Modulate Dopamine Neurotransmission Research Articles

Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood

The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.

Effects of food restriction on dopamine clearance and on behavioral effects of dopaminergic drugs in rats

Changes in nutritional status and in circulating insulin can affect dopamine (DA) neurotransmission. This study examined the effects of food restriction (10 g/day) on DA clearance and on behavioral effects of DA drugs such as amphetamine (locomotion, conditioned place preference [CPP]), the DA receptor agonist quinpirole (yawning), and the DA receptor antagonist raclopride (catalepsy). Because repeated treatment with amphetamine can restore DA clearance in hypoinsulinemic rats, the present study also examined the effects of amphetamine on DA clearance and on the behavioral effects of quinpirole and raclopride in food‐restricted rats. Amphetamine increased locomotion similarly in free‐feeding and in food‐restricted rats; however, amphetamine produced CPP in free‐feeding and not in food‐restricted rats. Food restriction reduced DA clearance, which was restored by repeated treatment with amphetamine or by free feeding. Food restriction reduced sensitivity to quinpirole and raclopride; normal sensitivity was restored by free feeding, and not by repeated treatment with amphetamine. These data support a role for insulin in modulating DA neurotransmission and demonstrate that the effects of drugs acting on DA systems vary markedly under different physiologic (feeding) conditions. Supported by DA17918 (CPF), DA14684 (AG), and DA018992 (LCD).

Insulin Replacement Restores the Behavioral Effects of Quinpirole and Raclopride in Streptozotocin-Treated Rats

Streptozotocin (STZ)-induced diabetes can modulate dopamine (DA) neurotransmission and thereby modify the behavioral effects of drugs acting on DA systems. Insulin replacement, and in some conditions repeated treatment with amphetamine, can partially restore sensitivity of STZ-treated rats to dopaminergic drugs. The present study sought to characterize the role of insulin and amphetamine in modulating the behavioral effects of drugs that selectively act on D2/D3 receptors. In control rats, quinpirole and quinelorane produced yawning, whereas raclopride and gamma-hydroxybutyric acid (GHB) produced catalepsy. Raclopride antagonized quinpirole- and quinelorane-induced yawning with similar potency. STZ treatment increased blood glucose concentration, decreased body weight, and markedly reduced sensitivity to quinpirole-induced yawning, quinelorane-induced yawning as well as to raclopride-induced catalepsy, while enhancing sensitivity to GHB-induced catalepsy. Repeated treatment with amphetamine partially restored sensitivity of STZ-treated rats to amphetamine-stimulated locomotion and also produced conditioned place preference, without affecting blood glucose and body weight changes. However, amphetamine treatment did not restore sensitivity to the behavioral effects of quinpirole, raclopride, or GHB, suggesting differential regulation of dopamine transporter activity and sensitivity of D2 receptors in hypoinsulinemic rats. Insulin replacement in STZ-treated rats normalized blood glucose and body weight changes and fully restored sensitivity to quinpirole-induced yawning, as well as to raclopride-induced catalepsy, while reducing sensitivity to GHB-induced catalepsy. Overall, these data indicate that changes in insulin status markedly affect sensitivity to the behavioral effects of dopaminergic drugs. The results underscore the importance of insulin in modulating DA neurotransmission; these effects might be especially relevant to understanding the co-morbidity of eating disorders and substance abuse.

Serotonergic modulation of dopamine neurotransmission: a mechanism for enhancing therapeutics in schizophrenia.

Although the principal mechanism by which all antipsychotic drugs act is the blockade of dopamine D-2 receptors, typical antipsychotics given in doses within the clinically effective range induce extrapyramidal symptoms (EPS). Serotonin Hydroxytryptamine, 5-HT can modulate the activity of dopaminergic neurons, while the activity of atypical antipsychotic agent towards serotonin receptors is involved in the ability of these agents to produce fewer EPS. In order to extend therapeutics in schizophrenia, it is important to examine the serotonergic modulation of neuroleptic activity. This review analyzes differences in neurochemical, behavioral and pharmacological profiles of typical and atypical antipsychotics and the role of serotonin receptors in the attenuation of EPS-induced by the typical neuroleptics. In addition to blocking dopamine receptors, the atypical antipsychotics also have affinities for serotonin receptors. Serotonergic modulation of motor activity appears primarily of inhibitory type. Stimulation of somatodendritic 5-HT-1A receptors decreases the availability of 5-HT at inhibitory 5-HT-2C receptors located on dopaminergic neurons to attenuate acute parkinsonian-like effects of typical antipsychotics. An increase in the effectiveness of pre and postsynaptic 5-HT-1A receptors following long-term administration of haloperidol raises the possibility that 5-HT agonists may also prove useful for the alleviation of late appearing tardive dyskinesias. Clinicians can now apply the knowledge of serotonergic modulation of neuroleptic action to the treatment of schizophrenic patients by using selected serotonergic anxiolytics and antidepressants as adjuvants in the treatment of schizophrenia.

Retinoid X Receptor and NUR77 modulate amphetamine‐induced locomotor activity

Amphetamine (AMPH) is a drug of abuse that modulates dopamine neurotransmission in the central nervous system. We recently showed that Nur77 expression is modulated by AMPH administration and that Retinoid X Receptor (RXR) ligands can modulate the effect of antipsychotic drugs. In the present study, we analyse the effect of HX531, a RXR antagonist, in wild type and Nur77 knockout mice in order to clarify the role of these transcription factors in AMPH-induced behaviors. We use the classic behavioral sensitization paradigm, which consists in a 5-day AMPH treatment followed by a 5-day washout period. Sensitization is evidenced with a subsequent AMPH challenge on day 11. Ambulatory movements are assessed in a flex field apparatus for a period of 2 h. AMPH induces a progressive increase (sensitization) in the locomotor activity of wild type and Nur77-deficient mice. The RXR antagonist reduces AMPH-induced locomotion, whereas it remains inactive in Nur77-deficient mice. The RXR antagonist also reduces basal locomotor activity of the mice and HX531 pre-treatment partially suppresses acute AMPH effect on ambulatory movements, again only in wild type mice. However, the locomotor sensitization observed following repeated exposure to AMPH is not modified by HX531. These results indicate that both RXR and Nur77 nuclear receptors (possibly as heterodimerization partners) are involved in AMPH-induced locomotor activity, but are not associated with the development of behavioral sensitization. Support contributed by the Canadian Institutes for Health Research (CIHR).

Ascorbate reduces morphine-induced extracellular DOPAC level in the nucleus accumbens: A microdialysis study in rats

Most drugs of abuse increase dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the shell of the nucleus accumbens. The effects of ascorbate, which is known to modulate dopamine neurotransmission, on the extracellular level of DOPAC in the nucleus accumbens of naive rats and of rats treated acutely with morphine were studied by using in vivo microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-ECD). Acute morphine (20 mg/kg ip) treatment increased the level of DOPAC in the nucleus accumbens to approximately 170% of basal level. Acute treatment with ascorbate (500 mg/kg ip) alone did not alter nucleus accumbens' DOPAC level, but pretreatment with ascorbate (500 mg/kg ip) 30 min before morphine administration attenuated the effects of acute morphine on the level of DOPAC. These results suggest that ascorbate modulates the mesolimbic dopaminergic pathway.

Hypocretin/Orexin Selectively Increases Dopamine Efflux within the Prefrontal Cortex: Involvement of the Ventral Tegmental Area

Hypocretins (HCRTs) modulate a variety of behavioral and physiological processes, in part via interactions with multiple ascending modulatory systems. Further, HCRT efferents from the lateral hypothalamus innervate midbrain dopamine (DA) nuclei, and DA cell bodies express HCRT receptors. Combined, these observations suggest that HCRT may influence behavioral state and/or state-dependent processes via modulation of DA neurotransmission. The current studies used in vivo microdialysis in the unanesthetized rat to first characterize the effect of intracerebroventricular infusion of HCRT-1 (0.07, 0.7 nmol) on extracellular levels of DA within the prefrontal cortex (PFC) and nucleus accumbens (Acc). Electroencephalographic/electromyographic measures of sleep-wake state were collected along with select behavioral measures (eg locomotor activity, grooming). HCRT-1 dose-dependently increased PFC dialysate DA levels, and these increases were closely correlated with increases in time spent awake. In contrast, Acc DA levels were unaffected. Additional studies examined whether HCRT-1 acts directly within the ventral tegmental area (VTA) to selectively increase PFC DA efflux and modulate behavioral state. Unilateral infusion of HCRT-1 (0.1, 1.0 nmol) within the VTA increased PFC, but not Acc, DA levels. Importantly, intra-VTA infusion of HCRT-1 increased the time spent awake and grooming. Moreover, HCRT-induced increases in both time spent awake and time spent grooming were significantly correlated with post-infusion PFC DA levels. The current observations predict a prominent modulatory influence of HCRT on PFC-dependent cognitive and affective processes that results, in part, from actions within the VTA. Additionally, these observations suggest that the activation of VTA DA neurons contributes to the behavioral state-modulatory actions of HCRT.

Sensitivity to psychostimulants in mice bred for high and low stimulation to methamphetamine

Methamphetamine (MA) and cocaine induce behavioral effects primarily through modulation of dopamine neurotransmission. However, the genetic regulation of sensitivity to these two drugs may be similar or disparate. Using selective breeding, lines of mice were produced with extreme sensitivity (high MA activation; HMACT) and insensitivity (low MA activation; LMACT) to the locomotor stimulant effects of acute MA treatment. Studies were performed to determine whether there is pleiotropic genetic influence on sensitivity to the locomotor stimulant effect of MA and to other MA- and cocaine-related behaviors. The HMACT line exhibited more locomotor stimulation in response to several doses of MA and cocaine, compared to the LMACT line. Both lines exhibited locomotor sensitization to 2 mg/kg of MA and 10 mg/kg of cocaine; the magnitude of sensitization was similar in the two lines. However, the lines differed in the magnitude of sensitization to a 1 mg/kg dose of MA, a dose that did not produce a ceiling effect that may confound interpretation of studies using higher doses. The LMACT line consumed more MA and cocaine in a two-bottle choice drinking paradigm; the lines consumed similar amounts of saccharin and quinine, although the HMACT line exhibited slightly elevated preference for a low concentration of saccharin. These results suggest that some genes that influence sensitivity to the acute locomotor stimulant effect of MA have a pleiotropic influence on the magnitude of behavioral sensitization to MA and sensitivity to the stimulant effects of cocaine. Further, extreme sensitivity to MA may protect against MA and cocaine self-administration.

Selective tolerance to the hypothermic and anticataleptic effects of a neurotensin analog that crosses the blood–brain barrier

NT69L, a neurotensin analog that crosses the blood–brain barrier, reduces body temperature, reverses apomorphine-induced climbing, haloperidol-induced catalepsy, and d-amphetamine- and cocaine-induced locomotor activity in rats. In this study we tested the development of tolerance to these effects of NT69L in rats. The blockade of apomorphine-induced climbing behavior and d-amphetamine- and cocaine-induced hyperactivity seen after a single acute injection did not show significant change with repeated daily injections of NT69L. Thus, for example, NT69L after five daily injections at a fixed dosage was as effective at reversing cocaine-induced hyperactivity as after the first injection. On the other hand, repeated daily injections of NT69L resulted in a diminished hypothermic response and a diminished anticataleptic effect against haloperidol. The effect of NT69L on blood glucose, cortisol, and thyroxine (T 4) were all back to control levels after five daily injections. Thus, tolerance developed to NT69L after the first injection, when it was tested for causing hypothermia, blockade of haloperidol-induced catalepsy, and change in blood glucose, cortisol and T 4 levels. Since tolerance did not develop to the effects of drugs acting as direct (apomorphine) or indirect ( d-amphetamine and cocaine) agonists at dopamine receptors over the course of 5 days, these findings suggest a selective role of neurotensin in the modulation of dopamine neurotransmission. Furthermore, due to the lack of development of tolerance, NT69L or similar analogs might be useful in modulating certain behavioral effects of psychostimulants or have potential use as an antipsychotic drug in humans.

Phosphatidylinositol 3-Kinase, Protein Kinase C, and MEK1/2 Kinase Regulation of Dopamine Transporters (DAT) Require N-terminal DAT Phosphoacceptor Sites

The dopamine transporter (DAT) modulates dopamine neurotransmission and is a primary target for psychostimulant influences on locomotion and reward. Selective DAT expression by dopaminergic neurons has led to use of cocaine analog DAT radioligands to assess rates of progression of dopamine neuronal degeneration in Parkinson's disease. We have documented that DAT is a phosphoprotein that is regulated by phosphorylation through pathways that include protein kinase C cascades. We now extend this work using drugs selective for phosphatidylinositol 3-kinase (PI3K), protein kinase C, MEK1/2, p38 kinase, and Ca2+/calmodulin kinase II. We compare the drug effects on wild type DAT to the effects on 20 DAT mutants and a DAT deletion. PI3K and MEK1/2 modulators exert strong effects on DAT expression patterns and dopamine uptake Vmax. PKC principally modulates Vmax. Neither p38 nor Ca2+/calmodulin kinase II agents exert significant influences on wild type DAT. Several mutants and a DAT with an N-terminal deletion display alterations that interact with the effects of kinase modulators, especially S7A for PKC effects; T62A, S581A, and T612A for PI3K effects; and S12A and T595A mutants for MEK1/2 effects. 32P-Labeling studies confirm several of these effects of kinase pathway modulators on DAT phosphorylation. DAT expression and activities can be regulated by kinase cascades that require phosphoacceptor sites most concentrated in its N terminus. These results have a number of implications for DAT regulation and mandate caution in using DAT radioligand binding to infer changes in dopaminergic neuronal integrity after treatments that alter activities of these kinase pathways.

Is cannabinoid transmission involved in rewarding properties of drugs of abuse?

Is cannabinoid transmission involved in rewarding properties of drugs of abuse?

Cocaine treatment increases extracellular cholecystokinin (CCK) in the nucleus accumbens shell of awake, freely moving rats, an effect that is enhanced in rats that are behaviorally sensitized to cocaine

Cholecystokinin (CCK) is co-localized with dopamine, is known to modulate dopamine neurotransmission and is involved in behavioral sensitization to psychostimulants. To better understand its role, CCK was measured by microdialysis in the nucleus accumbens (NAC) shell in response to cocaine in drug-naive rats and in rats that are behaviorally sensitized to cocaine. Basal extracellular levels of CCK in drug-naive rats were 0.17 pg/20 min fraction, while in cocaine-sensitized rats, they were significantly higher (0.56 pg). Treating drug-naive rats with cocaine caused a significant increase in CCK to 0.58 pg. Cocaine treatment of cocaine-sensitized rats increased CCK to 0.98. When analyzed as a function of time after cocaine treatment, these increases were sustained and were significantly different from CCK levels of saline-treated rats. In cocaine-sensitized rats, CCK levels following cocaine treatment were also significantly higher than levels in drug-naive animals receiving a single injection of cocaine. These results provide evidence for an activation of the mesolimbic and/or cerebral cortical CCK system in response to repeated cocaine administration. These results provide a neurochemical basis for an important role of CCK (via modulation of dopamine neurotransmission) in expression of cocaine sensitization.

Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease mice

One of the earliest changes, at the molecular level, that occurs in human Huntington’s disease patients is reduction in cannabinoid receptor ligand binding in the substantia nigra pars reticulata compared to neurologically normal controls. The loss of cannabinoid receptor binding is thought to occur early in or prior to the development of Huntington’s disease neuropathology. We wish to determine whether cannabinoid receptor messenger RNA levels were altered in a mouse model of Huntington’s disease. Transgenic mice hemizygous for the promoter sequence and exon 1 of the human Huntington’s disease gene exhibit a progressive neurological phenotype with many of the features of Huntington’s disease. This neurological phenotype develops in the absence of neural degeneration making these mice a model system to dissociate changes related to cell dysfunction from changes related to cell loss. We examine the steady-state levels and cellular distribution of the brain-specific cannabinoid receptor messenger RNA by northern blot and in situ hybridization. The cannabinoid receptor messenger RNA was expressed throughout the striatum, cortex and hippocampus of wild-type mice. At four and five weeks of age, there was no difference in the distribution of the cannabinoid receptor messenger RNA between the wild-type and transgenic Huntington’s disease mice. At six, seven, eight and 10 weeks of age, however, the Huntington’s disease mice exhibit reduced levels of cannabinoid receptor messenger RNA in the lateral striatum compared to age-matched controls. The Huntington’s disease mice also showed a loss of cannabinoid receptor messenger RNA within a subset of neurons in the cortex and hippocampus. We did not observe any difference in the expression of cannabinoid receptor between the wild-type and Huntington’s disease mice throughout Ammon’s horn of the hippocampus or in the medial striatum. The decrease in cannabinoid receptor messenger RNA levels preceded the development of the Huntington’s disease phenotype and neuronal degeneration and, therefore, these transgenic mice model early cellular changes observed in human patients. Our results demonstrate that the single copy cannabinoid receptor gene is subjected to cell-specific and time-dependent regulation of the steady-state level of its gene product as a result of the expression of the Huntington’s disease gene. As the endogenous cannabinoid receptor agonist, anandimide, has been shown to modulate dopamine neurotransmission within the basal ganglia, the loss of cannabinoid receptors may contribute to the development of motor symptoms or cognitive decline or both seen in Huntington’s disease patients.

Amphetamine microinfusion in the dorso-ventral axis of the prefrontal cortex differentially modulates dopamine neurotransmission in the shell-core subterritories of the nucleus accumbens.

The two main subdivisions of the nucleus accumbens (NAC), the dorsolateral core and the ventromedial shell, can be distinguished by a distinct connectivity pattern originating mainly from the prefrontal cortex (PFC).1,2 More specifically, the core of the NAC receives major projections from the anterior cingulate and dorsocaudal prelimbic cortices, which are referred to as the dorsal PFC.3,4 In contrast to the core, the shell of the NAC receives main afferents from the ventral prelimbic and rostral infralimbic cortices, which are termed the ventral PFC.3,4 The present study sought to evaluate the contributions of the ventral prelimbic/infralimbic cortices and shell subterritory of the NAC as well as the dorsal prelimbic/anterior cingulate cortices and core subregion of the NAC to the microinfusion of amphetamine (AMPHE) on dialysate DA levels using a dual-probe microdialysis design. Male Wistar rats were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and mounted on a stereotaxic apparatus. The skull was exposed and two holes were drilled for unilateral placement of microdialysis probes into (1) the core of the NAC and the dorsal PFC, and (2) the shell of the NAC and the ventral PFC. One-hourly dose of chloral hydrate (100 mg/kg, i.p.) was administered to maintain a constant level of anesthesia throughout the experiment. Following the determination of basal DA levels, 5 increasing concentrations of AMPHE (1, 10, 100, 500, 1000 μM) were substituted for the dialysis perfusate in the PFC for 60 min each. Both microdialysis procedures and chromatographic analyses of brain microdialysates were the same as described previously.5 Basal DA levels were significantly higher in the ventral PFC compared with the dorsal PFC and higher concentrations of DA were also observed in the core of the NAC compared with its shell counterpart (FIG. 1A). Reverse microdialysis of AMPHE in the ventral PFC produced a significant dose-dependent decrease in dialysate DA levels. In contrast, no significant alterations in DA levels were observed following AMPHE microinfusion in the dorsal PFC (FIG. 2A). Furthermore, the

Comparative Antipsychotic Profiles of Neurotensin and a Related Systemically Active Peptide Agonist

Sarhan, S., J. M. Hitchcock, C. A. Grauffel and J. G. Wettstein. Comparative antipsychotic profiles of neurotensin and a related systemically active peptide agonist. Peptides 18(8) 1223–1227, 1997.—Several lines of evidence have shown that neurotensin can modulate dopamine neurotransmission. It has been suggested that neurotensin has potential antipsychotic activity because it reduces dopaminergic activity preferentially in the nucleus accumbens. In the present study, the effects of neurotensin and NT1 (N α Me-Arg-Lys-Pro-Trp-TIe-Leu or Eisai hexapeptide), a metabolically stable and systemically active neurotensin agonist, were examined in several models of antipsychotic activity and side effect liability in mice; analgesic and hypothermic effects of both compounds also were determined. Up to high doses, neurotensin (5.0 and 10.0 μg, ICV) and NT1 (10.0 and 20.0 mg/kg, IP) did not produce catalepsy. A much lower dose of neurotensin (0.03 μg, ICV) significantly reduced amphetamine- and phencyclidine-stimulated locomotor activity; NT1 also diminished amphetamine- and phencyclidine-stimulated locomotion with ED 50 values of 0.3 and 0.4 mg/kg, IP, respectively. Neurotensin (0.01–0.3 μg, ICV) and NT1 (0.1–1.0 mg/kg, SC) also produced dose-dependent analgesia in the paw pressure test and decreased body temperature; these effects were insensitive to pretreatment with naloxone (10.0 mg/kg, IP). Together, the results support the hypothesis that neurotensin agonists have antipsychotic and analgesic activity. Moreover, the data suggest that such compounds may not produce extrapyramidal side effects.

Ascorbate potentiates amphetamine-induced conditioned place preference and forebrain dopamine release in rats.

In order to evaluate the effects of ascorbate, which is known to modulate dopamine neurotransmission, on the reinforcing effects of amphetamine, we coadministered ascorbate and amphetamine during the acquisition of conditioned place preference (CPP) in rats. Our results indicate that 100 mg/kg ascorbate potentiates the CPP induced by 0.5 mg/kg, but not 1.0 mg/kg, amphetamine. A higher dose of ascorbate (500 mg/kg) did not influence the CPP induced by either dose of amphetamine. In vitro release assays revealed that, whereas ascorbate alone (0.01-1.0 mM) did not influence striatal dopamine levels, this vitamin potentiated amphetamine-induced dopamine release in both the nucleus accumbens and neostriatum. Collectively, these results raise the possibility that ascorbate potentiates amphetamine-induced CPP by increasing the ability of this psychostimulant to release dopamine.

Chronic treatment of rats with the specific σ ligand D-pentazocine fails to modulate dopamine D 2 and σ binding in brain

Drugs that bind at the σ site have been proposed to have psychotomimetic and/or antipsychotic activity that is independent from that mediated by the phencyclidine (PCP) receptor. Some evidence suggests that σ ligands may produce their effects by modulation of dopamine neurotransmission. The present study examined potential interactions between the σ and dopamine system following chronic treatment with d-pentazocine, a specific σ ligand that has negligible affinity for either PCP or dopamine receptors. Rats treated for one month with either saline or 10 mg/kg per day d-pentazocine revealed no significant differences in either the K D or B max of [ 3H]haloperidol-labeled σ or [ 3H]YM-09151-2-labeled dopamine D 2 receptors across multiple brain regions. These results are discussed in relation to the pharmacology of putative σ-receptor subtypes.

The Mechanism of Action of Novel Antipsychotic Drugs

It is no longer tenable to attribute all the antipsychotic action of antipsychotic drugs to dopamine (DA) D2 receptor blockade and subsequent development of depolarization inactivation of the mesolimbic or mesocortical DA neurons. The chief evidence for this position is that clozapine (CLOZ) does not differ from typical antipsychotic drugs in these regards but is more effective than typical neuroleptic drugs. The mechanism of action of atypical antipsychotic drugs related to CLOZ may involve reduction of dopaminergic activity in the mesolimbic system by a variety of mechanisms, including D1 and D2 receptor blockade. Relatively higher affinity for the serotonin (5HT)2 receptor than for the D2 receptor may also be important to the action of CLOZ-like compounds. Enhanced DA release in the mesocortical system may be relevant to the effectiveness of these agents in treating negative symptoms. Several other classes of new agents alter the dopaminergic system by means of alternative mechanisms. Partial DA agonists may modulate DA neurotransmission more adequately than pure antagonists by producing a mix of direct agonist and antagonistic effects. DA autoreceptor agonists and 5HT3 antagonists appear to act by diminishing the release of DA from some, but not all, DA neurons. Substituted benzamides are "pure" D2 antagonists with some in vivo selectivity for limbic D2 over striatal D2 receptors. Highly selective D1 antagonists have been proposed to produce equivalent antipsychotic activity and fewer extrapyramidal symptoms than D2 antagonists. Antagonists of the recently identified D3 receptors are being sought. Excessive stimulation of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, leading to neurotoxicity or diminished activation of this receptor, is the target of novel approaches to treating schizophrenia. Phencyclidine (PCP) antagonists that would activate the NMDA receptor and sigma receptor antagonists are of interest as antipsychotic agents. Therapeutic strategies for treating schizophrenia, schizophrenia-related disorders, and other psychoses will likely be genuinely diverse in the next decade.

Autoradiographic evidence of [ 3H]neurotensin binding changes in discrete regions of brain in the rat model of persistent spasmodic dyskinesia induced by iminodipropionitrile

Chronic injection of iminodipropionitrile (IDPN) to rats causes a persistent set of abnormalities which includes hyperlocomotion, hyperexcitability, and dyskinetic movements of the neck. These behavioral changes are very similar to those observed after the acute administration of the dopamine (DA) agonist, amphetamine, in rodents. Because of the anatomical and functional evidence that neurotensin (NT) can modulate DA neurotransmission, the present receptor autoradiographic study investigated the binding of [ 3H]NT in the brains of IDPN-treated rats. There were significant decreases in binding in the frontal and cingulate cortices, the rhinal sulcus, the dorsolateral aspect of the caudate-putamen, and in the ventral tegmental area. These results provide the first evidence for the possible participation of the NT system in the manifestations of the IDPN-induced sydrome.

Neurotensin modulates dopamine neurotransmission at several levels along brain dopaminergic pathways

Neurotensin is a tridecapeptide that was isolated 15 years ago from bovine hypothalamus and, since then, has been shown to fulfill the major criteria that define a neurotransmitter/neuromodulator. There is considerable evidence that neurotensin interacts with mesencephalic dopamine systems. Anatomical and functional data indicate that neurotensin modulates dopamine neurotransmission at all levels along nigrostriatal and mesolimbic dopamine pathways. The peptide appears to functionally antagonize the effects that the amine exerts via both presynaptic (auto) and postsynaptic dopamine receptors. This confers a neuroleptic-like pharmacological profile to neurotensin. In addition, extensive neurotensin/dopamine colocalization occurs in a subpopulation of mesencephalic dopamine neurons that project to the prefrontal cortex. Recently, the neurotensin precursor has been shown to contain another neurotensin-like peptide, neuromedin N, that binds with high affinity to brain neurotensin receptors and displays some neuroleptic-like effects. Therefore, neuromedin N may be considered as a potential comodulator (with neurotensin) of dopamine functions. Given the implications of dopamine systems in certain neuropathological and psychotic disorders such as Parkinson's disease and schizophrenia it is likely, as already suggested by some experimental evidence, that neurotensin plays an important role in the etiology and pathogenesis of these diseases.