to apomorphine (AP) (0.25 mg/kg) or increased striatal ³H-spiroperidol binding, whereas treatment with haloperidol (0.5–1.0 mg/kg) produced manifestations of dopaminergic supersensitivity in both paradigms. Chronic treatment with a high dose of molindone (20 mg/kg) elicited a small, but significant increase in behavioral sensitivity to AP (57%) which was, however, significantly less than that produced by 1 mg/kg haloperidol (126%, P<0.01). Apparent tolerance to elevation of striatal and frontal cortical 3,4-dihydroxyphenylacetic acid (DOPAC) levels was obtained with chronic molindone treatment (5 or 20 mg/kg). None of the molindone doses used (2.5–50 mg/kg) increased striatal dopamine receptor binding. Scatchard analyses revealed no change in either maximal binding capacity (B _max) or dissociation constant (K _D). A significant (P<0.001) correlation of receptor binding acitivty and stereotypy score was obtained for haloperidol-, but not molindone-treated rats. These results with molindone in an animal model of tardive dyskinesia suggest that this drug may have a lower potential for eliciting this disorder in humans.     

Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0.1 mg/kg i.p.) and clozapine (10 mg/kg i.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kg i.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25–1 mg/kg i.p.) of rats, sensitized by a prior 10-day apomorphine treatment, did not reverse the established aggressive behaviour. The coadministration of apomorphine and cholecystokinin (CCK)-A or -B antagonists, devazepide or L-365,260 (0.01–2.5 mg/kg i.p.) respectively, neither affected development of apomorphine-induced aggressive behaviour nor intensity of aggressiveness in the sensitized rats.In binding studies neither density nor affinity of striatal dopamine D₂ receptors was changed by acute or chronic apomorphine treatment. The number of [³H]pCCK-8 binding sites in the frontal cortex increased already after a single injection of apomorphine. After 10-day administration of apomorphine, a significant upregulation of [³H]pCCK-8 binding sites occurred in the frontal cortex and striatum, but a downregulation was observed in the hippocampus. A challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day of experiment, normalized the upregulated CCK receptors in the frontal cortex and striatum. Acute apomorphine did not change [³H]-MK-801 binding in the rat brain. However, in rats treated for 10 days with apomorphine, the number of NMDA-gated channels in open state was increased in the frontal cortex and hippocampus. In these rats, a challenge dose of apomorphine (0.5 mg/kg s.c.) normalized also the in reased number of [³H]-MK-801 binding sites in the frontal cortex.In conclusion, repeated treatment with apomorphine seems to modify the function of dopamine D₂ receptors without affecting their number or affinity. The increased number of NMDA-gated channels in open state appears to be related to this alteration of dopamine D₂ receptors. The increased density of [³H]pCCK-8 binding sites in the frontal cortex may reflect anxiety and fear due to chronic exposure of rats to apomorphine.     

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol,sulpiride or clozapine in rats

Rats received therapeutically equivalent doses of either haloperidol (1.7–1.9 mg/kg/day), sulpiride (112–116 mg/kg/day) or clozapine (30–35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125–0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine.B_max values for striatal ³H-spiperione binding were erevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in B_max for striatal ³H-piperone binding.B_max values for striatal ³H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in B_max for ³H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in B_max for ³H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine.On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals.Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.     

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat

Administration of haloperidol (1.4–1.6 mg/kg/day) for up to 12 months or sulpiride (102–109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25–2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, sterotypy induced by high doses of apomorphine (0.5–1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats.B_max for specific striatal ³H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. B_max for ³H-NPA binding was elevated only after 12 months of both haloperidol and sulpiride treatment. B_max for ³H-piflutixol binding was not alfered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride.Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.     

Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity

Administration of sulpiride (2 × 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites (B_max) for [³H]spiperone, [³H]N,n-propylnorapomorphine and [³H]sulpiride. Neither drug altered the dissociation constant (K_D) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.     

The Involvement of Sigma and Phencyclidine Receptors in the Action of Antipsychotic Drugs

Abstract: An atypical antipsychotic drug clozapine and a selective sigma antagonist BMY 14802 were significantly less effective in the behavioural experiments (against apomorphine, d-amphetamine and MK-801), as well in the radioligand binding studies against ³H-spiperone (dopamine₂-receptors) and ³H-haloperidol (sigma receptors) in the rat brain, as compared to a typical antipsychotic compound haloperidol. Contrary to haloperidol and BMY 14802, clozapine was a relatively selective antagonist of MK-801-induced motor excitation in the mouse. A nearly 3-fold lower dose of clozapine was needed to block the effect of MK-801 (6.4 μmol/kg) as compared to the action of amphetamine (17 μmol/kg). Haloperidol and clozapine, but not BMY 14802, antagonized apomorphine-induced aggressiveness in the rat. After long-term treatment (for 15 days) with BMY 14802 (10 mg/kg daily), haloperidol (0.5 mg/kg daily) and clozapine (10 mg/kg daily) the motor depressant effect of apomorphine (0.15 mg/kg) was reversed. Chronic haloperidol treatment, but not administration of BMY 14802 and clozapine, increased the number of dopamine₂-receptors in the rat brain. BMY 14802 caused upregulation of sigma receptors in frontal cortex, whereas haloperidol induced the opposite change in cerebellum. Repeated treatment with clozapine significantly augmented the motor stimulating effect of MK-801 in rats. Simultaneously with a behavioural change the density of ³H-TCP binding sites in the rat forebrain was elevated after long-term treatment with clozapine, probably indicating the involvement of PCP binding sites at NMDA channel in the action of clozapine.     

Inhibition of neuroleptic-induced dopamine receptor supersensitivity by cyclo (Leu-Gly)

Behavioral supersensitivity of dopamine receptors was induced in mice by chronic administration of haloperidol (1 mg/kg/day for 21 days) and its subsequent withdrawal for 48 hr. This was evidenced by enhanced spontaneous locomotor activity and hypothermic responses to a dopamine agonist, apomorphine. Concurrent administration of cyclo (Leu-Gly), the enzymatically resistant diketopiperazine, an analog of melantropin release inhibiting factor, blocked haloperidol-induced dopamine receptor supersensitivity as evidenced by the blockade of apomorphine induced responses. Since many studies have linked the development of neuroleptic induced tardive dyskinesias with enhanced sensitivity of brain dopamine receptors, and the latter was blocked by cyclo (Leu-Gly), this agent may be of value in preventing the development of symptoms of neuroleptic-induced tardive dyskinesias.     

Prolonged antidopaminergic actions of single doses of butyrophenones in the rat

Rats were treated once with doses of haloperidol or of droperidol below and above the acute ID₅₀ vs the dopamine agonist apomorphine; they were later challenged with an acute dose of apomorphine (0.3mg/kg, SC) and rated for stereotyped behavioral responses. The two neuroleptics were similar in acute anti-apomorphine potency (ID₅₀=0.12 and 0.18mg/kg for haloperidol and droperidol, respectively). The antidopaminergic effects of droperidol persisted for nearly 1 week and those of haloperidol lasted for 20–40 days, depending on the dose given. The computed half-time of disappearance of their antidopaminergic effects was 7.6±1.0 days and 0.59±0.17 days for haloperidol and droperidol, respectively, following a dose of 0.3 mg/kg, and these indices of duration of action did not vary significantly at doses between 0.1 and 1.0mg/kg. Haloperidol reduced the acute entry of ³H-apomorphine into brain by 21.5% 1 week later. Treatment with apomorphine alone just prior to haloperidol (both at 0.3 mg/kg) prevented the prolonged antidopaminergic effects of the neuroleptic evaluated 1 week later. These results indicate that some neuroleptics may have very prolonged activity or retention in tissue at sites of action, even after moderate, single doses. Caution is recommended in the interpretation of studies which assume neuroleptic-free conditions of subjects previously exposed to a neuroleptic agent.     

Behavioural and biochemical alterations in the function of dopamine receptors following repeated administration of l-DOPA to rats

Rats received l-DOPA (40 or 200 mg/kg, i.p.) for 14 days, followed by a 3 day withdrawal period. Spontaneous locomotor activity was not altered by repeated administration of l-DOPA. Rats treated with l-DOPA (200 mg/kg) showed identical locomotor hypoactivity in response to small doses of apomorphine when compared to saline-treated control animals. However, hyperactivity induced by large doses of apomorphine was reduced by prior treatment with l-DOPA (200 mg/kg). The smaller dose of l-DOPA (40 mg/kg) did not alter the locomotion induced by apomorphine. Stereotyped behaviour induced by apomorphine was enhanced by prior treatment with both 40 and 200 mg/kg of l-DOPA. The treatment regimes with l-DOPA had no effect on the concentrations of apomorphine in the striatum.Administration of l-DOPA (40 or 200 mg/kg) followed by withdrawal for 3 days, had no effect on the concentrations of dopamine, homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. The B_max and K_D for the binding of [³H]spiperone. $\text{[}{}^3\text{H}\text{]N,n-}\text{propylnorapomorphme}$ (NPA) and [³H]piflutixol in the striatum was not altered by drug treatment. Similarly, the formation of dopaminestimulated cyclic AMP in homogenates of striatum was unaltered by repeated administration of l-DOPA.Repeated administration of l-DOPA for 14 days in the rat appears to result in altered behaviour mediated by dopamine in the absence of any apparent change in the function of dopamine receptors in the striatum.     

Presynaptic dopamine receptors: Insensitivity to kainic acid and the development of supersensitivity following chronic haloperidol

Summary The effects of kainic acid lesions and chronic haloperidol treatment on rat striatal dopaminergic presynaptic receptors were studied. Following the -butyrolactone-induced inhibition of dopaminergic impulse flow, and after dopa decarboxylase inhibition, dopa accumulation and its reversal by dopamine agonists was measured in vivo.³H-apomorphine (a dopamine receptor ligand with purported presynaptic specificity) was used for in vitro binding experiments. Presynaptic dopamine receptors, as assessed by both methods, were unaffected by intrastriatal kainic acid injection 5–6 days before sacrifice. Seven days after termination of chronic haloperidol treatment (28 days, 0.5 mg/kg/day s.c.) both an increased apomorphine response using the dopa accumulation method and an increase in³H-apomorphine binding were observed, indicating the development of presynaptic dopamine receptor supersensitivity.     

Effects of Dopamine D1 and D2 Receptor Agonists and Antagonists on Seizures Induced by Chemoconvulsants in Mice

Abstract: Dopamine agonists and antagonists with different affinities for D₁ and D₂ receptors in the brain were assessed for their ability to affect clonic seizures in mice induced by chemoconvulsants. The dopamine D₂ antagonists remoxipride (5-20 mg/kg) and raclopride (5-20 mg/kg), haloperidol (2.5 and 5 mg/kg) and the D₁ antagonist SCH 23390 (0.3, 1.5 mg/kg) did not markedly modify seizures induced by pentylenetetrazole, picrotoxin or bicuculline. The dopamine D₂ agonist quinpirole only weakly blocked the action of pentylenetetrazole while the D₁ agonist SKF 38393 (1-10 mg/kg subcutaneously) caused a dose-dependent blockade of pentylenetetrazole-induced seizures. The D₁/D₂ agonist apomorphine given at “postsynaptic” doses (1 and 2 mg/kg) blocked pentylenetetrazole-induced seizures. The protection afforded by apomorphine against pentylenetetrazole seizures appeared to be associated with its activation of both D₁ and D₂ receptors since both raclopride and SCH 23390 blocked the action of apomorphine. Reserpine and the two partial dopamine autoreceptor agonists, (—)3-PPP and HW-165, at high (non-autoreceptor selective) doses induced seizures in animals treated with the subconvulsive dose of pentylenetetrazole. The overall results suggest that dopamine receptor blockade has a minor or limited effect on seizures caused by GABA inhibition. The anticonvulsant effect of dopamine agonists such as apomorphine appears to be mediated by postsynaptic dopamine D₁ and D₂ receptors. Stimulation of dopamine D₁ receptors can reduce seizure activity caused by GABA receptor blockade possibly by facilitation of GABA transmission in the striatum and substantia nigra.     

Scopolamine modulates apomorphine-induced behavior in rats treated with haloperidol or SCH 23390

In acute experiments, scopolamine (1.0 mg/kg) potentiated apomorphine stereotypy and inhibited the antistereotypic effect of both haloperidol (0.5 mg/kg) and SCH 23390 (0.2 mg/kg). Daily administration of either haloperidol (0.5 mg/kg) or SCH 23390 (0.2 mg/kg) for 3 weeks produced enhanced stereotypic responses to apomorphine. Co-administration of scopolamine (1.0 mg/kg) with haloperidol or SCH 23390 significantly reduced the behavioral supersensitivity produced by haloperidol or SCH 23390 alone. It is suggested that both D-1 and D-2 dopamine receptors are linked to a cholinergic mechanism.     

Effects of intermittent haloperidol treatment on dopamine receptor sensitivity in guinea pigs

Intermittent haloperidol treatment in guinea pigs caused an increase in the behavioral response to apomorphine and an increase in ³H-spiroperidol binding in the striatum to the same degree as continual haloperidol treatment. These results do not support the claim that drug holidays can reduce the incidence of tardive dyskinesia.     

Dopamine receptor sensitivity after chronic dopamine agonists

Several previous reports have demonstrated that chronic administration of both directly and indirectly acting dopamine agonists produces a supersensitive behavioral response to challenge doses of dopamine agonists when compared to the responses induced by acute administration of these drugs. That is, a given dose of a dopamine agonist will produce a greater response after chronic dopamine agonist treatment than is observed upon acute administration of that dose. A similar behavioral phenomenon resulting from chronic administration of dopamine antagonists has been suggested to be due to an increase in the number of dopamine receptors present in relevant brain areas. The same hypothesis has been put forward for the hypersensitivity induced by chronic dopamine agonist administration. The present study was designed to investigate the effect of chronic administration of high doses of both direct and indirect dopamine agonists on the dopamine receptors labeled by ³H-spiroperidol. Groups of animals (CD-1 mice) were sacrificed 1, 3 and 5 days following the last chronic injection. Striatal tissue from these mice was incubated with ³H-spiroperidol and dopamine receptor binding evaluated. Affinity of the receptors for the ligand was unaltered by treatments. The receptors labeled by ³H-spiroperidol showed no significant differences in number following the chronic administration of high doses of apomorphine (30 mg/kg). The B _max was significantly decreased at only one time period following chronic administration of dextroamphetamine (4 mg/kg); however, these was a dramatic 30% reduction in the B _max in striatal tissue from those mice treated with N-n-propylnorapomorphine. These results suggest that the hypersensitive behavioral response in mice following chronic administration of direct and indirect acting dopamine agonists is not due to an increase in the number of dopamine receptors in the striatum which are labeled by ³H-spiroperidol.     

Altered sensitivity to d-methylamphetamine,apomorphine, and haloperidol in rhesus monkeys depleted of caudate dopamine by repeated administration of d-methylamphetamine

The long-term neurochemical and behavioral effects of repeated d-methylamphetamine (d-MA) administration were investigated using four male rhesus monkeys trained to lever-press for food on a DRL-40 s schedule of reinforcement. Dose-response curves for d-MA (0.0625–2.0 mg/kg), apomorphine (0.025–0.4 mg/kg), and haloperidol (0.005–0.04 mg/kg) on responding showed that repeated d-MA administration (0.5–16.0 mg/kg/day) decreased sensitivity to d-MA and to apomorphine but increased sensitivity to haloperidol. At 3–6 months after the last injection of d-MA, a 48.1% decrease in caudate dopamine (DA) was observed, with the frontal cortex, midbrain, and ponsmedulla showing no significant change. A trend toward increasing concentrations of norepinephrine was noted in the same brain areas, but only in the frontal cortex did this change reach significance. Specific binding of 3H-spiroperidol to caudate membrane preparations was not changed, while the V _max of the caudate DA re-uptake process declined 32%, with no change in K _m. These results suggest that exposure of DA neurons in the caudate nucleus to high concentrations of d-MA can lead to nerve terminal degeneration.     

Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics

Quantitative in vitro receptor autoradiography was used to examine changes in three ionotropic glutamate receptor subtypes using ³H-MK801 (NMDA-R antagonist), ³H-CNQX (AMPA-R antagonist) and ³H-kainic acid (kainate-R agonist) following subchronic (28 days) and chronic (8 months) treatment of rats with a typical antipsychotic, haloperidol (1.5 mg/kg per day), atypical antipsychotic, clozapine (25 mg/kg per day), the dopamine D₂/D₃ receptor antagonist, raclopride (10 mg/kg per day), and the dopamine D1 (D₁/D₅) receptor antagonist SCH23390 (0.5 mg/kg per day). Subchronic and chronic drug treatments did not significantly alter ³H-CNQX or ³H-kainate binding in any of brain regions examined. Subchronic SCH23390 treatment elevated ³H-MK801 binding in the hippocampal formation with significant increases in the CA₁ and dentate gyrus, suggesting a specific role for dopamine D1 receptors in the regulation of hippocampal NMDA receptor function. Subchronic, but not chronic, haloperidol and clozapine treatment significantly reduced ³H-MK801 binding in the medial prefrontal cortex. This suggests that typical and atypical antipsychotics may exert some of their clinical effects by affecting NMDA receptors in the medial prefrontal cortex. Both subchronic and chronic clozapine treatment decreased ³H-MK801 binding in the caudate putamen. The minimal extrapyramidal side effects produced by clozapine may result, in part, from the reduction in NMDA receptor binding in the caudate putamen. Received: 29 February 1996 /Final version: 15 July 1996     

Effects of the antidepressant trazodone,a 5-HT<Subscript>2A/2C</Subscript> receptor antagonist,on dopamine-dependent behaviors in rats

Rationale 5-Hydroxytryptamine, via stimulation of 5-HT_2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT_2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT_2A/2C receptor antagonist.Objectives To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system.Methods The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced oral stereotypies, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats.Results Trazodone at 2.5–20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies.Conclusions Our results indicate that trazodone at 2.5–20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT_2A and 5-HT_2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT_2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.     

Lithium dissociates haloperidol-induced behavioral supersensitivity from reduced dopac increase in rat striatum

Chronic lithium administration prevents both haloperidol-induced dopaminergic behavioral supersensitivity and increased tritiated neuroleptic binding to dopamine (DA) receptors in rat corpus striatum. Since chronic haloperidol treatment also induces tolerance to the activating effects of the drug on striatal DA synthesis, the ability of lithium to block neurochemical tolerance development was investigated. Whereas lithium treatment significantly (P<0.01) attenuated haloperidol-induced behavioral supersensitivity to apomorphine (0.33 and 0.66 mg/kg s.c.), it did not prevent tolerance to the elevation of striatal 3,4-dihydroxyphenylacetic acid (DOPAC) levels 1 h after the last treatment or in response to challenge with a low dose (0.1 mg/kg) of haloperidol during withdrawal. These results demonstrate a dissociation between the development of behavioral supersensitivity and the reduction in DOPAC increase. An assessment of lithium's demonstrated effects on supersensitivity development at various DA receptor sites suggests that tolerance may be mediated by presynaptic DA receptors on terminals of nigrostriatal neurons.