Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with supersensitization of the dopamine D1 agonist induction of oral activity. The present study was conducted to determine whether induced oral responses to serotonin (5-HT) agonists would be similarly altered in this rat model. At 3 days after birth, rats received desipramine HCl (20 mg/kg, IP) 1 h before 6-OHDA HBr (100 μg in each lateral ventricle) or saline-ascorbic acid (0.1%) vehicle. At approximately 9 mo, rats were challenged with the mixed 5-HT1C and 5-HT2 receptor agonist, m-chlorophenylpiperazine diHCl (m-CPP 2HCl; 0.30-6.0 mg/kg, IP) and were then observed for 1 min every 10 min over a 60-min period. m-CPP induced oral activity in both the vehicle and 6-OHDA groups, with the responses of the 6-OHDA group being much greater. An m-CPP dose of 3.0 mg/kg produced a maximal response of 63.6 ± 3.2 oral movements in the 6-OHDA group. A bell-shaped response curve was obtained, with lower and higher doses of m-CPP producing less of an effect. Attenuation of the m-CPP-induced response by the 5-HT receptor antagonist, mianserin HCl (1.0 mg/kg, IP, 30 min before m-CPP), indicates that the m-CPP effect is receptor mediated. These findings demonstrate that neonatal 6-OHDA treatment produces ontogenic long-lived supersensitization of a 5-HT receptor system in rats.

Parkinson's disease is a progressive neurodegenerative movement disorder, affecting mainly the elderly. One of the most important hallmarks of Parkinson's disease is the loss of neuronal cell bodies containing neuromelanin in the substantia nigra zona compacta, and subsequently, loss of dopamine terminals in basal ganglia nuclei of the brain. The discovery by Hornykiewicz and co-workers that levodopa could successfully treat Parkinson's disease in humans was one of the most important events of medicine in the 20th century. Since loss of nigrostriatal dopaminergic function is the basic underlying pathophysiology of this disease, drugs that enhance dopaminergic function in the striatum, including the exogenous precursor levodopa, remain the most effective symptomatic agents in the treatment of Parkinson's disease. However, there are some areas of controversy about levodopa-evoked motor complications (dyskinesias, on-off phenomena) as well as neuroprotective or neurotoxic activity of this drug, etc. In this article the authors try to clarify the molecular mechanisms involved in levodopa action, such as volume transmission - a crucial process for successful levodopa therapy, evidence that serotoninergic neurons may accumulate levodopa and convert it into dopamine as well as some aspects of neuroprotective action of levoda.

Enhanced oral activity is induced in neonatal 6-hydroxydopamine- (6-OHDA-) lesioned rats by systemic administration of the dopamine (DA) D1 receptor agonist SKF 38393 and serotonin (5-HT) 5-HT2A,2C agonist m-chlorophenylpiperazine (m-CPP). The DA D1 receptor antagonist SCH 23390 effectively attenuates the effect of SKF 38393 but not m-CPP. The 5-HT2antagonist mianserin attenuates the effects of both m-CPP and SKF 38393, suggesting that DA agonist effects are mediated by 5-HT neurochemical systems. To test whether DA and 5-HT agonist effects and interactions might occur within the neostriatum, rats were implanted with permanent injection cannulae, with tips in the ventral striatum. One group of rats was lesioned at 3 days after birth with 6-OHDA HBr (100 μg salt form, in each lateral ventricle; desipramine HCl pretreatment, 20 mg/kg IP, base form, 1 h), while controls received the vehicle in place of 6-OHDA. Cannulae were implanted when rats weighed 200-250 g. During a 1-h observation session SKF 38393 (5 nmol per side) produced 74.3±19.2 oral movements in intact rats and 310.7±97.0 oral movements in 6-OHDA-lesioned rats. m-CPP (10 nmol per side) produced 72.6±15.1 and 274.5±65.0 oral movements in these respective groups. These responses were several-fold greater than the 25.3±7.3 and 41.8±9.5 oral movements in the same groups after saline (0.5 μl per side) (P<0.05). Mianserin (6 nmol per side) alone had no effect on oral activity but attenuated responses to both SKF 38393 and m-CPP in intact and 6-OHDA-lesioned rats. These findings demonstrate that enhanced oral activity responses are produced by intrastriatal SKF 38393 and m-CPP in neonatal 6-OHDA-lesioned rats. Also, when the 5-HT2 receptor antagonist mianserin was administered intrastriatally, induction of oral activity by the DA D1 agonist SKF 38393 was attenuated. These findings indicate that ventral striatum represents at least one brain focus at which DA and 5-HT systems interact to modulate oral activity in rats.

l-Prolyl-l-leucyl-glycinamide (MIF-1) is known to attenuate apomorphine-induced stereotypies in adult rats that are lesioned as neonates with 6-hydroxydopamine (6-OHDA). To test whether MIF-1 would affect dopamine (DA) agonist-induced and serotonin (5-HT) agonist-induced oral activity, both intact and neonatal 6-OHDA-treated rats were studied. Rats at 3 days from birth were injected with desipramine (20 mg/kg, IP), 1 h before 6-OHDA HBr (100 μg, salt form, in each lateral ventricle) or its vehicle, saline-ascorbic acid (0.1%). At approximately 6 months rats were treated with MIF-1 (0.1, 1.0, or 10.0 mg/kg, IP), 10 min before SKF 39393 HCl (1.0 mg/kg, IP) or m-chlorophenylpiperazine 2HCl (m-CPP 2HCl; 0.5 mg/kg, IP), DA D1 and 5-HT1C,2 receptor agonists, respectively. Although both agonists increased oral activity in control and neonatal 6-OHDA-treated rats, MIF-1 did not modify the response. In rats that received either of the three doses of MIF-1 for 21 consecutive days, there was still no observed effect of MIF-1 on the oral response of control and 6-OHDA-lesioned rats to SKF 38393 and m-CPP. These findings indicate that MIF-1 does not modify the oral activity response of supersensitized D1 and 5-HT1C receptors in adult rats that are lesioned neonatally with 6-OHDA.

Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D2 receptor blockers. Also, acute DA D1 agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D1 receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA)-induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D16-lesioned rats treated with haloperidol for one year, there is a 2-fold increase in numbers of VCMs (versus intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT2 receptor antagonists, but not DA D1 receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT2 receptor antagonists, more specifically 5-HT2C receptor antagonists, as a rational treatment approach for TD in humans.

No description available.

Tardive dyskinesia (TD), first appearing in humans after introduction of the phenothiazine class of antipsychotics in the 1950s, is now recognized as an abnormality resulting predominately by long-term block of dopamine (DA) D2 receptors (R). TD is thus reproduced in primates and rodents by chronic administration of D2-R antagonists. Through a series of studies predominately since the 1980s, it has been shown in rodent modeling of TD that when haloperidol or other D2-R antagonist is added to drinking water, rats develop spontaneous oral dyskinesias, vacuous chewing movements (VCMs), after ~3 months, and this TD is associated with an increase in the number of striatal D2-R. This TD persists for the duration of haloperidol administration and another ~2 months after haloperidol withdrawal. By neonatally lesioning dopaminergic nerves in brain in neonatal rats with 6-hydroxydopamine (6-OHDA), it has been found that TD develops sooner, at ~2 months, and also is accompanied by a much higher number of VCMs in these haloperidol-treated lesioned rats, and the TD persists lifelong after haloperidol withdrawal, but is not associated with an increased D2-R number in the haloperidol-withdrawn phase. TD apparently is related in part to supersensitization of both D1-R and serotoninergic 5-HT2-R, which is also a typical outcome of neonatal 6-OHDA (n6-OHDA) lesioning. Testing during the haloperidol-withdrawn phase in n6-OHDA rats displaying TD reveals that receptor agonists and antagonists of a host of neuronal phenotypic classes have virtually no effect on spontaneous VCM number, except for 5-HT2-R antagonists which acutely abate the incidence of VCMs in part. Extrapolating to human TD, it appears that (1)5-HT2-R supersensitization is the crucial alteration accounting for persistence of TD, (2) dopaminergic-perhaps age-related partial denervation-is a risk factor for the development of TD, and (3) 5-HT2-R antagonists have the therapeutic potential to alleviate TD, particularly if/when an antipsychotic D2-R blocker is withdrawn.

Dopamine receptor supersensitivity (DARSS) often is invoked as a mechanism possibly underlying disordered thought processes and agitation states in psychiatric disorders. This review is focused on identified means for producing DARSS and associating the role of other monoaminergic systems in modulating DARSS. Dopamine (DA) receptors, experimentally, are prone to become supersensitive and to thus elicit abnormal behaviors when coupled with DA or a receptor agonist. In intact (control) rats repeated DA D1 agonist treatments fail to sensitize D1 receptors, while repeated D 2 agonist treatments sensitize D2 receptors. D2 RSS is attenuated by a lesion with DSP-4 (N-(2-chlorethyl)-N-ethyl-2- bromobenzylamine) in early postnatal ontogeny, indicating that noradrenergic nerves have a permissive effect on D2 DARSS. However, if DSP-4 is co-administered with 5,7-dihydroxytryptamine to destroy serotonin (5-HT) nerves, then D2 RSS is restored. In rats treated early in postnatal ontogeny with the neurotoxin 6-hydroxydopamine to largely destroy DA innervation of striatum, both repeated D1 and D2 agonists sensitize D1 receptors. 5-HT nerves appear to have a permissive effect on D1 DARSS, as a 5-HT lesion reduces the otherwise enhanced effect of a D1 agonist. The series of findings demonstrate that DARSS is able to be produced by repeated agonist treatments, albeit under different circumstances. The involvement of other neuronal phenotypes as modulators of DARSS provides the potential for targeting a variety of sites in the aim to prevent or attenuate DARSS. This therapeutic potential broadens the realm of approaches toward treating psychiatric disorders.

Dopamine (DA) receptor supersensitivity refers to the phenomenon of an enhanced physiological, behavioral or biochemical response to a DA agonist. Literature related to ontogenetic aspects of this process was reviewed. Neonatal 6-hydroxydopamine (6-OHDA) destruction of rat brain DA neurons produces overt sensitization to D1 agonist-induced oral activity, overt sensitization of some D2 agonist-induced stereotyped behaviors and latent sensitization of D1 agonist-induced locomotor and some stereotyped behaviors. This last process is unmasked by repeated treatments with D1 (homologous "priming") or D2 (heterologous "priming") agonists. A serotonin (5-HT) neurotoxin (5,7-dihydroxytryptamine) and 5-HT2C receptor antagonist (mianserin) attenuate some enhanced behavioral effects of D1 agonists, indicating that 5-HT neurochemical systems influence D1 receptor sensitization. Unlike the relative absence of change in brain D1 receptor number, DA D2 receptor proliferation accompanies D2 sensitization in neonatal 6-OHDA-lesioned rats. Robust D2 receptor supersensitization can also be induced in intact rats by repeated treatments in ontogeny with the D2 agonist quinpirole. In these rats quinpirole treatments produce vertical jumping at 3-5 wk after birth and subsequent enhanced quinpirole-induced antinociception and yawning. The latter is thought to represent D3 receptor sensitization. Except for enhanced D1 agonist-induced expression of c-fos, there are no changes in the receptor or receptor-mediated processes which account for receptor sensitization. Adaptive mechanisms by multiple "in series" neurons with different neurotransmitters may account for the phenomenon known as receptor supersensitivity.

Tardive dyskinesia (TD), marked by abnormal involuntary movements and frequently expressed as perioral activity, represents an adverse outcome of prolonged antipsychotic therapy, occurring in approximately 5 % of patients per treatment year. Although neuronal mechanisms underlying TD are largely unknown, more recent experimental studies in animal models of TD are providing insight into the neuronal mechanisms associated with TD and implicating newer treatment approaches. It is now evident that a predominance in the ratio of dopamine (DA) D1:D2 receptor (R) activation accounts for induction of perioral movements in rodent models of TD, in nonhuman primate models of TD, and in humans with TD. Experimentally, TD is produced in animal models of TD, in a manner analogous to that by which TD is produced in humans - by continuous and prolonged administration of a DA D2R antagonist (i.e., an antipsychotic drug). More recently, in a rodent model of TD, it has been shown that a lesion of dopaminergic - mainly nigroneostriatal - neurons reduces the time latency for occurrence of TD, also increases the severity of perioral activity, and results in permanence of TD after complete removal of D2R antagonist treatment. The induction of perioral activity is related to DAR supersensitivity but unrelated to numbers of D2R and D2R in the neostriatum, a brain region associated with perioral activity. More apropos, serotoninergic systems are now recognized as having a greater role in effecting perioral activity, and it appears that 5-HT2C receptor antagonists are most effective in abating perioral activity in a rodent model of TD. These processes and mechanisms, topics addressed in this chapter, highlight a newer understanding of mechanisms underlying TD and provide insight into new approaches towards treatment of TD in humans.